Chapter 16. Genetics
BS. Nguyễn Hồng Anh
Genetics is the study o genes, heredity, and the variation o
inherited characteristics. Medical genetics addresses the etiology and pathogenesis o human diseases that are at least
partially genetic in origin, as well as their prediction and prevention. Whereas a gene is a specic sequence o deoxyribonucleic acid (DNA) on a single chromosome that codes or
a particular protein, a genome is the entirety o all genes that
make up an organism. Genomics is the study o how genes
unction and interact with one other. Chromosomal, mendelian, and nonmendelian genetic conditions are reviewed in
this chapter. Prenatal and preimplantation genetic testing and
newborn genetic screening are discussed in Chapters 17 and
32, respectively.
Genetic disease is common. wo to 3 percent o newborns
have a recognized structural abnormality, another 3 percent are
diagnosed with an abnormality by age 5 years, and yet another
8 to 10 percent are ound to have a unctional or developmental abnormality beore reaching adulthood.
GENOMICS IN OBSTETRICS
Te Human Genome Project was an international research
program that sequenced the 3 billion base pairs and more
than 20,000 genes that make up the human genome. It paved
the way or research into gene organization and unction in
an eort to understand the molecular basis o disease. More
than 99 percent o our DNA is identical. Te coding regions o
DNA—exons—constitute only 1.5 percent o the genome. An
exome is the entirety o all the exons that an organism contains.
Introns are DNA sequences involved in coding regulation and
make up 24 percent o the genome. Intergenic DNA composes
the remainder.
Our genetic code varies once every 200 to 500 base pairs,
usually as a single-nucleotide polymorphism (SNP). Tus,
whole genome sequencing and whole exome sequencing,
described later (p. 327), hold tremendous potential to urther
elucidate genetic variants in disease.
oward this goal, genetic and genomic databases are maintained by the National Center or Biotechnology Inormation
(2021). Tese are reely accessible and can be indispensable
to providers who oer counseling and testing or genetic
conditions. Te GeneReviews database has in-depth clinical
inormation or more than 800 genetic conditions, including diagnostic criteria and management considerations. Te
Genetic Testing Registry (GTR) database contains inormation
or nearly 80,000 genetic tests and instructions or specimen
collection and transport to individual laboratories throughout
the world (National Center or Biotechnology Inormation,
2021). Te National Library o Medicine (2021) has also
established a genetic inormation database, the MedlinePlus
Genetics, which is intended or the lay population. It provides
explanations o more than 1300 genetic conditions, a glossary
o genetic concepts, and links to more comprehensive medical
resources.
CHROMOSOMAL ABNORMALITIES
Chromosomal abnormalities gure prominently in genetic disease. Tey account or >50 percent o rst-trimester miscarriages, approximately 20 percent o second-trimester losses, and
6 to 8 percent o stillbirths and early-childhood deaths (Reddy,
2012; Stevenson, 2004; Wou, 2016). Based on data rom
population-based registries, chromosomal abnormalities are
identied in 0.4 percent o recognized pregnancies (Wellesley,
2012). Most o these are aneuploidies. risomy 21 accounts or
>50 percent, trisomy 18 or nearly 15 percent, and trisomy 13
or 5 percent o cases (Fig. 16-1). I no karyotypic abnormality is identied in a etus with a structural anomaly, additional
testing with chromosomal microarray analysis is anticipated to
detect a chromosomal deletion or duplication—a copy number
variant—in approximately 6.5 percent o cases (American College o Obstetricians and Gynecologists, 2020c).
■ Standard Nomenclature
Chromosomal abnormalities are described using the International System or Human Cytogenomic Nomenclature
(McGowan-Jordan, 2020). Abnormalities all into two broad
categories: abnormal chromosome number, such as trisomy, and
abnormal chromosome structure, such as a DNA segment deletion or duplication. Each chromosome has a short arm, termed
the “p” or petit arm, and a long arm, known as the “q” arm,
selected because it is the next letter in the alphabet. Te two
arms are separated by the centromere.
When reporting a karyotype, the total number o chromosomes is listed rst, corresponding to the number o centromeres. Tis is ollowed by the sex chromosomes, XX or XY, and
then by a description o any structural variation. Specic chromosomal abnormalities are indicated by standard abbreviations,
such as del (deletion), inv (inversion), and t (translocation). Te
aected region or bands o the arms are then reported, so that
the reader will know the exact location. Examples are shown
in Table 16-1.
Nomenclature is similar or uorescence in situ hybridization (FISH), a technique used to rapidly identiy a specic
chromosome abnormality (p. 325). Te abbreviation ish applies
when in situ hybridization is perormed on metaphase cells and
nuc ish when perormed on interphase nuclei. I the result is
normal, ish is ollowed by the probe's specic chromosomal
region, such as 22q11.2, and then the name o the probe and
the number o signals visualized—or example, HIRAx2. I a
deletion is identied, del is included beore the chromosomal
region, and the name o the probe is ollowed by a minus sign
(HIRA–), as shown in able 16-1. Te 22q11.2 deletion syndrome is discussed later (p. 315).
For chromosomal microarray analysis (CMA), the designation begins with the abbreviation arr (p. 348). Tis is ollowed
by the version o the genome build to which the nucleotide
designations are aligned, such as GRCh38 or Genome Reerence Consortium human build 38. Next, the number o the
chromosome containing the abnormality is listed, ollowed by
the p or q arm, and then the specic bands in question. CMA
reports also include the aected base pair coordinates and thus
convey the exact size and location or every abnormality identi-
ed (see able 16-1). Te inormation is reported in the same
way whether the alteration is pathogenic or is o uncertain clinical signicance.
■ Abnormalities of Chromosome Number
Te most easily recognized chromosomal abnormalities are
numerical. Aneuploidy is the inheritance o either an extra
chromosome—resulting in trisomy, or loss o a chromosome—
monosomy. Tis diers rom polyploidy, which is an abnormal
number o whole haploid chromosome sets. For example, triploidy has 69 chromosomes. Te estimated incidence o various
numerical chromosomal abnormalities is shown in Figure 16-1
(Wellesley, 2012).
Autosomal Trisomies
risomy usually results rom nondisjunction, which is the
ailure o normal chromosomal pairing and separation during
meiosis. Nondisjunction may occur i the chromosomes: (1)
ail to pair up, (2) pair up properly but separate prematurely, or
(3) ail to separate. Although each chromosome pair is equally
likely to have a segregation error, trisomies other than 21, 18,
or 13 rarely result in term pregnancies. Each o these autosomal
54%
17%
5%
8%
5%
13%
Trisomy 21 (23:10,000)
Other (7:10,000)
47,XXX; 47,XXY; 47,XYY
(2:10,000)
45,X (3:10,000)
Trisomy 13 (2:10,000)
Trisomy 18 (6:10,000)
FIGURE 16-1 Prevalence and relative proportion of selected chromosomal abnormalities from EUROCAT (European Surveillance of
Congenital Anomalies) population-based registries that included
>10,000 aneuploid live births, fetal deaths, and pregnancy terminations, 2000–2006.310 The Fetal Patient
Section 6
TABLE 16-1. Examples of Karyotype Designations Using the 2020 International System for Human Cytogenomic
Nomenclature
Karyotype Description
46,XX Normal female chromosome constitution
47,XY,+21 Male with trisomy 21
47,XX,+21/46,XX Female who is a mosaic of trisomy 21 cells and cells with normal constitution
46,XY,del(4)(p14) Male with terminal deletion (del) of the short arm of chromosome 4 at band p14
46,XX,dup(5)(p14p15.3) Female with duplication (dup) of the short arm of chromosome 5 from band p14 to
band p15.3
45,XY,der(13;14)(q10;q10) Male with balanced robertsonian translocation (der) of the long arms of chromosomes
13 and 14—the karyotype now has one normal 13, one normal 14, and the
translocation chromosome, reducing the normal 46 chromosome complement to 45
46,XX,t(11;22)(q23;q11.2) Female with a balanced reciprocal translocation (t) between chromosomes 11 and 22,
with breakpoints at 11q23 and 22q11.2
46,XY,inv(3)(p21q13) Male with inversion (inv) of chromosome 3 that extends from p21 to q13—a pericentric
inversion because it includes the centromere
46,X,r(X)(p22.1q27) Female with one normal X and one ring (r) X chromosome, with the regions distal to
p22.1 and q27 deleted from the ring
46,X,i(X)(q10)
ish 22q11.2(HIRAx2)
ish del(22)(q11.2q11.2) (HIRA-)
arr[GRCh38] 18p11.32q23
(102328_79093443)x3
arr[GRCh38] 4q32.2q35.1
(163146681_183022312)x1
arr[GRCh38] 15q11.2q26
(23123715_101888908)x2 hmz
Female with one normal X chromosome and an isochromosome (i) of the long arm of
the other X
FISH of metaphase cells using a probe for the HIRA locus of the 22q11.2 region, with 2
signals identified (no evidence of microdeletion)
FISH of metaphase cells using a probe for the HIRA locus of the 22q11.2 region, with
only one signal identified, consistent with the microdeletion
Microarray analysis (arr), genome build GRCh38, showing a single copy gain on
chromosome 18 from band p11.32 to band q23 (essentially the entire chromosome),
consistent with trisomy 18
Microarray analysis (arr), genome build GRCh38, showing a copy loss on the long arm of
chromosome 4 at bands q32.2 through q35.1 (19.9 Mb)
SNP microarray analysis (arr), genome build GRCh 38, showing homozygosity for the
entire long arm of chromosome 15
FISH = fluorescence in situ hybridization; GRCh38 = Genome Reference Consortium human build 38; HIRA = histone cell
cycle regulator; SNP = single nucleotide polymorphism.
Used with permission from Dr. Kathleen S. Wilson.
trisomies has a spectrum o phenotypic severity. Some etuses
come to attention earlier in a pregnancy due to multiple major
organ abnormalities or hydrops etalis (p. 328). Others have
more subtle ndings or are detected only through prenatal
screening tests (Chap. 17, p. 337). Survival data are based on
cases with better prognosis, and this actors into counseling.
Te likelihood that a pregnancy will be complicated by an
autosomal trisomy rises steeply with maternal age and particularly ater age 35 (Fig. 16-2) (Mai, 2013). From birth until
ovulation, oocytes are suspended in midprophase o meiosis I. I
nondisjunction occurs ater completion o meiosis, one gamete
will have two copies o the aected chromosome, which leads
to trisomy i ertilized. Te other gamete, receiving no copy o
the aected chromosome, is nullisomic and will be monosomic
i ertilized. It is estimated that 10 to 20 percent o oocytes
are aneuploid secondary to meiotic errors compared with 3
to 4 percent o sperm. Ater a pregnancy with an autosomal
trisomy, the risk or any autosomal trisomy in a uture pregnancy approximates 1 percent until the woman's age-related
risk exceeds this. Screening and prenatal diagnosis o autosomal
0
<20
Prevalence per 10,000 live births
Maternal age at delivery (years)
20–24 25–29 30–34 35–39 40 or older
20
60
40
80
120
100
140
Trisomy 21
Trisomy 18
Trisomy 13
FIGURE 16-2 Prevalence of autosomal trisomies according to
maternal age found in population-based birth defect surveillance
programs in the United States, 2006–2010.
trisomies are discussed in Chapter 17 (p. 333). Parental chromosomal studies are not indicated unless the abnormality was
caused by an unbalanced translocation or other structural
re arrangement (p. 315).Genetics 311
CHAPTER 16
Trisomy 21—Down Syndrome. In 1866, J. L. H. Down
described a group o intellectually disabled children with distinctive physical eatures. Nearly 100 years later, Lejeune (1959)
demonstrated that Down syndrome stems rom an autosomal
trisomy (Fig. 16-3). risomy 21 causes 95 percent o Down
syndrome cases. Te nondisjunction event occurs during meiosis I in approximately 75 percent o cases and in meiosis II in
the remainder. Because chromosome 21 is acrocentric, a robertsonian translocation (p. 315) may occur, and this accounts
or 3 to 4 percent o Down syndrome births. Te remaining 1
to 2 percent are caused by isochromosome 21 or mosaicism or
chromosome 21 (p. 317).
Down syndrome is the most common nonlethal trisomy.
It is identied in approximately 1 in 450 pregnancies (Loane,
2013). In the United States, etal losses and pregnancy terminations yield an estimated prevalence o 1 case per 740 live births
(Mai, 2013; Parker, 2010). Te etal death rate beyond 20
weeks’ gestation approximates 5 percent. Coinciding with the
rise in overall number o pregnancies in women aged 35 years
and older, the proportion o pregnancies with Down syndrome
has increased approximately 33 percent during the past our
decades (Loane, 2013; Parker, 2010; Shin, 2009). Most Down
syndrome births at Parkland Hospital now occur in women in
this age group (Hussamy, 2019).
I major anomalies and minor aneuploidy markers are considered, 50 to 75 percent o pregnancies aected by Down syndrome are ound to have a sonographic abnormality (Chap. 17,
p. 340) (American College o Obstetricians and Gynecologists, 2020d; Hussamy, 2019). A major structural malormation is detected in the second trimester in approximately one
third o cases. Te most prevalent anomalies in aected children
are cardiac and gastrointestinal. Cardiac abnormalities occur
in approximately 50 percent, particularly endocardial cushion
deects and ventricular septal deects (Figs. 15-39A and 15-39B,
p. 291) (Bergstrom, 2016; Freeman, 2008; Stoll, 2015). Gastrointestinal abnormalities are identied in 6 to 12 percent and
include esophageal atresia, duodenal atresia, and Hirschsprung
disease (Fig. 15-48, p. 296) (Bull, 2011; Stoll, 2015).
Other health problems are also common with Down syndrome. Tese include hearing loss in 75 percent, optical reractive errors in 50 percent, cataracts in 15 percent, obstructive
sleep apnea in 60 percent, thyroid disease in 15 percent, transient myeloprolierative disorder in 10 percent o newborns,
early-onset Alzheimer's disease in 70 percent o adults, and
a higher incidence o leukemia (Bull, 2011; Hartley, 2015).
Women with Down syndrome are ertile, and nearly one third
o their ospring will have Down syndrome. Males with Down
syndrome have markedly reduced spermatogenesis and are
almost always sterile. Te average intelligence quotient (IQ)
score is 35 to 70. Social skills in aected children are usually
higher than predicted by their IQ scores.
Characteristic eatures o Down syndrome are shown in
Figure 16-4. ypical ndings include brachycephaly; epicanthal olds and up-slanting palpebral ssures; Brusheld spots,
which are whitish spots on the periphery o the iris; a at nasal
bridge; and hypotonia. Inants oten have loose skin at the
FIGURE 16-3 Male karyotype with trisomy 21 (47,XY,+21), consistent with Down syndrome. (Reproduced with permission from
Dr. Prasad Koduru.)
A B C
FIGURE 16-4 Newborn with Down syndrome, karyotype 47,XX,+21 (trisomy 21). A. Characteristic facial features include epicanthal folds
and a flattened nasal bridge. B. The hand has a single palmar crease (arrow) and hypoplasia of the middle phalanx of the fifth digit (arrowhead). C. The “sandal gap” between the first and second toes is also known as hallux varus. (Reproduced with permission from Dr. Aldeboran N. Rodriguez.)312 The Fetal Patient
Section 6
nape o the neck, a prominent space or “sandal-gap” between
the rst and second toes, short ngers, a single palmar crease,
and clinodactyly o the th digit, in which hypoplasia o the
middle phalanx causes inward curvature. Discussed in Chapter
17, some o these ndings are seen during prenatal ultrasound
examination.
Data suggest that approximately 95 percent o liveborn
inants with Down syndrome survive the rst year. Te 10-year
survival rate is at least 90 percent overall and is 99 percent
i major malormations are absent (Rankin, 2012; Vendola,
2010). Average lie expectancy is 55 to 60 years. Several organizations oer education and support or prospective parents aced with prenatal diagnosis o Down syndrome. Tese
include the March o Dimes, National Down Syndrome Congress (www.ndsccenter.org), and National Down Syndrome
Society (www.ndss.org).
Trisomy 18—Edwards Syndrome. Te association between
this constellation o abnormalities and an autosomal trisomy
was rst described by Edwards (1960). In population-based
series o abortuses, stillbirths, and live births, trisomy 18 approximates 1 per 2000 recognized pregnancies (Goel, 2019; Loane,
2013; Parker, 2010). High in-utero lethality and termination
o many aected pregnancies explains a live birth prevalence o
just 1 per 6600 to 10,000. Unlike Down syndrome and Patau
syndrome, which may result rom a robertsonian
translocation because they
involve acrocentric chromosomes, Edwards syndrome uncommonly stems
rom a chromosomal rearrangement.
Virtually every organ
can be aected by trisomy 18. Common major
anomalies include heart
deects in more than 90
percent, particularly ventricular septal deects.
Cerebellar vermian agenesis, myelomeningocele,
diaphragmatic hernia, omphalocele, imperorate anus,
and renal anomalies such
as horseshoe kidney are
others (Rosa, 2011; Springett, 2015; Watson,
2008). Sonographic images
o these abnormalities are
shown in Chapter 15.
Frequent cranial and extremity abnormalities in
aected etuses include a
“strawberry-shaped” cranium, abnormally wide
cavum septum pellucidum, choroid plexus cysts,
micrognathia, clenched hands with overlapping digits, radial
aplasia with hyperexed wrists, and rockerbottom or clubbed
eet (Fig. 16-5) (Abele, 2013). Importantly, choroid plexus
cysts only raise the risk or trisomy 18 in the setting o other
risk actors, such as etal structural abnormalities or an abnormal aneuploidy screening test result (Reddy, 2014).
Pregnancies with trisomy 18 that reach the third trimester oten develop etal-growth restriction, and the mean
birthweight is <2500 g (Lin, 2006; Rosa, 2011). When
undiagnosed, trisomy 18 has resulted in emergency cesarean
or “etal distress” in nearly 50 percent o cases (Schneider,
1981; Houlihan, 2013). Mode o delivery and management
o heart rate abnormalities should be discussed in advance.
Discussed in Chapter 35 (p. 628), perinatal palliative care
consultation should be oered (American College o Obstetricians and Gynecologists, 2019).
In the National Birth Deects Prevention Study, median
neonatal survival with trisomy 18 was 8 days, and the 5-year
survival rate was 12 percent (Meyer, 2016). Not unexpectedly,
major anomalies lower survival rates. Data rom the Society o
Toracic Surgeons indicate that inants with trisomy 18 who
undergo cardiac surgery have mortality rates 3 to 5 times higher
than those without trisomy 18 (Cooper, 2019). Tus, among
the minority with trisomy 18 who survive until birth, the condition is severely lie limiting.
A B
C D
FIGURE 16-5 Trisomy 18—Edwards Syndrome. A. This transventricular sonographic view shows fetal
choroid plexus cysts and an angulated “strawberry-shaped” skull. B. Radial clubhand is manifested as a
single forearm bone (radius), with the hands in a fixed, hyperflexed position at right angles to the forearms.
C. This three-dimensional (3-D) sonographic image shows the characteristic hand position of clenched fist
with overlapping digits. D. 3-D sonographic image displays a rockerbottom foot (vertical talus).Genetics 313
CHAPTER 16
Trisomy 13—Patau Syndrome. Tis constellation o etal abnormalities and their association with an autosomal trisomy was rst
described by Patau and colleagues (1960). Te incidence o trisomy 13 approximates 1 case in 5000 recognized pregnancies,
which includes abortuses and stillbirths. Most aected etuses are
lost or terminated. Te live birth prevalence is 1 per 12,000 to
18,000 (Goel, 2019; Loane, 2013; Parker, 2010).
At least 80 percent o pregnancies with Patau syndrome
result rom trisomy 13. With rare exception, the remainder are
caused by a robertsonian translocation involving chromosome
13. Te most common translocation involves chromosomes
13 and 14, der(13;14)(q10;q10), which is carried by approximately 1 in 1300 phenotypically normal individuals. Among
translocation carriers, ewer than 2 percent give birth to a live
inant with Patau syndrome.
risomy 13 may be associated with abnormalities o any
organ system. Abnormalities o the brain, heart, kidneys, and
extremities are the most requent. Holoprosencephaly, usually the alobar type, is present in two thirds o cases and oten
is accompanied by severe acial abnormalities (Fig. 15-13,
p. 279). Tese may include hypotelorism or cyclopia, microphthalmia, and nasal abnormalities that range rom a single
nostril to a proboscis. Cardiac deects are ound in up to 90
percent (Shipp, 2002). Other abnormalities that suggest trisomy 13 include cephalocele, microcephaly, omphalocele,
cystic renal dysplasia, polydactyly, rockerbottom eet, aplasia
cutis, and clet lip-palate, which may be median (Lin, 2007;
Springett, 2015). Sonographic images o several o these are
shown in Chapter 15. Aected etuses oten also have bilateral
echogenic intracardiac oci. For the etus or newborn with a
cephalocele, cystic kidneys, and polydactyly, the dierential diagnosis includes trisomy 13 and the autosomal-recessive Meckel–
Gruber syndrome.
risomy 13 is lie limiting, even more so than trisomy
18 (Domingo, 2019). In the National Birth Deects Prevention Study, median survival o neonates with trisomy 13 was
5 days, and the 5-year survival rate was below 10 percent
(Meyer, 2016). Occasionally children with trisomy 13 have
been candidates or palliative surgical procedures. Most o these
have a milder phenotype that lacks brain, cardiac, gastrointestinal, or genitourinary abnormalities (Nelson, 2016). Counseling
regarding prenatal diagnosis and management options is similar
to that described or trisomy 18.
Unlike other aneuploidies, etal trisomy 13 coners risk to
the pregnant woman. Continuing pregnancies have at least a
25-percent risk or hypertensive complications (Dotters-Katz,
2018; uohy, 1992). Te risk or preeclampsia with severe eatures is increased more than tenold and oten develops prior
to 32 weeks’ gestation. Chromosome 13 contains the gene or
soluble ms-like tyrosine kinase-1 (sFlt-1), which is an antiangiogenic protein associated with preeclampsia (Chap. 40,
p. 694). Investigators have documented overexpression o the
sFlt-1 protein by trisomic 13 placentas and in serum o women
with preeclampsia (Bdolah, 2006; Silasi, 2011).
Other Trisomies. Live births are extremely rare with any other
autosomal trisomy. risomy 22 has been described in case
reports and series (Heinrich, 2013; Kehinde, 2014). Aected
etuses have severe growth restriction, microcephaly with an
abnormal-shaped cranium, midace hypoplasia, and cardiac
and genitourinary abnormalities. risomy 16 is the most prevalent trisomy among rst-trimester losses, accounting or 16
percent. risomies 21 and 22 are also common among rst
trimester losses. risomy 1 has never been reported.
Monosomy
Nondisjunction creates an equal number o nullisomic and
disomic gametes. As a rule, missing chromosomal material is
more devastating than extra chromosomal material, and almost
all monosomic conceptuses are lost beore implantation. Te
one exception is monosomy or the X chromosome (45,X),
urner syndrome, which is discussed subsequently. Unlike
autosomal trisomies, which increase in incidence with maternal
age, monosomy and maternal age lack an association.
Polyploidy
Tis is dened as more than two complete haploid chromosomal sets. Polyploidy accounts or approximately 20 percent
o spontaneous abortions but is rarely ound later in gestation.
riploid pregnancies have three haploid sets, 69 chromosomes. I extra set o chromosomes is paternal, the result is
diandric triploidy, and i maternal, digynic triploidy, relevant
because the phenotype reects the parent o origin. Tis is an
example o imprinting (p. 322). Diandric or type I triploidy
occurs ater ertilization o one egg by two sperm or by one
abnormal diploid sperm. Diandric triploidy produces a partial
molar pregnancy, discussed in Chapter 13 (p. 237). With digynic or type II triploidy, the extra chromosomal set is maternal,
and the egg ails to undergo the rst or second meiotic division
beore ertilization. Digynic triploid placentas do not develop
molar changes. However, the etus usually develops asymmetrical growth restriction. Although diandric triploidy accounts or
the majority o triploid conceptions, the early loss rate is so
high that two thirds o triploid pregnancies identied beyond
the rst trimester are digynic ( Jauniaux, 1999).
riploidy is recognized in 1 per 5000 pregnancies (Zalel,
2016). It is considered lethal, and etuses with either the diandric or digynic orm typically have multiple structural anomalies. Te brain, heart, kidneys, and extremities are commonly
aected (Massalska, 2017; Zalel, 2016). Counseling, prenatal
diagnosis, and delivery management are similar to those or
trisomies 18 and 13. Te recurrence risk or a woman whose
triploid etus survived past the rst trimester is 1 to 1.5 percent,
and thus prenatal diagnosis is oered in uture pregnancies.
etraploid pregnancies have our haploid sets o chromosomes,
resulting in either 92,XXXX or 92,XXYY. Tis suggests a postzygotic ailure to complete an early cleavage division. Te conceptus
invariably succumbs, and the recurrence risk is minimal.
Sex Chromosome Abnormalities
45,X—Turner Syndrome. First described by urner (1938),
this syndrome later was ound to be caused by monosomy
X (Ford, 1959). Te birth prevalence o urner syndrome is
approximately 1 in 2500 girls (Cragan, 2009; Dolk, 2010). Te
missing X chromosome is paternally derived in 80 percent o
cases (Cockwell, 1991; Hassold, 1990).314 The Fetal Patient
Section 6
urner syndrome is the only monosomy compatible with
lie, but it is also the most common aneuploidy in rst-trimester
losses, accounting or 20 percent. Tis is explained by its wide
range in phenotype. Approximately 98 percent o aected conceptuses are so abnormal that they abort early in the rst trimester. O the remainder, many maniest large, septated cystic
hygromas in the late rst or early second trimester, oten in
the setting o edema that progresses to hydrops etalis. When
cystic hygromas are accompanied by hydrops, the prognosis is
extremely poor (Chap. 15, p. 286).
Fewer than 1 percent o pregnancies with urner syndrome
result in a liveborn neonate. O these, only hal are actually
monosomy X—approximately a ourth have mosaicism or
monosomy X, such as 45,X/46,XX or 45,X/46,XY, and another
15 percent have isochromosome X. It is thought that surviving
individuals with 45,X may have had the benet o “rescue” by
an additional cell line containing 46,XX during critical phases
o development that was subsequently lost (Hook, 2014).
Abnormalities associated with urner syndrome include
let-sided cardiac deects—such as coarctation o the aorta,
hypoplastic let heart syndrome, or bicuspid aortic valve—in 30
to 50 percent; renal anomalies, particularly horseshoe kidney;
and hypothyroidism. Other eatures are short stature, broad
chest with widely spaced nipples, congenital lymphedema—
pufness over the dorsum o hands and eet, and a “webbed”
posterior neck resulting rom cystic hygromas. Intelligence
scores are generally in the normal range, but there may be
impairments in visual-spatial organization, nonverbal problem
solving, and interpretation o social cues. A consensus guideline is available that addresses screening and treatment or the
range o health problems aected individuals ace (Graveholt,
2017). Growth hormone is typically administered in childhood
to ameliorate short stature. More than 90 percent have ovarian dysgenesis and require estrogen repletion at puberty. An
exception is mosaicism involving the Y chromosome, as this
coners risk or germ cell neoplasm—regardless o whether the
child is phenotypically male or emale. Accordingly, eventual
prophylactic bilateral gonadectomy is indicated (Cools, 2011;
Schorge, 2020).
47,XXX. Approximately 1 in 1000 emale newborns has an
additional X chromosome—47,XXX (Berglund, 2020). Te
extra X is maternally derived in more than 90 percent o cases.
Te prevalence o 47,XXX is weakly associated with maternal
age, and cell-ree DNA screening has resulted in increased diagnoses. No specic pattern o malormations has been described,
but genitourinary problems and seizure disorders are more
common (Wigby, 2016). Aected inants do not have a characteristic appearance. When children do come to attention, eatures may include tall stature, hypertelorism, epicanthal olds,
kyphoscoliosis, clinodactyly, and hypotonia (artaglia, 2010;
Wigby, 2016). More than one third are diagnosed with a learning disability, hal have attention decit disorder, and overall
cognitive scores are in the low-average range. Pubertal development is unaected. Primary ovarian insufciency has been
reported. In the absence o prenatal diagnosis, it is estimated
that 47,XXX is ascertained in only 10 percent o aected children (artalgia, 2010).
Females with two or more extra X chromosomes—48,XXXX
or 49,XXXXX—are likely to have physical abnormalities apparent at birth. Tese abnormal X complements are associated
with intellectual disability. For both males and emales, the IQ
score is lower with each additional X chromosome.
47,XXY—Klinefelter Syndrome. Tis is the most common
sex chromosome abnormality. It occurs in approximately 1 in
700 male inants (Radicioni, 2010). Te additional X chromosome is maternally or paternally derived with equal propensity
(Jacobs, 1995; Lowe, 2001). Tere is a weak association with
advanced maternal and paternal age.
Like 47,XXX, newborns with 47,XXY usually appear phenotypically normal and do not have a higher incidence o anomalies. As children, boys are typically taller than average and have
normal prepubertal development. However, they have gonadal
dysgenesis, do not undergo normal virilization, and require testosterone supplementation. Tey may develop gynecomastia.
IQ scores usually lie in the average to low-average range, with
increased rates o delayed language development (Boada, 2009;
Girardin, 2011). Initiation o hormone replacement was previously recommended to begin in adolescence. However, more
recent research suggests that therapy earlier in childhood results
in improved working memory and executive unctioning and
a decrease in anxiety disorders (Samango-Sprouse 2019; ran,
2019).
47,XYY. Tis aneuploidy occurs in approximately 1 in 1000
male newborns (Berglund, 2020). As with 47,XXX and XXY
individuals, aected boys tend to be tall. A third have macrocephaly, nearly two thirds demonstrate hypotonia, and tremors are common (Bardsley, 2013). Rates o major anomalies
are not elevated, although hypertelorism and clinodactyly may
be identied in more than hal. Pubertal development is normal, and ertility is unimpaired. Aected individuals do have
increased rates o oral and written language impairments, attention decit disorder, developmental delays, and autism spectrum disorder (Bardsley, 2013; Joseph, 2018).
Males with more than two Y chromosomes—48,XYYY—
or with both additional X and Y chromosomes—48,XXYY or
49,XXXYY—are more likely to have congenital abnormalities,
medical problems, and intellectual disability (artaglia, 2011).
■ Abnormalities of Chromosome Structure
Structural chromosomal abnormalities include deletions, duplications, translocations, isochromosomes, inversions, ring chromosomes, and mosaicism (see able 16-1). Identication o
a structural chromosomal abnormality in ospring raises two
primary questions. First, what phenotypic or later developmental abnormalities are associated with the nding? Second,
is parental karyotype evaluation indicated? In other words, are
the parents at increased risk o carrying this abnormality, and i
so, what is their risk o having uture aected ospring?
Deletions and Duplications
A chromosome with a deletion has a stretch o DNA that is
missing, whereas one with a duplication has a region that is
included twice. Most deletions and duplications occur duringGenetics 315
CHAPTER 16
meiosis and result rom malalignment or mismatching during
the pairing o homologous chromosomes. Te misaligned segment may then be deleted, or i the mismatch remains when
the two chromosomes recombine, it may result in a deletion
in one chromosome and duplication in the other (Fig. 16-6).
When a deletion or duplication is identied in a etus or inant,
parental karyotyping should be oered, because i either parent carries a balanced translocation, the recurrence risk in
subsequent pregnancies is signicantly increased. Deletions
involving DNA segments large enough to be seen with standard cytogenetic karyotyping are identied in approximately
1 in 7000 births. Common deletions may be reerred to by
eponyms—or example, del 5p is called cri du chat syndrome.
Microdeletions and Microduplications. When a deletion or
duplication is smaller than 3 to 5 million base pairs, it is too
small to be detected with a standard karyotype analysis. CMA
permits identication o these microdeletions and microduplications (p. 325). When CMA is used, the region o DNA that is
missing or duplicated is termed a genomic copy number variant.
A microdeletion or duplication may involve a stretch o DNA
that contains multiple genes. Tis causes a contiguous gene syndrome, which can encompass serious but unrelated phenotypic
abnormalities (Schmickel, 1986). In some cases, a microduplication may involve the exact DNA region that causes a recognized microdeletion syndrome (Table 16-2). When a specic
microdeletion syndrome is suspected clinically, it is conrmed
using either CMA or FISH.
22q11.2 Microdeletion Syndrome. Tis syndrome is also
known as DiGeorge syndrome, Shprintzen syndrome, and
velocardioacial syndrome. It is the most common microdeletion, with a prevalence o 1 case in 3000 to 6000 births. Inheritance is autosomal dominant—ospring o aected individuals
have a 50-percent chance o inheriting the syndrome. However,
more than 90 percent o cases arise rom a de-novo mutation.
Te ull deletion contains 3 million base pairs, encompasses 40
genes, and includes 180 dierent eatures (Shprintzen, 2008).
Tis is emblematic o a contiguous gene syndrome and poses
counseling challenges because eatures can vary widely, even
among amily members. With prenatal diagnosis o an aected
etus, genetic testing is oered to the pregnant patient and her
partner.
Approximately 75 percent o aected individuals have an associated conotruncal cardiac anomaly, such as tetralogy o Fallot,
truncus arteriosus, interrupted aortic arch, or ventricular septal
deect (McDonald-McGinn, 2015). Immune deciency, such as
-cell lymphopenia, also develops in 75 percent. More than 70
percent have velopharyngeal insufciency or clet palate. Characteristic acial eatures include short palpebral ssures, bulbous
nasal tip, micrognathia, short philtrum, and small or posteriorly
rotated ears. Learning disabilities, autism spectrum disorder, and
intellectual disability also are common. Other maniestations
include hypocalcemia, renal anomalies, esophageal dysmotility,
hearing loss, behavioral disorders, and psychiatric illness, particularly schizophrenia.
Chromosomal Translocations
Tese are DNA rearrangements in which a DNA segment
breaks away rom one chromosome and attaches to another.
Te rearranged chromosomes are called derivative (der) chromosomes. Te two types are reciprocal and robertsonian translocations.
Reciprocal Translocations. A double-segment or reciprocal translocation results when breaks occur in two dierent
chromosomes and the broken ragments are exchanged. Each
aected chromosome receives a ragment o the other. I no
chromosomal material is gained or lost, the translocation is
considered balanced. Te prevalence o reciprocal translocations approximates 1 in 600 births.
Te carrier o a balanced translocation will usually have a
normal phenotype. However, repositioning o specic genes
within chromosomal segments may cause major structural or
developmental abnormalities in approximately 6 percent o
apparently balanced translocation carriers. Using CMA technology, up to 20 percent o individuals who appear to have
a balanced translocation are ound instead to have missing or
redundant DNA segments (Manning, 2010).
Balanced translocation carriers are at risk to produce unbalanced gametes, resulting in abnormal ospring. As shown in
Figure 16-7, i an oocyte or sperm contains a translocated chromosome, ertilization results in an unbalanced translocation—
monosomy or part o one aected chromosome and trisomy
or part o the other. In general, translocation carriers identied
ater the birth o an abnormal child have a 5- to 30-percent risk
o producing liveborn ospring with an unbalanced translocation. Carriers identied or other reasons, or example, during
an inertility evaluation, have only a 5-percent risk. Tis risk
is lower because gametes are so abnormal that conceptions are
nonviable.
Robertsonian Translocations. Tese involve only the acrocentric chromosomes—13, 14, 15, 21, and 22. Acrocentric
Meiosis I Meiosis II
Normal Del Dupl Normal
FIGURE 16-6 A mismatch during pairing of homologous chromosomes may lead to a deletion in one chromosome and a duplication in the other. Del = deletion; Dupl = duplication.316 The Fetal Patient
Section 6
chromosomes have extremely short p arms, and the p arms
contain redundant copies o genes coding or ribosomal RNA.
In a robertsonian translocation, the q arms o two acrocentric
chromosomes use at one centromere to orm a derivative chromosome, and the other centromere and both p arms are lost.
Te lost DNA is present in multiple copies on other acrocentric chromosomes, and thus the translocation carrier is usually
phenotypically normal. Because the number o centromeres
determines the chromosome count, a robertsonian translocation carrier has only 45 chromosomes.
Balanced robertsonian carriers have reproductive difculties.
During ertilization, i the derivative chromosome pairs with a
normal haploid chromosome, the resulting ospring will have
trisomy. I the used chromosomes are homologous, that is,
rom the same chromosome pair, the carrier can produce only
unbalanced gametes. Each egg or sperm contains either both
copies o the translocated chromosome, which would result in
trisomy i ertilized, or no copy, which would result in monosomy. I the used chromosomes are nonhomologous, our o
the six possible gametes would be abnormal.
Robertsonian translocations are ound in 1 in 1000 individuals. Te risk to have an abnormal ospring approximates
15 percent i a robertsonian translocation is carried by the
mother and 2 percent i carried by the ather. However, robertsonian translocations are not a major cause o miscarriage and
are identied in ewer than 5 percent o couples evaluated or
recurrent pregnancy loss. I a etus or child is ound to have a
translocation trisomy, both parents should be oered karyotype analysis. I neither parent is a carrier, the recurrence risk is
extremely low. Te most common robertsonian translocation
TABLE 16-2. Selected Microdeletion Syndromes
Syndrome Prevalence Location Features
Alagille 1:70,000 20p12.2 Cholestasis (paucity of intrahepatic bile ducts),
cardiac disease, skeletal disease, ocular
abnormalities, dysmorphic facies
Angelman 1:12,000 to 1:20,000 15q11.2–q13
(maternal genes)
Dysmorphic facies—“happy puppet” appearance,
intellectual disability, ataxia, hypotonia, seizures
Cri-du-chat 1:20,000 to 1:50,000 5p15.2–15.3 Abnormal laryngeal development with “cat-like”
cry, hypotonia, intellectual disability
Kallmann syndrome 1:30,000 males Xp22.3 Hypogonadotropic hypogonadism, anosmia
Langer-Giedion Rare 8q23.3 Trichorhinophalangeal syndrome, dysmorphic
facies, skeletal abnormalities, sparse hair
Miller-Dieker Rare 17p13.3 Neuronal migration abnormalities with
lissencephaly and microcephaly (profound
impairment), dysmorphic facies
Prader-Willi 1:10,000 to 1:30,000 15q11.2–q13
(paternal genes)
Obesity, hypotonia, hypogonadotropic
hypogonadism, small hands and feet,
intellectual disability
Retinoblastoma 1:280,000 13q14.2 Retinoblastoma, retinoma (benign neoplasm),
non-retinal (second primary) tumors
Rubenstein-Taybi 1:100,000 to 1:125,000 16p13.3 Dysmorphic facies, broad thumbs and toes,
intellectual disability, increased tumor risk
Smith-Magenis 1:15,000 to 1:25,000 17p11.2 Dysmorphic facies, speech delay, hearing loss,
sleep disturbances, self-destructive behaviors,
intellectual disability
Velocardiofacial
syndrome
1:3000 to 1:6000 22q11.2 Conotruncal cardiac defects, cleft palate,
velopharyngeal incompetence, thymic and
parathyroid abnormalities, intellectual disability
WAGR 1:500,000 11p13 Wilms tumor, aniridia, genitourinary anomalies.
intellectual disability (mental retardation)
Williams-Beuren 1:7500 to 1:10,000 7q11.23 Dysmorphic facies, dental malformation, aortic and
peripheral pulmonary artery stenosis, intellectual
disability
Wolf-Hirschhorn 1:20,000 to 1:50,000 4p16.3 Dysmorphic (“Greek helmet”) facies, delayed
growth and development, cleft lip/palate,
coloboma, cardiac septal defects
X-linked ichthyosis 1:6000 Xp22.3 Steroid sulfatase deficiency, corneal opacities
Prevalence reflects live births.
Data from National Library of Medicine, 2021; Johns Hopkins University, 2021.Genetics 317
CHAPTER 16
is der(13;14)(q10;q10), which accounts or up to 20 percent o
cases o Patau syndrome (p. 313).
Isochromosomes
When either two p arms or two q arms rom the same chromosome use together, an isochromosome results. Tis may occur
i the centromere breaks transversely instead o longitudinally
during meiosis II or mitosis. Alternately, an isochromosome can
result rom a meiotic error in a chromosome with a robertsonian
translocation. I the isochromosome is acrocentric, it is composed
o two q arms and will behave like a homologous robertsonian
translocation. Such a carrier is phenotypically normal but can
produce only abnormal, unbalanced gametes. I the isochromosome is nonacrocentric, it may be composed o either two p arms
or two q arms. Functionally this results in trisomy o the genes on
the arms that are present and monosomy o the genes on the arms
that are lost. Tus, the carrier is usually phenotypically abnormal
and produces abnormal gametes. Te most common isochromosome involves the long arm o the X chromosome, i(Xq), which is
the etiology o 15 percent o cases o urner syndrome.
Chromosomal Inversions
When the same chromosome breaks in two places, the intervening genetic material may invert beore the breaks are repaired.
Although no genetic material is lost or duplicated, an inversion
may alter gene unction. Tere are two types—pericentric and
paracentric inversions.
Pericentric Inversion. Tis results rom breaks in both the p and
q arms o a chromosome, such that the inverted material spans
the centromere (Fig. 16-8). A pericentric inversion causes problems in chromosomal alignment during meiosis and coners signicant risk or the carrier to produce abnormal gametes and
abnormal ospring. Te observed risk o abnormal ospring is
5 to 10 percent i ascertainment is made ater the birth o an
abnormal child. Te risk is only 1 to 3 percent i prompted by
another indication. An important exception is inv(9)(p11q12), a
pericentric inversion on chromosome 9 that is a normal variant
and present in approximately 1 percent o the population.
Paracentric Inversion. I one arm o a chromosome suers the
two breaks, the inverted material does not include the centromere, and the inversion is paracentric (see Fig. 16-8). Te carrier makes either normal balanced gametes or gametes that are
so abnormal as to preclude ertilization. Tus, although inertility may be a problem, the risk o having an abnormal ospring
is extremely low.
Ring Chromosome
I a deletion occurs at each end o the same chromosome, the
ends may come together to orm a ring chromosome. Te telomere regions at the ends o each chromosome contain redundant nucleoprotein complexes that stabilize the chromosome.
I only the telomeres are lost, all necessary genetic material is
retained, and the carrier is balanced. I a deletion extends more
Balanced translocation carrier
B Balanced
translocation
carrier
C Unbalanced
duplicationdeletion
D Unbalanced
duplicationdeletion
Normal
A Normal
Zygotes Gametes Parents
FIGURE 16-7 A carrier of a balanced translocation may produce offspring who are also carriers of the balanced rearrangement (B), offspring with unbalanced translocations (C, D), or offspring with normal chromosomal complements (A).318 The Fetal Patient
Section 6
should be oered. In a series o more than 1000 pregnancies with mosaicism at chorionic villus sampling, subsequent
amniocentesis identied true etal mosaicism in 13 percent.
Conned placental mosaicism accounted or 85 percent o
cases, and uniparental disomy, discussed later (p. 322), was
ound in 2 percent (Malvestiti, 2015). I mosaicism is detected
or a chromosome known to contain imprinted genes—such
as chromosomes 6, 7, 11, 14, or 15—testing or uniparental
disomy should be considered, as there may be etal consequences (Grati, 2014a).
Although outcomes with conned placental mosaicism are
generally good, risks o etal-growth restriction and stillbirth are
higher (Reddy, 2009). Fetal-growth restriction may stem rom
impaired unctioning o the aneuploid placental cells (Baero,
2012). In a recent series o 5500 pregnancies undergoing chorionic villus sampling, the preterm birth rate in pregnancies with
conned placental mosaicism was 45 percent, and 50 percent
o aected newborns were small or gestational age (outain,
2018). Placental mosaicism or trisomy 16 coners a particularly poor prognosis, with as ew as 1 in 3 pregnancies resulting
in normal outcome (Grau Madsen, 2018).
Gonadal Mosaicism
Also called germline mosaicism, this reers to having one cell
line in gametes and another in somatic cells. A genetic abnormality that is conned to gamete cells will aect all cells in the
ospring. Tus, gonadal mosaicism can account or apparently
de-novo diseases in the ospring o normal parents. Because
spermatogonia and oogonia divide throughout etal lie, and
spermatogonia continue to divide throughout adulthood, a
meiotic error can occur in germ cells that were previously normal. New mutations identied in an ospring whose ather is
older than 40 may arise through this mechanism, as discussed
later (p. 319) (Wilkie, 2017). Gonadal mosaicism also explains
the 6-percent recurrence risk ater the birth o a child with a
disease caused by a “new” mutation.
MODES OF INHERITANCE
A monogenic or mendelian disorder is caused by a mutation
or alteration in a single locus or gene in one or both members
o a gene pair. ypes o mendelian inheritance include autosomal dominant, autosomal recessive, X-linked, and Y-linked
(Table 16-3). Other monogenic inheritance patterns include
mitochondrial inheritance, uniparental disomy, imprinting,
and trinucleotide repeat expansion.
■ Relationship between Phenotype
and Genotype
When considering inheritance, it is the phenotype that is dominant or recessive, not the genotype. I a disease is dominant, a
normal gene directs the production o normal protein, but the
phenotype will be abnormal because o protein produced by
the abnormal gene. A heterozygous carrier o a recessive disease
may produce detectable levels o an abnormal gene product but
have no eatures o the condition, because the phenotype is
directed by the product o the normal co-gene. For example,
FIGURE 16-8 Pericentric inversion involves the centromere,
whereas paracentric inversion does not. Individuals with pericentric
inversions are at risk to have offspring with a duplication/deletion.
Those with paracentric inversions are at increased risk for early
pregnancy loss.
proximally than the telomere, the carrier is likely to be phenotypically abnormal. An example o this is the ring X chromosome, which may result in urner syndrome.
■ Mosaicism
A mosaic individual has two or more cytogenetically distinct
cell lines that are derived rom a single zygote. Phenotypic
expression o mosaicism depends on several actors, including
whether the cytogenetically abnormal cells involve the etus,
part o the etus, just the placenta, or some combination. Mosaicism is ound in approximately 0.3 percent o amnionic uid
cultures (Carey, 2014). When abnormal cells are present in
only a single ask o amnionic uid, the nding is likely pseudomosaicism, caused by cell-culture artiact (Bui, 1984; Hsu,
1984). When abnormal cells involve multiple cultures, however, true mosaicism is more likely. Further testing veries a
second cell line in 60 to 70 percent o these etuses (Hsu, 1984;
Worton, 1984).
Confined Placental Mosaicism
Mosaicism involving a gene abnormality is detected in 1 to 2
percent o chorionic villus sampling specimens. AmniocentesisGenetics 319
CHAPTER 16
erythrocytes rom carriers o sickle-cell anemia contain approximately 30 percent hemoglobin S, but because the other 70 percent is hemoglobin A, these cells do not usually sickle in vivo.
Heterogeneity
Genetic heterogeneity explains how dierent genetic mechanisms
may result in the same phenotype. Locus heterogeneity indicates
that a specic disease phenotype can be caused by mutations in
dierent genetic loci. It also explains why some diseases appear
to ollow more than one type o inheritance. For example, retinitis pigmentosa may develop ollowing mutations in at least 35
dierent genes or loci and may result in autosomal dominant,
autosomal recessive, or X-linked orms. Allelic heterogeneity
describes how dierent mutations o the same gene may aect
presentation o a particular disease. For example, although only
one gene has been associated with cystic brosis—the cystic
brosis conductance transmembrane regulator gene—more than
2000 mutations in this gene have been described and result in
variable disease severity (Chaps. 17, p. 342 and 54, p. 968).
Phenotypic heterogeneity explains how dierent disease states can
arise rom dierent mutations in the same gene. As an example, mutations in the broblast growth actor receptor 3 (FGFR3)
gene may result in several dierent skeletal disorders, including
achondroplasia and thanatophoric dysplasia, both o which are
discussed in Chapter 15 (p. 302).
■ Autosomal Dominant Inheritance
I only one copy o a gene pair determines the phenotype, that
gene is considered to be dominant. Carriers have a 50-percent
chance o passing on the aected gene with each conception.
A gene with a dominant mutation generally species the phenotype in preerence to the normal gene. Tat said, not all
individuals will necessarily maniest an autosomal dominant
condition the same way. Factors that aect the phenotype o
an autosomal dominant condition include penetrance, expressivity, and presence o codominant genes.
Penetrance
Tis characteristic describes whether a dominant gene is
expressed. A gene with recognizable phenotypic expression in
all individuals has complete penetrance. Penetrance is incomplete i some carriers express the gene but others do not. A gene
that is expressed in 80 percent o individuals is 80-percent penetrant. Incomplete penetrance explains why some autosomal
dominant diseases may appear to “skip” generations.
Expressivity
Individuals with the same autosomal dominant trait may maniest the condition dierently, even within the same amily.
Genes with variable expressivity can produce disease maniestations that range rom mild to severe. Examples include neurobromatosis, tuberous sclerosis, and adult polycystic kidney
disease.
Codominant Genes
I two dierent alleles in a gene pair are both expressed in the
phenotype, they are considered to be codominant. Blood type,
or example, is determined by expression o dominant A and B
red-cell antigens that can be expressed simultaneously. Another
example o codominance is the group o genes responsible or
hemoglobin production. I one gene directs production o
hemoglobin S and the other directs production o hemoglobin C, that individual will produce both S and C hemoglobin
(Chap. 59, p. 1053).
Advanced Paternal Age
Paternal age older than 40 is associated with increased risk
or spontaneous genetic mutations. Spermatogonia undergo
TABLE 16-3. Selected Monogenic (Mendelian) Disorders
Autosomal Dominant
Achondroplasia
Acute intermittent porphyria
Adult polycystic kidney disease
Antithrombin III deficiency
BRCA1 and BRCA2 breast and/or ovarian cancer
Ehlers-Danlos syndrome
Familial adenomatous polyposis
Familial hypercholesterolemia
Hereditary hemorrhagic telangiectasia
Hereditary spherocytosis
Huntington disease
Hypertrophic obstructive cardiomyopathy
Long QT syndrome
Marfan syndrome
Myotonic dystrophy
Neurofibromatosis type 1 and 2
Tuberous sclerosis
von Willebrand disease
Autosomal Recessive
α1-Antitrypsin deficiency
Congenital adrenal hyperplasia
Cystic fibrosis
Gaucher disease
Hemochromatosis
Homocystinuria
Phenylketonuria
Sickle-cell anemia
Tay-Sachs disease
Thalassemia syndromes
Wilson disease
X-Linked
Androgen insensitivity syndrome
Chronic granulomatous disease
Color blindness
Fabry disease
Fragile X syndrome
Glucose-6-phosphate deficiency
Hemophilia A and B
Hypophosphatemic rickets
Muscular dystrophy—Duchenne and Becker
Ocular albinism type 1 and 2320 The Fetal Patient
Section 6
mitotic division every 16 days, and the many replications raise
the risk or single base-pair mutations. As a result, ospring
o older athers are at risk or new autosomal dominant disorders and X-linked carrier states. Several in particular have
been termed paternal age efect disorders (Goriely 2012). Tese
include mutations in the broblast growth actor receptor 2
(FGFR2) gene, which may cause craniosynostosis syndromes
such as Apert, Crouzon, and Peier syndromes; mutations in
the FGFR3 gene, which may result in achondroplasia and thanatophoric dysplasia; and mutations in the RET proto- oncogene,
which may cause multiple endocrine neoplasia syndromes
(oriello, 2008).
Using whole genome sequencing to study SNPs among o-
spring o older athers, Kong and associates (2012) ound an
increase o approximately two mutations or each year o paternal age past 40. Te absolute risk or any specic condition
is low, because individual autosomal dominant disorders are
uncommon. Tus, no screening or testing is specically recommended.
■ Autosomal Recessive Inheritance
Recessive diseases develop only when both gene copies are
abnormal. Unless carriers are screened or a specic disease,
they usually are recognized only ater the birth o an aected
child or the diagnosis o an aected amily member. I a couple
has a child with an autosomal recessive disease, the recurrence
risk is 25 percent or each subsequent pregnancy. Tus, 1/4 o
ospring will be homozygous normal, 2/4 will be heterozygous
carriers, and 1/4 will be homozygous abnormal. In other words,
three o our children will be phenotypically normal, and 2/3 o
phenotypically normal siblings are actually carriers.
A heterozygous carrier o a recessive condition is only at risk
to have aected children i her or his partner is heterozygous
or homozygous or the disease. Genes or rare autosomal recessive conditions have low prevalence in the general population.
Tus, the likelihood that a partner will be a gene carrier is
small, unless there is consanguinity or the partner is a member
o an at-risk group. Carrier screening is discussed in Chapter 17
(p. 342). Preimplantation genetic testing allows a blastocyst to
be genetically evaluated prior to intrauterine transer during in
vitro ertilization and is described also in Chapter 17 (p. 348).
Inborn Errors of Metabolism
Most o these autosomal recessive diseases result rom absence
o a crucial enzyme, leading to incomplete metabolism o proteins, lipids, or carbohydrates. Te metabolic intermediates that
build up are toxic to various tissues and may result in intellectual disability or other abnormalities.
Phenylketonuria. Also known as phenylalanine hydroxylase
(PAH) deciency, this autosomal recessive disease is caused by
mutations in the PAH gene. PAH metabolizes phenylalanine to
tyrosine, and homozygotes have diminished or absent enzyme
activity. Tis leads to abnormally high levels o phenylalanine,
which results in progressive intellectual impairment, autism,
seizures, motor decits, and neuropsychological abnormalities (Blau, 2010). Because phenylalanine competitively inhibits
tyrosine hydroxylase, which is essential or melanin production,
aected individuals also have hair, eye, and skin hypopigmentation. More than 600 PAH gene mutations have been characterized, and the carrier requency varies by ethnicity. For those o
Northern European origin, carrier requency is 1 in 50, such
that the disease aects up to 1 in 10,000 newborns (American
College o Obstetricians and Gynecologists, 2020b). Prompt
diagnosis and restriction o dietary phenylalanine beginning
early in inancy are essential to prevent neurological damage.
All states mandate newborn screening or phenylketonuria
(PKU).
Phenylalanine restriction alone would result in inadequate
protein consumption, and phenylalanine-ree amino acid–
based supplementation is required. Maintenance o phenylalanine concentrations in the range o 2 to 6 mg/dL (120 to
360 μmol/L) is recommended rom at least 3 months prior
to pregnancy and continuing throughout pregnancy (American
College o Obstetricians and Gynecologists, 2020b).
Unortunately, phenylalanine is actively transported to the
etus. Women with PKU whose phenylalanine levels remain
above the recommended range during pregnancy are at risk to
have otherwise normal (heterozygous) ospring who sustain
signicant in utero damage as a result o being exposed to toxic
phenylalanine concentrations. Hyperphenylalaninemia raises
the risk or miscarriage and or PKU embryopathy, which is
characterized by intellectual disability, microcephaly, seizures,
growth impairment, and cardiac anomalies. Among women
on unrestricted diets, the risk to have a child with intellectual
disability exceeds 90 percent, microcephaly develops in more
than 70 percent, and as many as 1 in 6 children have cardiac
deects. Te Maternal Phenylketonuria Collaborative Study,
which included 572 pregnancies ollowed more than 18 years,
reported that maintenance o serum phenylalanine levels in the
recommended range signicantly reduced the etal abnormality
risk and resulted in normal childhood IQ scores (Koch, 2003;
Platt, 2000).
Approximately 25 to 50 percent o individuals with PKU
experience a signicant decline in phenylalanine levels when
treated with the synthetic PAH coactor tetrahydrobiopterin
(sapropterin) (Vockley, 2014). Based on registry data, sapropterin is considered a treatment option or those in whom
phenylalanine levels remain elevated despite dietary therapy
(Grange, 2014). Preconceptional counseling and consultation
with providers rom experienced PKU centers is recommended.
Consanguinity
In medical genetics, a union is consanguineous i between second cousins or closer relatives. Although uncommon in Western countries, the global estimate o consanguineous parentage
approximates 10 percent o the population (Oniya, 2019). More
than 1 billion people are estimated to live in countries in which
20 to 50 percent o marriages are consanguineous (Romeo,
2014). First-degree relatives share hal o their genes, seconddegree relatives share a ourth, and third-degree relatives—
rst cousins—share one eighth. Because o the potential or
shared deleterious genes, consanguinity coners an increased
risk to have ospring with otherwise rare autosomal recessive diseases or multiactorial disorders. In population-basedGenetics 321
CHAPTER 16
series, rst cousins have twice the risk or ospring with congenital abnormalities (Sheridan, 2013; Stoltenberg, 1997).
Consanguinity is also associated with a greater rate o stillbirth
(Kapurubandara, 2016). Because CMA perormed using a SNP
platorm may identiy consanguinity, it is important that preprocedural counseling include this possibility.
Incest is dened as a sexual relationship between rst-degree
relatives such as parent-child or brother-sister and is universally
illegal. Progeny o such unions carry the highest risk o abnormal outcomes. Older studies reported that up to 40 percent o
ospring were abnormal as a result o recessive and multiactorial disorders (Baird, 1982; Freire-Maia, 1984).
■ XLinked and YLinked Inheritance
Most X-linked diseases are recessive. Common examples
include color blindness, hemophilia A and B, and Duchenne
and Becker muscular dystrophy. A male with an X-linked
recessive gene is usually aected by the disease it causes,
because he lacks a second X chromosome to express the normal dominant gene. However, a male with an X-linked disease cannot have aected sons because they do not receive
his X chromosome. When a woman carries a gene causing an
X-linked recessive condition, each son has a 50-percent risk
o being aected, and each daughter has a 50-percent chance
o being a carrier.
Women with an X-linked recessive gene are generally una-
ected by the disease it causes. In some cases, however, the random inactivation o one X chromosome in each cell—termed
lyonization—is skewed, and emale carriers may have eatures
o the condition. For example, approximately 10 percent o
emale carriers o hemophilia A will have actor VIII levels less
than 30 percent o normal, and a similar proportion o emale
hemophilia B carriers have actor IX levels less than 30 percent.
Levels below these thresholds coner a greater risk or abnormal
bleeding when aected women give birth (Plug, 2006). Indeed,
even with higher levels, carriers are reported to be at increased
risk or bleeding complications (Olsson, 2014). Female carriers
o Duchenne or Becker muscular dystrophy carry an elevated
risk or cardiomyopathy, and periodic evaluation or cardiac
dysunction and neuromuscular disorders is recommended
(American Academy o Pediatrics, 2008).
X-linked dominant disorders mainly aect emales, because
they tend to be lethal in males. wo examples are vitamin D–
resistant rickets and incontinentia pigmenti. An important
exception is ragile X syndrome, discussed subsequently.
Te prevalence o Y-linked disorders is low. Te Y-chromosome carries genes important or sex determination and various
cellular unctions related to spermatogenesis and bone development. Deletion o genes on the long arm o Y results in severe
spermatogenic deects, whereas genes at the tip o the short
arm are critical or chromosomal pairing during meiosis and
or ertility.
■ Mitochondrial Inheritance
Human cells contain hundreds o mitochondria, each with
its own genome and associated replication system. Oocytes
have approximately 100,000 mitochondria. Sperm have only
about 100, and the latter are destroyed ater ertilization. Each
mitochondrion has multiple copies o a 16.5-kb circular DNA
molecule that contains 37 genes. Mitochondrial DNA encodes
peptides required or oxidative phosphorylation and encodes
ribosomal and transer RNAs.
Mitochondria are inherited exclusively rom the mother.
Tus, although males and emales both can be aected by a
mitochondrial disorder, a male cannot transmit the condition to his ospring. When a cell replicates, mitochondrial
DNA sorts randomly into each o the resulting cells, a process
termed replicative segregation. As a consequence o replicative
segregation, any mitochondrial mutation will be propagated
randomly into the newly ormed cells. Because each cell holds
multiple copies o mitochondrial DNA, the mitochondrion
may contain only normal or only abnormal DNA, termed
homoplasmy. Alternatively, it may contain both normal and
mutated DNA, namely heteroplasmy. I a heteroplasmic oocyte
is ertilized, the relative proportion o mutated DNA may
aect whether the individual maniests a given mitochondrial
disease. It is not possible to predict the potential degree o
heteroplasmy among ospring, and this poses challenges or
genetic counseling.
Tere are 33 mitochondrial diseases or conditions with
known molecular bases (Johns Hopkins University, 2020).
Examples include myoclonic epilepsy with ragged red bers
(MERRF), Leber optic atrophy, Kearns-Sayre syndrome, Leigh
syndrome, and several orms o mitochondrial myopathy and
cardiomyopathy.
■ DNA Triplet Repeat Expansion
Mendel's rst law is that genes are passed unchanged rom parent
to progeny, and barring new mutations, this is oten true. Certain
genes, however, contain a region o DNA trinucleotide repeats
that can expand during parent-to-child transmission. Te expansion can occur during male meiosis, as in Huntington disease,
or during emale meiosis, as in ragile X syndrome. Clinically,
DNA triplet repeat expansion is maniested by anticipation—a
phenomenon in which a disease may maniest at an earlier age or
become more severe with each successive generation. Examples
o DNA triplet repeat diseases are shown in Table 16-4.
Fragile X Syndrome
Tis is the most common inherited intellectual disability. Fragile X syndrome aects approximately 1 in 3600 males and 1 in
TABLE 16-4. Some Disorders Caused by DNA Triplet
Repeat Expansion
Dentatorubral-pallidoluysian atrophy
Fragile X syndrome
Friedreich ataxia
Huntington disease
Spinal and bulbar muscular atrophy
Myotonic dystrophies
Spinocerebellar ataxias322 The Fetal Patient
Section 6
4000 to 6000 emales (American College o Obstetricians and
Gynecologists, 2020a). It is caused by expansion o a repeated trinucleotide DNA segment—cytosine-guanine-guanine (CGG)—
at chromosome Xq27.3. When the CGG repeat number reaches
a critical size—the ull mutation—the ragile X mental retardation 1 (FMR1) gene becomes methylated and inactivated. Inactivation halts expression o the FMR1 protein, which is abundant
in nerve cells and necessary or normal cognitive development.
Individuals with ragile X syndrome may have speech and
language problems, attention-decit/hyperactivity disorder,
and autism or autistic-like behaviors. Intellectual disability is
generally more severe in males, in whom average IQ scores
are 35 to 45 (Nelson, 1995). Te syndrome has characteristic
phenotypic eatures—a narrow ace with large jaw, prominent
ears, connective tissue abnormalities, and macroorchidism in
postpubertal males.
Both the sex o the aected individual and the number o
CGG repeats determine the degree o clinical impairment.
Clinically, our groups have been described (American College
o Obstetricians and Gynecologists, 2020a):
• Full mutation—more than 200 repeats
• Premutation—55 to 200 repeats
• Intermediate—45 to 54 repeats
• Unaected—fewer than 45 repeats.
Full mutations are expressed in all males and many emales.
Males with ull mutations typically have signicant cognitive and behavioral abnormalities and phenotypic eatures. In
emales, random X chromosome inactivation results in variable
expression, and the disability may be much less severe. With
rare exception, the parent o origin o repeat expansion that
leads to a ull mutation is emale (Monaghan, 2013).
Counseling or a premutation is more complex. Te woman
with a ragile X premutation may have ospring with the ull
mutation, and the risk ranges rom ≤5 percent with ewer than
70 CGG repeats to >95 percent with 100 to 200 CGG repeats
(Nolin, 2003). Expansion is extremely unlikely in a male premutation carrier, but all o his daughters will carry the premutation. Among women with no risk actors, approximately 1 in
250 carries a ragile X premutation, and in those with a amily
history o intellectual disability, the risk approximates 1 in 90
(Cronister, 2008).
Fragile X premutation carriers may themselves experience
signicant health consequences. Males with a premutation
are at risk or the ragile X tremor ataxia syndrome (FXAS),
which is characterized by memory loss, executive unction de-
cits, anxiety, and dementia (Monaghan, 2013). Females are at
decreased risk or FXAS, but they have a 20-percent risk or
ragile X-associated primary ovarian insufciency (POI).
Carrier screening is recommended or women with a amily history o ragile X syndrome, or those with unexplained
intellectual disability, developmental delay, or autism, and
or women with POI (American College o Obstetricians
and Gynecologists, 2020a). Prenatal diagnosis can be accomplished by amniocentesis or chorionic villus sampling. Either
type o specimen can be used to evaluate the CGG repeat number, but chorionic villus sampling may not accurately determine
FMR1 gene methylation status.
■ Imprinting
Usually, one copy o each gene is inherited rom each parent,
and both copies are expressed. Imprinting reers to the situation in which gene expression varies according to the parent
o origin. With maternal imprinting, a gene inherited rom the
mother is transcriptionally silent and the gene inherited rom
the ather is active. Paternal imprinting is the opposite. Tis
phenomenon explains the phenotypic dierences that occur in
triploid pregnancies according to whether the extra chromosomal set is maternal or paternal (p. 313).
Imprinting aects gene expression by epigenetic control,
that is, it modies the phenotype without altering the underlying genetic structure or genotype. Importantly, the eect may
be reversed in a subsequent generation, because a emale who
inherits an imprinted gene rom her ather will pass it in her
oocytes with a maternal—rather than paternal—imprint, and
vice versa.
An example o imprinting can be ound in two very dierent diseases associated with the same region o DNA. PraderWilli syndrome is characterized by pronounced hyperphagia
with obesity, along with short stature, small hands and eet,
and mild mental retardation. In more than 70 percent o cases,
Prader-Willi is caused by microdeletion or disruption o a
DNA segment on the paternal chromosome 15, 15q11.2-q13.
Te remaining cases are due to maternal uniparental disomy
or due to maternal gene imprinting with the paternal gene
inactivated.
In contrast, individuals with Angelman syndrome have normal stature and weight but severe intellectual disability, absent
speech, seizures, ataxia, jerky arm movements, and paroxysms
o inappropriate laughter. In approximately 70 percent o
cases, Angelman syndrome is caused by microdeletion or the
15q11.2-q13 DNA segment on the mother's chromosome 15.
Tis segment contains a gene that codes or ubiquitin protein
ligase E3A, an important neural protein. Paternal gene imprinting deects—with maternal genes inactivated—account or 2
to 3 percent, and 2 percent result rom paternal uniparental
disomy. Table 16-5 lists selected diseases that can involve
imprinting.
■ Uniparental Disomy
Tis occurs when both members o a chromosome pair are
inherited rom the same parent. Uniparental disomy usually
TABLE 16-5. Some Disorders That Can Involve Imprinting
Disorder
Chromosomal
Region
Parental
Origin
Angelman 15q11.2–q13 Maternal
Beckwith-Wiedemann 11p15.5 Paternal
Myoclonus-dystonia 7q21 Maternal
Prader-Willi 15q11.2–q13 Paternal
Pseudohypoparathyroidism 20q13.2 Variable
Russell-Silver syndrome 7p11.2 Maternal
Data from Johns Hopkins University, 2021.Genetics 323
CHAPTER 16
has no clinical consequences, because gene expression is not
generally aected by the parent o origin and because both copies o a chromosome pair are not usually identical. However,
i chromosomes 6, 7, 11, 14, or 15 are involved, ospring are
at increased risk or an abnormality because o parent-o-origin
dierences in gene expression, that is, because o imprinting
(Shaer, 2001). Several genetic mechanisms may cause uniparental disomy, the most common o which is trisomic rescue,
shown in Figure 16-9. Ater a nondisjunction event produces
a trisomic conceptus, one o the three homologues may be
lost, resulting in uniparental disomy or that chromosome in
approximately one third o cases.
Uniparental isodisomy occurs when an individual receives
two identical copies o one chromosome rom the same parent.
Tis mechanism has explained cases o cystic brosis in which
only one parent is a carrier but the etus inherits two copies o
the same gene mutation (Spence, 1988; Spotila, 1992).
■ Multifactorial Inheritance
raits or diseases that are determined by the combination o
multiple genes and environmental actors are considered to
have multiactorial inheritance (Table 16-6). Polygenic traits
are determined by the combined eects o more than one gene.
Many congenital and acquired conditions and common traits
display multiactorial inheritance. Examples include malormations such as neural-tube deects, cardiac deects, and acial
clets; diseases such as diabetes and atherosclerosis; and traits
such as head size or height. Multiactorial abnormalities tend
to recur in amilies, but not according to a mendelian pattern.
I a couple has had 1 child with a multiactorial birth deect,
the risk that another child will be aected is empirically 3 to 5
percent. Tis risk declines exponentially with successively more
distant amily relationships.
Multiactorial traits that have a normal distribution in the
population are termed continuously variable. A measurement that
is more than two standard deviations above or below the population mean may be considered abnormal. Continuously variable
traits tend to be less extreme in the ospring o aected individuals, because o the statistical principle o regression to the mean.
TABLE 16-6. Characteristics of Multifactorial Diseases
There is a genetic contribution
No mendelian pattern of inheritance
No evidence of single-gene disorder
Nongenetic factors are also involved in disease
causation
Lack of penetrance despite predisposing genotype
Monozygotic twins may be discordant
Familial aggregation may occur
Relatives are more likely to have disease-predisposing
alleles
Expression more common among close relatives
Greater concordance in monozygotic than dizygotic
twins
Becomes less common in less closely related relatives—
fewer predisposing alleles
Adapted from Nussbaum, 2016.
Normal Uniparental
disomy
Normal
A B
FIGURE 16-9 Mechanism of uniparental disomy arising from trisomic “rescue.” A. In normal meiosis, one member of each pair of homologous chromosomes is inherited from each parent. B. If nondisjunction results in a trisomic conceptus, one homologue is sometimes lost. In
a third of cases, loss of one homologue leads to uniparental disomy.324 The Fetal Patient
Section 6
Threshold Traits
Some multiactorial traits do not appear until a threshold is
exceeded. Genetic and environmental actors that create propensity or liability or the trait are themselves normally distributed, and only individuals at extremes o the distribution
exceed the threshold and exhibit the trait or deect. Te phenotypic abnormality is thus an all-or-none phenomenon.
Certain threshold traits have a clear male or emale predominance. I an individual o the less aected gender has the
characteristic or deect, the risk is greater in his or her ospring
(Fig. 16-10). An example is pyloric stenosis, which is approximately our times more common in males (Krogh, 2012). A
emale with pyloric stenosis has likely inherited more predisposing genetic actors than are necessary to produce the deect
in a male, and the recurrence risk or her children or siblings is
thus higher than the expected 3 to 5 percent. Her brothers and
sons would have the highest liability because they not only will
inherit more than the usual number o predisposing genes but
also are the more susceptible gender.
Te recurrence risk or threshold traits is also greater i the
deect is severe. For example, the recurrence risk ater the birth
o a child with bilateral clet lip and palate approximates 8 percent, but it is only about 4 percent ollowing a child with unilateral clet lip alone.
Cardiac Defects
Structural cardiac anomalies are the most common birth
deects, with a birth prevalence o 8 cases per 1000. Te risk o
having a child with a cardiac anomaly approximates 5 to 6 percent i the mother has the deect and 2 to 3 percent i the ather
is aected (Burn, 1998). Selected let-sided lesions, including
hypoplastic let heart syndrome, coarctation o the aorta, and
bicuspid aortic valve, may have recurrence risks our- to six-
old higher (Lin, 1988; Lupton, 2002; Nora, 1988). Observed
recurrence risks or specic cardiac malormations are listed in
able 52-4 (p. 920).
Neural-tube Defects
Risk or developing a neural-tube deect (ND) is inuenced by
amily history, hyperthermia, hyperglycemia, teratogen exposure, obesity, ethnicity, and etal gender. More than 50 years
ago, Hibbard and Smithells (1965) postulated that abnormal
olate metabolism was responsible or many NDs. However,
most ND cases do not occur in the setting o maternal olic
acid deciency, and it has become clear that the gene-nutrient
interactions underlying olate-responsive NDs are complex.
For a woman with a prior aected child, the 3- to 5-percent
recurrence risk declines by at least 70 percent with 4 mg/d
o periconceptional oral olic acid supplementation (Grosse,
2007; MRC Vitamin Study Research Group, 1991). Periconceptional olic acid supplementation also appears to ameliorate
the etal ND risk in women with pregestational diabetes and
in those with exposure to antiepileptic medications, ever during embryogenesis, and obesity (Kerr, 2017; Petersen, 2019).
Sonographic eatures o NDs are described in Chapter 15
(p. 276), their prevention with olic acid is discussed in Chapter
9 (p. 168), and etal therapy or myelomeningocele is reviewed
in Chapter 19 (p. 372).
GENETIC TESTS
All pregnant women should have the option o prenatal aneuploidy screening and prenatal genetic diagnosis (American College o Obstetricians and Gynecologists, 2018). Screening or
etal aneuploidy may be either serum analyte-based or cell-ree
DNA-based. Prenatal genetic carrier screening tests or cystic brosis and spinal muscular atrophy carrier status also are
routinely oered. Additional carrier screening tests are oered
to at-risk individuals. Expanded genetic carrier screening panels also are available. Te American College o Obstetricians
and Gynecologists considers ethnic-specic, panethnic, and
expanded carrier screening acceptable strategies (American College o Obstetricians and Gynecologists, 2020a). Tese screening tests are discussed in Chapter 17 (p. 342).
For prenatal genetic diagnosis, the most commonly used
tests are chromosomal microarray analysis (CMA), cytogenetic
analysis (karyotyping), and uorescence in situ hybridization
(FISH). esting may be perormed on amnionic uid or chorionic villi. In selected circumstances, whole genome or whole
exome sequencing may be considered, but these are not recommended or routine use. o diagnose a specic disease whose
genetic basis is known, DNA-based tests are oten employed,
typically using polymerase chain reaction (PCR) or rapid
amplication o DNA sequences.
■ Cytogenetic Analysis
Also known as karyotyping, cytogenetic analysis tests or
numerical chromosomal abnormalities—aneuploidy or polyploidy. It can also identiy balanced or unbalanced structural
rearrangements o at least 5 to 10 megabases in size. Karyotyping has diagnostic accuracy exceeding 99 percent.
Any tissue containing dividing cells or cells that can be stimulated to divide is suitable or cytogenetic analysis. Te dividing cells are arrested in metaphase, and their chromosomes are
stained to reveal light and dark bands. Te most commonly
used technique is Giemsa staining, which yields the G-bands
shown in Figure 16-3. Each chromosome has a unique banding pattern that permits its identication and detection o
Unaffected Affected
THRESHOLD
Males
Females
Population
Trait Liability
FIGURE 16-10 Schematic example of a threshold trait, such as
pyloric stenosis, which has a predilection for males. Each gender is
normally distributed, but at the same threshold, more males than
females will develop the condition.Genetics 325
CHAPTER 16
deleted, duplicated, or rearranged segments. Te accuracy o
cytogenetic analysis rises with the number o bands produced.
Metaphase banding routinely yields 450 to 550 visible bands
per haploid chromosome set, whereas prophase banding generally yields 850 bands.
Only dividing cells can be evaluated, so the growth o cultured cells aects the rapidity with which results are obtained.
Amnionic uid, which contains amniocytes, epithelial cells,
and gastrointestinal mucosal cells, will usually yield results in
7 to 10 days (Chap. 17, p. 344). Fetal blood cells may provide results in 36 to 48 hours but are rarely needed. I etal
skin broblasts are evaluated postmortem, stimulation o cell
growth can be more difcult. Cytogenetic analysis may take 2
to 3 weeks in such cases and has largely been replaced by CMA
(Chap. 35, p. 627).
■ Fluorescence In Situ Hybridization
Tis technique is most commonly used or rapid identication
o a specic chromosomal abnormality, such as trisomy 21, 18,
or 13. Because o its 1- to 2-day turnaround time, FISH is typically selected or cases in which ndings may alter pregnancy
management. It may also be used to veriy a suspected deletion syndrome, such as the 22q11.2 microdeletion (p. 315),
although CMA is preerred. Te American College o Obstetricians and Gynecologists (2018) recommends that decisionmaking based on FISH should incorporate clinical inormation
consistent with the suspected diagnosis. Supportive data may
be an abnormal aneuploidy screening test result, a sonographic
nding, or a conrmatory diagnostic test such as karyotyping
or CMA.
o perorm FISH, cells are xed onto a glass slide, and
uorescent-labeled probes are hybridized to the xed chromosomes (Fig. 16-11). Each probe is a DNA sequence that is complementary to a chromosome region or gene being investigated.
I the DNA sequence is present, hybridization is detected as a
bright signal visible by microscopy. Te number o signals indicates the number o chromosomes or genes o that type in the
cell. FISH does not provide inormation on the entire chromosomal complement but merely the chromosomal or gene region
o interest. Figure 16-12 shows an example o interphase FISH
using α-satellite probes or chromosomes 18, X, and Y to con-
rm trisomy 18.
■ Chromosomal Microarray Analysis
Tis test is 100 times more sensitive than karyotyping and
detects microduplications and microdeletions as small as 50
to 100 kilobases. Direct CMA, which is perormed on uncultured cells, can yield results in 3 to 7 days. I cultured cells are
required, results may take 10 to 14 days (American College o
Obstetricians and Gynecologists, 2018).
DNA
probe
DNA probe
labeled with
fluorescent dye
DNA denatured
and separated
Probe creation
Probe hybridized with
patient chromosomes
Fluorescent probe
illuminates chromosome
region of interest
FIGURE 16-11 Steps in fluorescence in situ hybridization (FISH).
Interphase FISH
Y Chromosome = Red
18 Chromosome = Light blue
X Chromosome = Green
FIGURE 16-12 Interphase fluorescence in situ hybridization (FISH)
using α-satellite probes for chromosomes 18, X, and Y. In this case,
the three light blue signals, two green signals, and absence of red
signals indicate that this is a female fetus with trisomy 18. (Reproduced with permission from Dr. Frederick Elder.)326 The Fetal Patient
Section 6
Microarrays use either a comparative genomic hybridization (CGH) platorm, a SNP platorm, or a combination o
the two. Te CGH microarray platorm compares specimen
DNA with a normal control sample. Shown in Figure 16-13,
the CGH chip contains reerence DNA ragments o known
sequence—oligonucleotides. Fetal DNA rom the amniocentesis or chorionic villus sampling specimen is labeled with a
uorescent dye and then hybridized to the DNA on the chip.
Normal control DNA is labeled with a dierent probe and also
hybridized to the same chip. Te intensity o the uorescent
signals rom the two samples is compared. With a SNP array,
the chip contains known DNA sequence variants, that is, singlenucleotide polymorphisms. When etal DNA is labeled and
hybridized to the chip, the uorescent signal intensity indicates
copy number variation.
Both types o platorms detect aneuploidy, unbalanced
translocations, and microdeletions and microduplications. In
addition, SNP arrays are able to identiy triploidy and can
detect absence o heterozygosity. Te latter can occur with uniparental disomy, in which both copies o a chromosome are
inherited rom one parent. Absence o heterozygosity may
also occur with consanguinity, and counseling prior to perormance o an SNP array should include this possibility (p. 321).
Importantly, neither type o array platorm currently detects
balanced chromosomal rearrangements. For this reason, couples
with recurrent pregnancy loss should be oered karyotyping as
the rst-line test (Society or Maternal-Fetal Medicine, 2016).
In addition to identiying pathogenic copy number variants, CMA may detect variants that are unable to be classied as
benign or pathologic and thus are considered to be o uncertain
clinical signicance. In recent series, these variants o uncertain
signicance are identied in approximately 1 percent o prenatal
specimens (Brady, 2014; Chong, 2019; Wang, 2018). Not unexpectedly, variants o uncertain signicance may be a source o
distress to amilies, even with comprehensive pretest counseling.
Clinical Applications
In pregnancies at increased risk or autosomal trisomy based
on aneuploidy screening results, karyotyping or FISH plus
karyotyping should be oered, and CMA should be made
available (American College o Obstetricians and Gynecologists, 2018). Clinicians are increasingly oering CMA in
this setting. I the karyotype is normal, CMA has identied
clinically relevant copy number variants in approximately 6.5
percent o pregnancies with etal abnormalities and in 1 to 2
percent o those without obvious etal abnormality (Callaway,
2013; Chong, 2019). Te American College o Obstetricians
and Gynecologists (2018) and the Society or Maternal-Fetal
Medicine (2016) recommend CMA as the rst-tier test when
etal structural abnormalities are identied. I a particular
1.28 cm
1.28 cm
Actual size of chip
500,000 cells on each chip
One cell on chip
Nonhybridized
DNA
Hybridized DNA
A
B
C
D E
F
Thousands of identical nucleotide
strands on one cell
Labeled fetal DNA is presented
to the cells
FIGURE 16-13 Chromosomal microarray analysis. A. Actual microarray chip size. B. Each chip contains thousands of cells (squares).
C & D. Each cell contains thousands of identical oligonucleotides on its surface and is unique in its nucleotide content. E. During genetic
analysis, a mixture containing tagged fetal DNA is presented to the chip. Complementary DNA sequences bind. F. If a laser is shined on the
chip, DNA sequences that have bound will glow thus identifying a matching sequence. (Modified with permission from Doody KJ: Treatment
of the infertile couple. In Hoffman BL, Schorge JO, Schaffer JI, et al (eds): Williams Gynecology, 2nd ed. New York, NY: McGraw Hill; 2012.)Genetics 327
CHAPTER 16
anomaly that strongly suggests a specic aneuploidy is identied, such as an endocardial cushion deect (trisomy 21)
or alobar holoprosencephaly (trisomy 13), then karyotyping
or FISH may be oered as the initial test. Genetic counseling should include inormation regarding the benets and
limitations o both CMA and karyotyping. Each should be
made available to women who elect prenatal diagnosis (Society or Maternal-Fetal Medicine, 2016). CMA may identiy
instances o autosomal dominant genetic disorders that have
not yet maniested in an aected parent, and it may also
identiy instances o nonpaternity.
For stillbirth evaluation, CMA is signicantly more likely
than standard karyotyping to provide a genetic diagnosis, in
part because it does not require dividing cells. Te Stillbirth
Collaborative Research Network ound that when karyotyping
was uninormative, approximately 6 percent o cases had either
aneuploidy or a pathogenic copy number variant identied
with CMA (Reddy, 2012). In a recent metaanalysis o more
than 900 stillbirths with normal karyotype, CMA identied
pathogenic copy number variants in 6 percent with structural
abnormalities and 3 percent with no abnormalities evident
(Martinez-Portilla, 2019). Overall, CMA yielded results 15
percent more oten than karyotyping alone.
■ Whole Genome and Whole Exome
Sequencing
Most etuses with structural abnormalities have a normal
karyotype and a normal CMA result. Whole genome sequencing (WGS) is a technique or analyzing the entire genome.
Whole exome sequencing (WES) analyzes only the DNA coding regions, which account or approximately 1.5 percent o the
genome. Tese next-generation sequencing tools are increasingly used postnatally to evaluate suspected genetic syndromes
and intellectual disability.
Several prospective, multicenter series have evaluated WES
or pregnancies in which etuses have structural abnormalities,
no karyotypic evidence o aneuploidy, and normal CMA. WES
identied genetic abnormalities in approximately 10 percent
o such cases (Lord, 2019; Petrovski, 2019). Utility was higher
in cases with cardiac, skeletal, or multiorgan system anomalies.
Importantly, WGS and WES have signicant limitations in
their current orm. Tese include prohibitively long turnaround
times, high costs, and increased rates o alse-positive and alsenegative results and variants o uncertain signicance (American
College o Medical Genetics, 2012; Atwal, 2014). In addition,
because sequencing is generally perormed on the etus and parents simultaneously, one parent may be identied or suspected
to have an unrelated but medically actionable nding, which
urther complicates counseling (American College o Obstetricians and Gynecologists, 2020c). As a result, the clinical utility
o this promising technology or prenatal cases is currently limited, and it is not recommended or routine clinical use.
■ Fetal DNA in the Maternal Circulation
Fetal cells are present in maternal blood at a very low concentration, only 2 to 6 cells per milliliter (Bianchi, 2006). Intact
etal cells sometimes persist in the maternal circulation or
decades ollowing delivery. Persistent etal cells may engrat in
the mother, causing microchimerism (Chap. 62, p. 1109). Tis
has been implicated in maternal autoimmune diseases such as
scleroderma, systemic lupus erythematosus, and Hashimoto
thyroiditis (Kinder, 2017). From the standpoint o prenatal
diagnosis, use o intact etal cells rom maternal blood is limited by low cell concentration, cell persistence into successive
pregnancies, and difculties in distinguishing etal and maternal
cells. Cell-ree DNA overcomes these limitations.
Cell-free DNA
Also known as cell-ree etal DNA or noninvasive prenatal
screening (NIPS), this screening test uses DNA ragments
derived rom maternal cells and rom apoptotic placental trophoblast cells. “Fetal” is thus a misnomer. Cell-ree DNA is
reliably detected in maternal blood ater 9 to 10 weeks’ gestation (Bianchi, 2018). Te proportion o total cell-ree DNA
that is placental is called the etal raction, and it accounts or
approximately 10 percent o the total circulating cell-ree DNA
in maternal plasma. Unlike intact etal cells, cell-ree DNA is
cleared within minutes rom maternal blood.
Current clinical applications o cell-ree DNA are aneuploidy screening and Rh D genotyping (Fig. 16-14). Commercial laboratories have also oered two other applications
o cell-ree DNA: (1) screening or selected microdeletion and
microduplication syndromes and (2) genome-wide screening
or deletions and duplications larger than 7 megabase pairs.
Currently, prospective data on these promising applications
are limited, and neither is recommended or routine screening
(American College o Obstetricians and Gynecologists, 2020c).
Additional applications or cell-ree DNA are on the horizon. In research settings, numerous single-gene disorders have
been detected and include skeletal dysplasias, hemoglobinopathies, cystic brosis, congenital adrenal hyperplasia, hemophilia,
muscular dystrophy, myotonic dystrophy, and spinal muscular
atrophy (Camunas-Soler, 2018; Jenkins, 2018; Zhang, 2019).
Aneuploidy Screening. Several dierent assay platorms are
used to screen or etal autosomal trisomies and sex chromosomal aneuploidies. Tese include massively parallel sequencing,
which is a WGS technique; chromosome-selective or targeted
sequencing; and analysis o SNPs (American College o Obstetricians and Gynecologists, 2018, 2020c). By simultaneously
sequencing millions o chromosome-specic DNA ragments,
investigators can identiy whether the proportion or ratio o
ragments rom one chromosome is higher than expected. Tus,
samples rom women with a Down syndrome etus will have
a larger proportion o DNA sequences rom chromosome 21.
Te screening perormance o cell-ree DNA is excellent. In
a metaanalysis o 35 studies o largely high-risk pregnancies,
the pooled sensitivity to detect Down syndrome was 99.7 percent, and to identiy trisomies 18 and 13, 98 and 99 percent,
respectively (Gil, 2017). For each, the specicity was at least
99.9 percent, such that the cumulative alse-positive rate was
below 1 percent. Aneuploidy screening reports commonly include
inormation about etal sex, which may be clinically useul i
the etus is at risk or an X-linked disorder or or congenital
adrenal hyperplasia (Chap. 17, p. 335). In a metaanalysis, the328 The Fetal Patient
Section 6
sensitivity o cell-ree DNA testing or etal sex determination
was reported to be 95 percent between 7 and 12 weeks’ gestation and 99 percent ater 20 weeks (Devaney, 2011).
Causes o alse-positive and alse-negative screening results are
listed in Table 16-7. As with any other screening test, diagnostic conrmation should be perormed beore irreversible medical
intervention. Cell-ree DNA screens do not yield a result in 2 to
4 percent o cases. Tis may be due to assay ailure, high assay
variance, or low etal raction (Norton, 2012; Pergament, 2014;
Quezada, 2015). Importantly, such pregnancies carry a greater
risk or etal aneuploidy. In addition, results may not reect the
etal DNA complement but rather may indicate conned placental mosaicism, early demise o an aneuploid co-twin, maternal mosaicism, or rarely, occult maternal malignancy (Bianchi,
2015; Curnow, 2015; Grati, 2014b; Wang, 2014). Recommendations or counseling are discussed in Chapter 17 (p. 336).
Rh D Genotype Evaluation. Many etuses o Rh D-negative
women are also Rh D-negative. In a predominantly white
population, this prevalence approaches 40 percent. Fetal Rh D
genotype assessment rom maternal blood can eliminate administration o anti-D immune globulin in such cases, thereby
reducing costs and potential risk. When Rh D alloimmunization is suspected, early identication o an Rh D-negative etus
might avoid unnecessary middle cerebral artery Doppler assessment or amniocentesis. Evaluation using cell-ree DNA is done
using real-time PCR to target several exons o the RHD gene,
typically exons 4, 5, 7, and 10.
Rh D-genotyping is perormed routinely with cell-ree
DNA in Denmark, Finland, and the Netherlands (Clausen,
2012; de Haas, 2016; Haimila, 2017). In population-based
studies o more than 35,000 Rh D-negative women screened
at 24 to 27 weeks’ gestation, the alse-negative rate—in which
Rh D-negative status was missed—was only 0.03 percent.
Te alse-positive rate—in which Rh immune globulin would
be given unnecessarily—was less than 1 percent (de Haas,
2016; Haimila, 2017). Similar results were reported rom the
United Kingdom, although the alse-negative rate was higher
in the rst trimester. Investigators concluded that alse-negative screening results might increase the alloimmunization
risk but by less than 1 case per million births (Chitty, 2014).
Rh D alloimmunization is discussed in Chapter 18 (p. 353).
TABLE 16-7. Selected Etiologies Creating Inaccurate
Cell-free DNA Results
Abnormality not detected—false negative
Low fetal fraction
Fetal chromosomal abnormality
Multifetal gestation
Maternal obesity
Low-molecular-weight heparin
Confined placental mosaicism (normal placenta,
aneuploid fetus)
Normal fetus but abnormal screen—false positive
Confined placental mosaicism (normal fetus, aneuploid
placenta)
Multifetal gestation with loss of aneuploid fetus
Maternal aneuploidy (e.g. 47,XXX)
Maternal mosaicism (e.g. 46,XX/45,X) or fetal mosaicism
Maternal cancer (lymphoma, breast, colon, leukemia,
others)
Vitamin B12 deficiency
Data from Bianchi, 2018.
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