CHAPTER 2

Non-Mendelian Genetics
SUSAN KLUGMAN, MD • SARA SCHONFELD RABIN-HAVT, MD

INTRODUCTION in a variety of largely neurologic conditions. Typically,

Mendel wrote in 1865 that when crossing plants, the age of onset is earlier and/or the symptoms are
“numerous experiments have demonstrated that the more severe with increasing number of repeats.
common characters are transmitted unchanged to the
hybrids and their progeny.”1 Mendel described that WHAT ARE EXAMPLES OF DISORDERS DUE
“common characters,” or genes, are passed unchanged TO HEREDITARY UNSTABLE DNA REPEATS?
from the parent to the offspring, and therefore Fragile X Syndrome
Mendelian patterns of inheritance are very predictable.1 Fragile X syndrome is the most common inherited form of
Classically, these include single-gene disorders that intellectual disability, with a prevalence of approximately
follow autosomal dominant, autosomal recessive, and 16–25/100,000 in males and half of that for females.3,4
X-linked inheritance patterns. Non-Mendelian patterns Clinical characteristics can be variable and include
of inheritance are seen with disorders that occur due intellectual disability, which is typically moderate for
to hereditary unstable DNA repeats, parent-of-origin males and more mild for females. Males with fragile X
specific disorders, mitochondrial disorders, mosaicism, syndrome have characteristic facial features, connective
and a broad category of disorders with complex, mul- tissue findings such as lax joints, and macroorchidism,
tifactorial patterns of inheritance. It is important to although some have few or no physical findings. About
remember, however, that even with Mendelian disor- 25% of individuals with fragile X syndrome also meet
ders, while the genes may be transmitted unchanged, criteria for autism spectrum disorder (ASD).
the disease phenotype may not follow a predictable Fragile X syndrome is a trinucleotide repeat dis-
pattern because of variable expressivity and/or reduced order that results from expansion of a trinucleotide
penetrance. cytosine-guanine-guanine (CGG) segment of DNA of
the fragile X mental retardation 1 (FMR1) gene on the
long arm of the X chromosome (Xq27.3). If the region
WHAT ARE HEREDITARY UNSTABLE DNA expands to include greater than 200 CGG repeats, this
REPEAT DISORDERS? leads to hypermethylation and inactivation of the gene
Variants that follow Mendelian patterns of inheritance product (fragile X mental retardation protein), which
are, in most cases, unchanged when passed from par- is expressed in many tissues but most abundantly in
ent to offspring. Diseases that occur due to hereditary neurons.2
unstable DNA repeat expansions do not follow this Normally, noncarrier individuals have fewer than 45
rule. These conditions are a group of approximately 20 CGG repeats in this gene; the average is approximately 29
neurodevelopmental disorders that include fragile X repeats. Individuals with 55–200 repeats are referred to
syndrome, Huntington disease, Friedreich ataxia, and as “premutation carriers” and are at risk of expansion
myotonic dystrophy (DM1 and DM2)2 (Table 2.1). For to a full mutation (more than 200 repeats) in their off-
some disorders, the unstable repeat sequence is within spring (Fig. 2.1). Although premutation carriers have a
the transcribed region of the gene, and for others, the 50% chance of passing on the abnormal allele, whether
expansion is in the noncoding region. The inheritance it expands to a full mutation and results in a child with
pattern of these disorders is characterized by unstable fragile X syndrome depends on the size of the premuta-
transmission and so-called genetic anticipation, in tion. The chance of expansion of the gene, if it is passed
which the length of the segment including the repeats on, ranges from about 3% with premutations that are
increases in size with subsequent generations. Expansion 55–65 repeats, to nearly 100% if the premutation is larger
of the repeats, which are in most (but not all) cases tri- than 100 repeats. Although premutation size alleles can
nucleotide repeats, can disrupt gene function and result be present in either parent, they only expand when passed
Perinatal Genetics. https://doi.org/10.1016/B978-0-323-53094-1.00002-3
Copyright © 2019 Elsevier Inc. All rights reserved. 11
12 Perinatal Genetics

TABLE 2.1
Examples of Unstable DNA Repeat Disorders
Disorder Symptoms Repeats (Gene) Effect of Repeats
Fragile X syndrome ID, ASD, dysmorphic facial CGG n ≥ 200 (FMR1) Methylation and silencing of
features gene
Myotonic Dystrophy 1 Muscle weakness and CTG n ≥ 50 (DMPK) Repeats bind to RNA-binding
Myotonic Dystrophy 2 wasting CCTG n ≥ 75 (CNBP) proteins
Huntington Disease Neurodegenerative disorder, CAG n ≥ 40 (HTT) Repeats lead to mutant
­chorea, death protein
Spinocerebellar ataxia Ataxia, dysarthria, bulbar CAG ≥ 39 in (ATXN1) Repeats lead to abnormal
Type 1 (SCA1) dysfunction protein

ASD, atrial septal defect; DNA, deoxyribonucleic acid; RNA, ribonucleic acid.

Fragile X syndrome in both men and women. Female premutation carriers

are at risk for premature ovarian insufficiency (POI),
CGG repeats
p q (FMR1, Xq27)
defined as menopause earlier than 40 years old.6 Male,
and sometimes female, premutation carriers are also
at risk for fragile X–­associated tremor/ataxia syndrome
(FXTAS), a progressive, neurodegenerative disease that
Normal
5-44 can lead to cerebellar symptoms and memory loss,
as well as other neurologic deficits that increase with
45-54 Intermediate
age.2 Individuals who have fragile X syndrome do not
55-200 Premutation
develop ataxia—it only affects premutation carriers.
Testing for fragile X syndrome can be performed on
>200
DNA from blood (to identify female carriers or affected
Pathologic
individuals) or on amniotic fluid or chorionic villi (to
identify affected fetuses) through a combination of
http://www.genetics4medics.com/fragile-x-syndrome.html
polymerase chain reaction (PCR) and Southern blot
FIG. 2.1 Fragile X syndrome (http://www.genetics4me analysis.7 Ideally, carrier screening for fragile X syn-
dics.com/fragile-x-sydrome.html). Clinical significance of drome should be done in the preconception period,
increasing number of CGG repeats in the fragile X mental although it can also be performed during pregnancy.
retardation 1 (FMR1) gene. Individuals with 6–44 repeats The American College of Obstetricians and Gynecolo-
are unaffected, those with 45–54 are in an intermediate
gists (ACOG) recommends carrier screening for fragile
range, 55–200 are premutation carriers, and >200 repeats
is a full mutation and is associated with the syndrome.
X syndrome for women who are pregnant or consider-
ing pregnancy who have a family history of a fragile X–
related disorder or of intellectual disability.8 ACOG also
on by the mother and are stable in size when passed on recommends testing for fragile X syndrome for women
by the father.5 Individuals with 45–54 repeats are referred with unexplained premature ovarian failure or insuffi-
to as intermediate or “gray zone” carriers, as their gene ciency, but at the present time, ACOG does not recom-
may expand to the carrier or premutation size range but mend universal screening for fragile X syndrome.8
will not expand to a full mutation. Therefore, they are at
risk to have grandchildren with fragile X syndrome, but Myotonic Dystrophy
not ­children. Expansion of less than 55 repeats to a full Myotonic dystrophy 1 (DM1) is a neuromuscular condi-
mutation has not been reported in a single generation. In tion with symptoms that include muscle spasm (myo-
families affected by fragile X syndrome, it is common to tonia) and muscle weakness. It affects a variety of organ
see more affected family members in subsequent genera- systems, leading to cardiac conduction defects, tes-
tions due to genetic anticipation. ticular atrophy, insulin resistance, cataracts, and in the
Unlike most autosomal recessive diseases, there congenital form, intellectual disability. The pathogen-
are risks associated with being a premutation carrier esis of DM1 is expansion (to 50 repeats or greater) of a
 CHAPTER 2 Non-Mendelian Genetics 13

cytosine-thymine-guanine (CTG) repeat in the 3′ untrans- WHAT ARE IMPRINTING DISORDERS AND
lated region of the DMPK gene. DM1 has a severe, lethal UNIPARENTAL DISOMY?
congenital form that includes severe neonatal hypotonia Genomic imprinting and uniparental disomy (UPD)
and weakness, respiratory failure, death, and intellectual refer to the genetic parent-of-origin and are relevant
disability in those that survive the neonatal period. to a specific group of genes that have different func-
Myotonic dystrophy 2 (DM2) shares many of the tion depending on whether they were inherited from
clinical features of DM1 but occurs due to a tetranu- the mother or the father. Mendelian patterns of inher-
cleotide (CCTG) repeat expansion in the gene CNBP. itance typically dictate that we receive one copy of
Clinically, the presentations of DM1 and DM2 are each of our genes from each of our parents and, usu-
very similar, except that DM2 does not have a con- ally, that they are both equally active or functional.
genital form. With both forms of myotonic dystro- However, there are times when only the maternal or
phy, the chance of passing on the abnormal allele is paternal copy is active (because of genomic imprint-
50%, so the genetics are similar to classical autoso- ing). A number of different genetic conditions result
mal dominant inheritance. However, the expansion from situations in which the normal active gene is not
demonstrates anticipation and increased severity of present, because of either a deletion of the active gene
symptoms with repeat size and through generations, or the presence of two copies of the inactive form of
as is seen with other trinucleotide repeat disorders. the gene.
The congenital form of myotonic dystrophy results Genomic imprinting is a process whereby methyla-
from anticipation and expansion to greater than 1000 tion (the addition of methyl groups to DNA during
repeats. There is also a mild, late onset adult form, a oogenesis or spermatogenesis) deactivates one copy of
more classical adult form, as well as a childhood form. a gene. It is not entirely understood why some genes
function differently when they are paternally or mater-
Huntington Disease nally inherited.10 However, for a number of genes,
Huntington disease is a neurodegenerative disorder that only the maternal or paternal copy is active because
follows an autosomal dominant pattern of inheritance, of genomic imprinting. Many imprinted genes affect
leading to chorea, uncontrolled limb writhing move- fetal and/or postnatal growth. For example, macroso-
ments, psychiatric abnormalities, dementia, and death mia is seen in Beckwith-Wiedemann syndrome and
usually by age 60 years.9 In this disorder, the expanding fetal growth restriction seen in Russell-Silver syn-
repeat sequence is a cytosine-adenine-glycine (CAG) drome. Approximately 80% of imprinted genes are
repeat (to greater than or equal to 40 repeats) in the HTT found in clusters on specific regions of chromosomes,
gene. When this expansion occurs, it results in forma- and about 75 imprinted genes have been identified in
tion of an abnormal form of a protein called huntingtin humans.10
that becomes toxic to neurons. As with other trinucleo- Uniparental disomy occurs when both copies of the
tide repeat disorders, Huntington disease demonstrates same chromosome are inherited from one parent.
anticipation, with increasing number of repeats seen in UPD can happen due to trisomic rescue, when a zygote
subsequent generations and associated with younger with trisomy loses the extra chromosome. Although
age of onset. Inheritance through the father can lead to the embryo is no longer trisomic, if the two remain-
greater repeat expansion and earlier onset of symptoms. ing chromosomes were inherited from the same par-
Huntington disease is 100% penetrant, and essentially ent, UPD will result. In many cases, UPD has no effect
all affected individuals develop symptoms, usually at the because most genes do not undergo genomic imprint-
same age or somewhat earlier than their affected parent. ing (i.e., both copies are active and there is no conse-
In most cases, individuals do not become symptomatic quence if both copies come from the same parent).
until age 40 years or older, generally after they have had However, in cases of an imprinted gene, UPD may lead
children. Many patients wish to have unaffected chil- to loss of function of a gene. For example, if imprint-
dren but prefer not to learn their own status given that ing normally deactivates the maternal copy of the gene
treatment is not available. In such situations, a form of and the embryo is left with two copies of the maternal
nondisclosure preimplantation genetic testing can be per- gene, there will be no active copies,12 and therefore,
formed, in which only unaffected embryos are implanted, no functional gene. UPD can also result in unmask-
but the parents are not informed as to whether any of the ing of an autosomal recessive disorder if, for example,
embryos are affected. It is also possible in some cases to the mother carries a recessive condition (such as cystic
perform prenatal diagnosis through linkage analysis with- fibrosis) and the fetus has UPD for the chromosome
out revealing the status of the parent. carrying that gene. Even if the father is not a carrier, if
14 Perinatal Genetics

TABLE 2.2
Imprinting Disorders
Disorder Symptoms Region Parent-of-Origin Defect
Prader-Will syndrome Mild ID, obesity, hypogonadism 15q11-13 Paternal
Angelman syndrome Severe ID, seizures, developmental delay 15q11-13 Maternal
Beckwith-Wiedemann Macrosomia, macroglossia, omphalocele, 11p15 Maternal
syndrome predisposition to embryonic tumors
Russell-Silver ­syndrome Intrauterine growth restriction, poor postna- 11p15.5 Paternal
tal growth, triangular faces, developmental
delay, learning disabilities

both copies of the gene are inherited from the mother Prader-Willi syndrome : Genetic mechanisms
and she is a carrier, the fetus may be affected.
A classic example of UPD that obstetrician-­ P M P M M M P M
gynecologists encounter is complete hydatidiform
mole, which affects about 1 in 1500 pregnancies.11
Hydatidiform moles have 46 chromosomes, all of 15q13
paternal origin. Partial moles, in contrast, demon-
strate triploidy and have 69 chromosomes (typically
23 of maternal and 46 of paternal origin).

WHAT ARE EXAMPLES OF DISORDERS Normal Paternal Maternal Imprinting

deletion UPD Defects
THAT OCCUR DUE TO IMPRINTING AND (65-75%) (20-30%) (2-5%)
UNIPARENTAL DISOMY?
FIG. 2.2 Genetic mechanisms of Prader-Willi syndrome
Prader-Willi Syndrome
(http://www.genetics4medics.com/prader-willi-sydrome.html).
Prader-Willi syndrome affects approximately 1 in Schematic depiction of the chromosomal basis of Prader-
10,000–30,000 individuals.13 It is characterized by Willi syndrome (PWS). Different mechanisms can lead to lack
hypotonia and failure to thrive in infancy, progress- of expression of the paternal chromosome 15q11-q13 and
ing to developmental delay, short stature, rapid cause PWS. M, maternal; P, paternal. http://www.genetics4
weight gain and obesity due to hyperphagia (exces- medics.com/prader-willi-sydrome.html.
sive appetite), and intellectual disability. Prader-Willi
syndrome is caused by loss of function of specific
paternally derived genes on chromosome 15. Several Angelman Syndrome
different mechanisms can lead to the loss of the pater- Angelman syndrome has a prevalence of 1 in 12,000–
nal copy of these genes. Most cases (70%) are due to a 24,000 and is characterized by severe intellectual dis-
deletion of a segment of paternal chromosome 15. In ability, developmental delay, seizures, and difficulty
30% of cases, there are no paternal genes because of with balance and walking.14 Angelman syndrome
maternal uniparental disomy, in which two maternal results from abnormalities in the same gene region as
copies, and no paternal copies, of chromosome 15 are Prader-Willi syndrome but occurs due to loss of the
present. In rare cases, Prader-Willi syndrome can be maternal contribution, with only the paternal genes
caused by a chromosomal translocation, an imprint- present. This can occur from multiple genetic mecha-
ing defect or even a single gene mutation. Patients nisms that lead to lack of the maternally derived active
with a family history of Prader-Willi syndrome can gene, including a deletion, paternal UPD, an imprint-
be reassured that there is usually no increased risk to ing error, or a single-gene mutation of the maternal
their children given that in most cases this condition copy of the gene2 (Table 2.3). In contrast to the mild
is caused by a random error of oogenesis or spermato- intellectual disability seen with Prader-Willi syn-
genesis (see Fig. 2.2; Table 2.3). drome, patients with Angelman syndrome have severe
 CHAPTER 2 Non-Mendelian Genetics 15

and it is thought to result from abnormal regulation

TABLE 2.3
in certain genes that control growth. In most cases, it
Genomic Mechanisms Causing Prader-Willi and
is caused by either an imprinting defect at 11p15.5 or
Angelman Syndrome
maternal UPD of chromosome 7.
Prader-Willi Angelman
Mechanism Syndrome Syndrome
15q11.2-q13 ∼70% (paternal) ∼70% (maternal) WHAT IS MULTIFACTORIAL INHERITANCE?
deletion Multifactorial inheritance refers to disorders caused by
Uniparental ∼20–30% ∼7% (paternal) multiple genes and environmental factors. This group
disomy (­maternal) of disorders includes a broad range of medical (cardiac
disease and diabetes), congenital (birth defects includ-
Imprinting center ∼2.5% ∼3%
mutation ing cardiac malformations, neural tube defects, and cleft
lip and/or palate), and neuropsychiatric (ASD, schizo-
Gene mutations Rare ∼10% (UBE3A
phrenia, bipolar disorder) diseases. Family and twin
mutations)
studies have shown that these diseases have a genetic
Unidentified <1% ∼10% component; however, it is also clear that there are envi-
ronmental contributors. Sometimes, gender can affect
Data from Cassidy SB, Schwartz S, Miller JL, et al. Prader -Willi
syndrome. Genet Med. 2012;14:10–26; Dagli AI, Williams CA.
inheritance. For example, research has shown that a
Angelman syndrome. In: Pagon RA, Adam MP, Bird TD, et al, eds. male sibling is more likely to be diagnosed with ASD if
GeneReviews [Internet]. University of Washington, Seattle: Seattle; a sibling has been diagnosed.18 Many neuropsychiatric
1993–2013. http://www.ncbi.nlm.nih.gov/books/NBK1144/. diseases and birth defects demonstrate complex multi-
factorial inheritance (Table 2.4; Reprinted with permis-
developmental delay, intellectual disability, and speech sion, originally Box 1 in ACOG Technology Assessment
impairment. Patients with Angelman syndrome also in Obstetrics and Gynecology No. 11: Genetics and
exhibit a characteristic behavioral pattern of inappro- Molecular Diagnostic Testing [Reference #7])
priate laughing, smiling, and excitability.14

Beckwith-Wiedemann Syndrome WHAT ARE EXAMPLES OF DISORDERS

Beckwith-Wiedemann syndrome is characterized by over- THAT EXHIBIT MULTIFACTORIAL
growth due to excess IGF2 expression (which regulates INHERITANCE?
growth). It is associated with macrosomia, an enlarged Neuropsychiatric Disorders
placenta, macroglossia, cardiomyopathy, and a predis- Neuropsychiatric disorders, although common (with a
position to development of embryonal tumors (includ- prevalence of 4%), present a challenge for counseling on
ing Wilms tumor and hepatoblastoma). An increased recurrence risk because of their multifactorial etiology.2
risk for Beckwith-Wiedemann syndrome, as well as for Major depressive disorder, bipolar disorder, and schizo-
Angelman syndrome, both of which can arise due to phrenia are examples of diseases that commonly affect
a maternal imprinting defect, has been observed after reproductive-age women, and therefore OB/GYN provid-
use of assisted reproductive technology (ART), spe- ers will often be involved in their diagnosis and manage-
cifically IVF and intracytoplasmic sperm injection.15 ment. Twin and family studies have shown that there is
In one study of nearly 380,000 live births, the risk of a genetic component to schizophrenia, as monozygotic
Beckwith-Wiedemann was 10-fold higher in patients twins are four to six times more likely to be affected than
conceived through ART.16 It is thought that there is no dizygotic twins. First- and second-degree relatives of indi-
increased risk of Prader-Willi syndrome with IVF given viduals with schizophrenia are more likely to be affected,
that paternal imprinting takes place well before IVF.2 with a recurrence risk of 8%–46% for first-degree relatives
As the use of ART advances, more research is needed to and 1%–8% for second-degree relatives2 (see Table 2.4).
clarify the cause and magnitude of these risks. Prenatal diagnosis for most multifactorial dis-
eases is not available, and the same is true for neuro-
Russell-Silver Syndrome psychiatric diseases. At this time, a few specific genes
Russell-Silver syndrome has a prevalence of approximately that contribute to neuropsychiatric diseases have been
1:100,00017 and is characterized by fetal growth restric- identified,2 for example, genetic deletions such as the
tion, postnatal growth restriction, and dysmorphism. 22q11 deletion syndrome. 22q11 deletion syndrome
The genetics of Russell-Silver syndrome are complex, can be detected prenatally by chromosomal microarray
16 Perinatal Genetics

contrast, are typically not caused by genetic intrinsic fac-

TABLE 2.4
tors but by physical constraints (such as contractures due
Characteristics of Multifactorial Inheritance
to preterm premature rupture of membranes [PPROM] or
• Disorder is familial, but pattern of inheritance is not oligohydramnios) or destruction of normal tissue (such
apparent as an amputation due to amniotic bands). Deformations,
• Risk to first-degree relatives is the square root of the as opposed to malformations or disruptions, can some-
population risk times resolve after birth.
• Risk is significantly decreased for second-degree There are multiple genetic contributors to birth
relatives defects. Approximately one-quarter of all birth defects
are due to aneuploidy, 10% are due to copy number
• Recurrence risk is increased if more than one family
variants identifiable by CMA, and 20% are due to
member is affected
mutations in single genes (such as in achondroplasia
• Risk is increased if the defect is more severe (e.g., or Smith-Lemli-Opitz syndrome)2 (Fig. 2.3). The other
recurrence risk for bilateral cleft lip is higher than 40% of birth defects are multifactorial—there is no
unilateral cleft lip)
obvious genetic etiology, but recurrence risk is higher
• If the defect is more common in one sex than in the in families than would be expected in the general pop-
other sex, the recurrence risk is higher if the affected ulation. Some examples of this include cleft lip with
individual is of the less commonly affected sex or without cleft palate, congenital heart defects, and
Reprinted with permission from Genetics and Molecular Diagnostic
neural tube defects (Table 2.5). For most multifactorial
Testing. Technology assessment in obstetrics and gynecology. disorders, the risk to a sibling is about 3%–4% (10%
No. 11. American College of Obstetricians and Gynecologists. with two affected siblings), the risk to a second-degree
Obslet Gynecol. 2014;123(2):394–413. https://doi.org/10.1097/01. relative (uncle, aunt, nephew, or niece) is about 0.5%,
AOG.0000443280.91145.4f.
and the risk to a third-degree relative (first cousin) is
about 0.17%.20,21
(CMA) or fluorescence in situ hybridization (FISH)
through chorionic villus sampling or amniocentesis.
Although 22q11 deletion accounts for less than 2% of WHAT IS MITOCHONDRIAL INHERITANCE?
schizophrenia, 25% of patients with 22q11 deletion Mitochondrial diseases, although rare, have a unique
syndrome develop schizophrenia. Other deletions and inheritance pattern and can present in a wide range
duplications that are detectable with CMA have also of organ systems and diseases. Mitochondria are the
been associated with a variety of psychiatric disorders. organelles in each of the body’s cells that are respon-
sible for energy production and aerobic respiration.
Birth Defects Although the majority of human DNA is contained in
Birth defects (congenital anomalies) are abnormalities the nucleus of the cell, mitochondria contain their own
in the development of organs or structures that are pres- DNA, which encodes 37 genes. Mitochondrial disorders
ent at birth.2 Structural birth defects represent a com- can present at any age but often present in infancy with
mon yet complex multifactorial group of disorders that hypotonia, failure to thrive, and neurodegeneration.
obstetrical providers often encounter. They are a major According to the Society for Inherited Metabolic
cause of infant morbidity and mortality, and 20% of Disorders, mitochondrial diseases can present with any
infant deaths are due to birth defects and genetic dis- symptom, in any organ system, and at any age. Mitochon-
orders.19 Congenital disorders also contribute to both dria, and therefore mitochondrial defects, are inherited
physical and intellectual disability and morbidity.2 maternally. Each human oocyte contains approximately
Counseling regarding recurrence risk of birth defects 100,000 mitochondria, whereas the 100 mitochondria
is challenging because of the varied etiologies (genetic, found in sperm are eliminated during fertilization.5 This
environmental, or a combination). is referred to as matrilineal inheritance. Mitochondrial
Birth defects can be grouped into three classes based diseases can develop if an oocyte that contains mutated
on their etiology: malformations, deformations, and mitochondrial DNA is fertilized. Although both male
disruptions. Malformations are due to intrinsic genetic and female offspring of an affected female will inherit
mutations and are therefore often associated with other the disease, in general, the offspring of an affected male
malformations (due to an intrinsic abnormality of a devel- will not inherit the disease as the male does not contrib-
opmental pathway). One example is congenital heart ute mitochondria to his offspring.
malformations in association with aneuploidy such as tri- Because mitochondria play a key role in energy
somies 21, 18, and 13. Deformations and disruptions, by production, mitochondrial diseases primarily affect
 CHAPTER 2 Non-Mendelian Genetics 17

Teratogen Chromosome
5% imbalance
25%

Multifactorial
40%
Copy number
variants
10%

Single-gene
defects
20%
FIG. 2.3 The relative contribution of single-gene defects, chromosome abnormalities, copy number variants,
multifactorial traits, and teratogens to birth defects. (Reprinted from Nussbaum RL, McInnes RR, Huntington
FW. Thompson & Thompson Genetics in Medicine; 2016. https://doi.org/10.1001/jama.1992.03480150121052.
Thompson and Thompson 2016 (Reference #7), originally Figure 14-4 on page 285.)

TABLE 2.5
Common Birth Defects
Genetic Causes Other Causes
Congenital heart disease 22q11 microdeletion syndrome, aneuploidy Congenital rubella, maternal DM, teratogens
Neural tube defects Aneuploidy, 22q11 microdeletion syn- Folic acid deficiency, teratogens
drome, Waardenburg syndrome
Cleft lip with or without Trisomy 13, other rare syndromes Pierre-Robin sequence, teratogenic medica-
cleft palate tions (Accutane, antiepileptics), maternal DM,
maternal smoking
Club foot Single-gene mutations, aneuploidy, rare Bone or connective tissue disease, oligohy-
syndromes dramnios

Adapted from Nussbaum RL, McInnes RR, Huntington FW. Thompson & Thompson Genetics in Medicine; 2016. https://doi.org/10.1001/
jama.1992.03480150121052.

organ systems with high energy requirements, such WHAT IS MOSAICISM?

as the brain and nervous system, heart, and musculo- Mosaicism is the presence of two or more different cell
skeletal system. Unlike the 46 nuclear chromosomes, lines in an individual, tissue, or organ.2 Mosaicism can
which divide in a highly predictable way, mitochon- result from an error of mitosis or meiosis (depending
drial DNA (mtDNA) are replicated and then sort on when it occurs), and there are several different types
randomly to daughter cells. Therefore, daughter cells of mosaicism that can affect an embryo. Confined pla-
can have variable amounts of normal mtDNA and cental mosaicism (CPM) occurs when mosaicism is
mutant mtDNA, which explains why mitochondrial detected in the cytotrophoblast (developing placenta)
disorders have variable phenotypes and reduced pen- but not the embryo. Confined placental mosaicism
etrance.2 These features of mitochondrial diseases can complicate the interpretation of invasive prenatal
also make prenatal testing challenging. In addition, testing, more commonly CVS testing. In CVS samples,
testing of family members may be of limited value, 1%–2% show a discrepancy between the placenta and
because at times, the mutation is not found in blood. the fetus (as determined by amniocentesis or cord
Patients who have a family of history of mitochon- blood at birth). When mosaicism is identified by CVS,
drial disorders should be referred for genetic consul- amniocentesis is generally recommended to evaluate
tation (Table 2.6). the fetus more directly and to rule out CPM.
18 Perinatal Genetics

TABLE 2.6
Examples of Mitochondrial Diseases
Disorder Phenotype
Mitochondrial DNA depletion syndrome Infantile muscle weakness, hypotonia, poor growth, respiratory
failure, death
Leigh syndrome Infantile neurodegeneration, hypotonia, developmental delay, optic
atrophy, respiratory abnormalities
MELAS (mitochondrial encephalopathy with Myopathy, encephalomyopathy, lactic acidosis, diabetes, deafness
lactic acidosis and strokelike episodes)
MERRF (myoclonic epilepsy with ragged-red Epilepsy, myopathy, ataxia, sensorineural deafness, dementia
fibers)
LHON (Leber hereditary optic neuropathy) Optic nerve atrophy leading to rapid onset of blindness, affects
males > females
NARP (neuropathy, ataxia, retinitis pigmentosa) Neuropathy, ataxia, retinitis pigmentosa
Kearns-Sayre syndrome Ophthalmoplegia (eye muscle weakness), cardiomyopathy, heart
block, ptosis, retinal pigmentation, ataxia, diabetes

Adapted from Nussbaum RL, McInnes RR, Huntington FW. Thompson & Thompson Genetics in Medicine; 2016. https://doi.org/10.1001/
jama.1992.03480150121052.

Somatic mosaicism occurs when mosaicism is of inheritance patterns, screening and testing options,
present in some (segmental) or all of the tissues of and ability to reassure and refer are essential parts of
the embryo but is not present in the gametes. Germ- providing obstetrical care in a rapidly changing perina-
line mosaicism is present in the gametes and can tal genetic environment.
result in a phenotypically unaffected individual who
has the potential to pass on a pathogenic variant to
offspring. REFERENCES
Germline mosaicism may be the cause of genetic 1. Mendel G. Experiments on plant hybridization. Proc Nat
conditions that did not seem to be present in the fam- Hist Soc Brünn. 1865.
2. Nussbaum RL, McInnes RR, Huntington FW. Thomp-
ily previously. The possibility of germline mosaicism
son & Thompson Genetics in Medicine; 2016. https://doi.
should be considered in families with two or more
org/10.1001/jama.1992.03480150121052.
affected siblings and no previous family history. If a 3. Saul RA, Tarleton JC. FMR1-Related disorders. Gene Rev.
child is diagnosed with an autosomal dominant or University of Washington, Seattle. 1998. http://www.ncbi.
X-linked disorder, and the parents are not affected, nlm.nih.gov/pubmed/20301558.
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