To analyze chromosomes, a karyotype is produced (Figure 11-1). The chromosomes are paired and organized according to size. The overall structure and banding pattern is evaluated and is reported according to the International System for Cytogenetic Nomenclature. According to this nomenclature, a karyotype designation includes the total chromosome number followed by the sex chromosome constitution. Females are 46,XX and males are 46,XY. If there are any variants or abnormalities, this is reported after the sex chromosomes (Table 11-1).28 Chromosome disorders can be either structural or numerical. The consequence of the abnormality depends on the amount of genomic imbalance and the genes involved. TABLE 11-1 Abbreviations Used for Description of Chromosomes and Their Abnormalities From Nussbaum RL et al. Thompson and Thompson genetics in medicine. 7th ed. Philadelphia: Saunders; 2007:66. Epidemiologic studies suggest that women are having fewer children, often later in life. The birth rate for women 40 to 44 years old increased 51% between 1990 and 2002.41 With the advent of assisted reproductive technology (ART), women in their 50s and 60s can achieve pregnancy. Although it cannot be emphasized enough that the effects of increasing age occur as a continuum, the term advanced maternal age has historically referred to pregnant women who will be 35 or older on their expected date of confinement. Chromosomal analysis of samples from spontaneous abortions, prenatal diagnosis, and live births reveals that there is a steady increase in aneuploidy as a woman ages (Figure 11-2). The basis for this increase is unknown, although it may be related to a decrease in the number of normal oocytes available or cumulative oxidative stress on the finite number of oocytes with which females are born. Along with chromosomal abnormalities, it has been observed that congenital anomalies increase with increased maternal age. The FASTER trial reported rates of congenital anomalies for women younger than 35 years old as 1.7%; women 35 to 39 years old and 40 years old or older had rates of 2.8% and 2.9%, respectively.22 The most common mechanism for aneuploidy is meiotic nondisjunction, in which a pair of chromosomes fails to separate during either of the meiotic divisions (Figure 11-3). Nondisjunction can rarely occur during a mitotic division after the formation of the zygote. If this happens early in cleavage, mosaicism may occur. In this situation, two or more different chromosome complements are present in one individual. The clinical significance of mosaicism is difficult to evaluate and depends on the developmental timing when the mosaicism occurred, the tissues affected, and the proportion of tissue affected. Structural rearrangements include deletions, insertions, ring chromosomes, isochromosomes, and translocations (Figure 11-4). One unique type of translocation is the Robertsonian translocation, in which two acrocentric chromosomes lose their short arms and fuse near the centromeric region. Because the short arms of acrocentric chromosomes contain only genes for ribosomal RNAs, loss of the short arm is rarely deleterious. The result is a balanced karyotype with only 45 chromosomes, including the translocated chromosome, which comprises the long arms of two chromosomes. Carriers of Robertsonian translocations are phenotypically normal, but have the risk of producing unbalanced gametes. The main clinical relevance of a Robertsonian translocation is that one involving chromosome 21 could result in a child with Down syndrome. About 4% of cases of Down syndrome have 46 chromosomes, one of which is a Robertsonian translocation between chromosome 21 and another chromosome. Approximately half of Mendelian disorders are inherited in an autosomal dominant fashion. Inheritance usually exhibits a vertical pattern of transmission, meaning that the phenotype usually appears in every generation, with each affected person having an affected parent (Figure 11-5). For each offspring of an affected parent, the risk of inheriting the mutated allele is 50%. An example of a disorder inherited in an autosomal dominant fashion is osteogenesis imperfecta. Biochemical defects in either the amount or the structure of collagen result in various clinical phenotypes depending on the mutation. The link between advanced maternal age and genetic abnormalities has been well established. The role of advanced paternal age, defined as 40 or older, is not as clear. It has been established that the rate of base substitution mutations during spermatogenesis increases as a man ages. The risk of de novo autosomal dominant disorders in offspring of fathers 40 years old or older is estimated at 0.3% or lower.21 Some evidence has suggested that advanced paternal age is associated with an increased risk for complex disorders such as schizophrenia, autism, and congenital anomalies. The relative risk for these conditions is 2% or less. Although there may be slightly increased risk for a range of disorders associated with advanced paternal age, the overall risk remains low. No screening or diagnostic tests target conditions associated with advanced paternal age. Pregnancies that are fathered by men 40 years old or older should be treated according to standard guidelines established by the American College of Medical Genetics (ACMG) and the American College of Obstetrics and Gynecology (ACOG).34 An autosomal recessive condition occurs when an individual possesses two mutant alleles that were inherited from heterozygous parents. For autosomal recessive diseases, an individual with one normal allele does not manifest the disease because the normal gene copy is able to compensate. Autosomal recessive disorders exhibit horizontal transmission, meaning that if the phenotype appears in more than one family member, it is typically in the siblings of the proband, not in parents, offspring, or other relatives (Figure 11-6). If both parents are carriers of a mutated allele, 25% of offspring have the autosomal recessive disease. Consanguineous unions (mating between individuals who are second cousins or closer) are at increased risk for an autosomal recessive disorder because there is a higher likelihood that both individuals carry the same recessive mutation. A common autosomal recessive disease is cystic fibrosis. Carrier screening and prenatal implications are discussed in a later section. An X-linked recessive mutation is phenotypically expressed in all males, but is expressed only in females who are homozygous for the mutation. As a result, X-linked recessive disorders are generally seen in males and rarely seen in females. An example of such a condition is hemophilia A. X-linked dominant disorders may manifest differently among heterozygous females in the same family because of different patterns of X chromosome inactivation. X-linked inheritance is classically characterized by the lack of male-to-male transmission because males transmit their Y chromosome to their sons, not their X chromosome (Figure 11-7). More than 100 different mutations in mtDNA have been identified to cause disease in humans.42 Most of these involve the central nervous system or musculoskeletal system (Table 11-2). TABLE 11-2 Common Mitochondrial Diseases and Their Manifestations Epigenetics refers to modification of genes that determines whether a gene is expressed or not (see Chapter 17). These modifications, an example of which is methylation, affect the expression of a gene, but not the primary DNA sequence itself. Imprinting refers to a phenomenon in which genetic material is differentially expressed depending on whether it was inherited from the father or the mother. A different phenotype can result depending on the parent of origin because for certain genes, only the allele from one parent is transcriptionally active. Fragile X syndrome, the most common hereditary form of mental retardation, has an incidence of approximately 1 in 4000 births. The normal number of triplet repeats in the Xq27.3 region (FMR1 gene) is less than 45; a full mutation is considered to be greater than 200 repeats. Individuals with 45 to 54 repeats are referred to as intermediate carriers—these individuals are not at risk for any phenotypic abnormalities and are not at risk for expansion to a full mutation in their offspring. Individuals with 55 to 200 repeats are known as premutation carriers. Besides the risk of having an offspring with the full mutation, these premutation carriers are also at risk for adult-onset cerebellar dysfunction (known as fragile X-associated tremor/ataxia syndrome) and premature ovarian failure.20 Individuals who have any family or personal history of developmental delay, mental retardation, ovarian dysfunction, or tremor should be offered screening for fragile X syndrome. At this time, population carrier screening is not recommended.32 An illustrative example of multifactorial inheritance is the occurrence of neural tube defects (NTDs). Spina bifida and anencephaly are NTDs that cluster in families and are a leading cause of fetal loss and handicap. Spina bifida is the result of incomplete fusion of vertebral arches and manifests in various degrees of severity. Anencephaly is a devastating condition in which the forebrain, overlying meninges, bone, and skin are absent. Most fetuses with anencephaly are stillborn. Although some NTDs can be explained by teratogens, amniotic bands, or chromosomal disorders, most are multifactorial. Decreased levels of maternal folic acid have been inversely correlated with the risk of NTDs. Folic acid levels are affected by two factors—dietary intake and enzymatic processing. Folic acid levels are detrimentally affected by a mutation in the enzyme 5,10-methylenetetrahydrofolate reductase (MTHFR). Fifteen percent of the population is homozygous for the mutation. It has been shown that the mothers of infants with NTDs were twice as likely to have MTHFR mutations than controls. Preconceptual supplementation of folic acid has been shown to decrease the risk of NTDs.39 All reproductive-age women should consume 0.4 mg of folic acid daily. Prenatal screening for NTDs is discussed later in this chapter. Environmental exposures—medications, maternal conditions, or infections—are the etiology of malformations in 10% of cases. The impact of the agent relates to the timing and amount of exposure (duration and dosage). The susceptibility of a fetus depends on its stage of development when an exposure takes place (Figure 11-8)26 (see Chapter 15). Most commonly prescribed medications can be used with relative safety during pregnancy. For the medications that are suspected or known teratogens, genetic counseling should emphasize relative risk. That is, risk increases should be presented in relation to a woman’s baseline risk of a birth defect, which is 2% to 3%. The possibility that certain medical conditions if left untreated pose greater threat to the fetus than the medications used to treat the condition should be addressed. The US Food and Drug Administration has categorized the potential risk according to available safety evidence (Table 11-3). TABLE 11-3 FDA Guidelines Categorizing Pregnancy-Related Risk
Genetic Aspects of Perinatal Disease and Prenatal Diagnosis
Principles of Inheritance
Chromosomal Disorders
Abbreviation
Meaning
Example
Condition
46,XX
Normal female
46,XY
Normal male
+
Gain of
47,XX,+21
Female with trisomy 21
−
Loss of
45,XX,−22
Female with monosomy 22
t
Translocation
46,XY,t(2;8)(q22;p21)
Male with balanced translocation between chromosome 2 and 8, with breaks in 2q22 and 8p21
/
Mosaicism
46,XX/47,XX,8
Female with two populations of cells, one with a normal karyotype and one with trisomy 8
Maternal Age Considerations
Abnormalities of Chromosome Number
Aneuploidy.
Abnormalities of Chromosome Structure
Single-Gene Disorders
Autosomal Dominant Disorders
affected male; 
affected female; 
unaffected male; 
unaffected female.
Advanced Paternal Age.
Autosomal Recessive Disorders
unaffected male; 
unaffected female; 
affected male; 
affected female. (From Nussbaum RL, et al. Thompson and Thompson genetics in medicine. 7th ed. Philadelphia: Saunders; 2007:123.)
Sex-Linked Disorders
Non-Mendelian Patterns of Inheritance
Mitochondrial Inheritance
Name
Abbreviation
Disease Characteristics
Myoclonic epilepsy associated with ragged red fibers
MERRF
Progressive myoclonic epilepsy, short stature, clusters of diseased mitochondria accumulated in subsarcolemmal region of muscle fiber (appear as “ragged red fibers” when stained)
Mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke
MELAS
Muscle weakness, headaches, loss of appetite, seizures, lactic acidosis, stroke
Neuropathy, ataxia, and retinitis pigmentosa
NARP
Numbness and tingling in limbs, muscle weakness, ataxia, deterioration of light-sensing cells of retina
Leber hereditary optic neuropathy
LHON
Acute onset of visual loss and optic atrophy usually in early young adulthood
Myoneurogastrointestinal disorder and encephalopathy
MNGIE
Ptosis, progressive external ophthalmoplegia, diffuse leukoencephalopathy, gastrointestinal motility dysfunction
Epigenetics and Uniparental Disomy
Trinucleotide Repeat Expansion
Multifactorial Inheritance
Teratogens
Bars indicate when the organ system is susceptible to teratogenic exposure. CNS, Central nervous system. (From Moore K. The developing human: clinically oriented embryology. 10th ed. Philadelphia: Saunders; 2016.)
Category
Interpretation
A
Controlled studies show no risk. Adequate, well-controlled studies in pregnant women have failed to show risk to the fetus.
B
No evidence of risk in humans. Either animal findings show risk (but human findings do not) or, if no adequate human studies have been done, animal findings are negative.
C
Risk cannot be ruled out. Human studies are lacking, and animal studies are either positive for fetal risk or lacking as well. Potential benefits may justify potential risk.
D
Positive evidence of risk. Investigational or postmarketing data show risk to fetus. Potential benefits may outweigh risk.
X
Contraindicated in pregnancy. Studies in animals or humans, or investigational or postmarketing reports have shown fetal risk that clearly outweighs any possible benefit to the patient.
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unaffected male; 
unaffected female; 
affected male; 
affected female. 