anomalies are structural or functional anomalies that occur during gestation and can be identified prenatally, at birth, or sometimes later in life.11 The word congenital means presence at or before birth, but it does not refer to the genetic origin of the defect, nor a hereditary origin.12
of a chromosome loses one of these chromosomes to form a normal diploid chromosome complement. The most common placental-fetal dichotomy involves placental trisomy for chromosome 16.17
Table 11.1 Frequency of Chromosome Abnormalities in Liveborn Infants
estimated that approximately 1% of people in the general population have a single-gene disorder.9
An individual who is affected has a 50% risk of transmitting the gene to each of his or her offspring.
Both males and females may be affected in equal proportions.
Both males and females are likely to transmit the disorder to male and female children.
An individual who is affected has one affected parent, or the disorder has appeared for the first time as a “de novo” variant in that individual (eg, approximately seven out of eight individuals with achondroplasia are due to a dominant de novo gene pathogenic variant).
The phenotype of a dominant gene pathogenic variant is determined by penetrance, which indicates whether or not that variant is expressed. Complete penetrance means that the dominant gene pathogenic variant expresses in all individuals who carry that variant (eg, neurofibromatosis 1 [NF 1] has complete penetrance after childhood, which means that all individuals who carry a pathogenic variant in the NF1 gene will manifest the disorder). Incomplete penetrance is expressed as a percentage, which means the number of individuals who carry the variant that expresses the phenotype. For example, 70% penetrance means that 70% of individuals with the pathogenic dominant gene variant expresses the phenotype. Incomplete penetrance may account for some AD disorders that seem to “skip” generations and may be a manifestation of the interaction of other genes.
Table 11.2 Examples of Chromosome Microdeletion Syndromes
Severe mental retardation, ataxia, jerky movements, inappropriate laughter, absent speech
Variable mental retardation, dysmorphic facies, multiple exostoses, sparse scalp hair, cone-shaped epiphyses
Severe mental retardation, lissencephaly, dysmorphic facies, vertical furrowing in forehead when crying
Mild mental retardation, infantile hypotonia, obesity, hypopigmentation, hypogonadism
Retinal malignancy, typical facies, possible mental retardation
Variable mental retardation, dysmorphic facies, broad thumbs/toes
Mental retardation, dysmorphic facies, self-destructive behavior, microcornea, renal abnormalities, hearing impairment
Steroid sulfatase deficiency
Frequent stillbirths, ichthyosis, low maternal estriol in urine and plasma
Overlapping clinical features: mental retardation, cleft palate, cardiac defects, learning disabilities, hypocalcemia, hypoplastic lymphoid tissue, T-cell deficiency, dysmorphic facies
Wilms tumor, aniridia, genitourinary abnormalities, mental retardation
Mental retardation, dysmorphic “elfin” facies, cardiac defect, renal anomalies, infantile hypercalcemia
Data from Mc Kinlay Gardner RJ, Amor DJ. Gardner and Sutherland’s Chromosome Abnormalities and Genetic Counseling. 5th ed. Oxford; 2018, Petracchi F, Colaci DS, Igarzabal L, et al. Cytogenetic analysis of first trimester pregnancy loss. Int J Gynaecol Obstet. 2009;104(3):243-244.
Figure 11.4 Autosomal dominant inheritance. Affected parent (red) has a 50% risk of affected offspring (red) and 50% of healthy offspring not carriers of the disease (gray).
The phenotype of a dominant gene is also determined by expressivity or the variability in clinical expression (the range of phenotypic features). Variable expressivity means that the dominant gene produces a range of phenotypic features from mild to severe; therefore, not all individuals will show identical phenotypes (eg, the phenotype of individuals with dominant pathogenic variants in genes associated with nonsyndromic holoprosencephaly is extremely variable, ranging from alobar holoprosencephaly to microforms with single central maxillary incisor).20
identical pathogenic variants] or compound heterozygous [two different pathogenic variants in both alleles of a gene]). Examples of AR disorders are cystic fibrosis, Tay-Sachs disease, and spinal muscular atrophy.
Two unaffected individuals who are heterozygous or carriers of one pathogenic recessive gene variant have a 25% risk of having an affected offspring in each pregnancy (one of four children will be affected; three of four will be phenotypically normal with two of these being carriers).
Carriers of pathogenic recessive gene variants are at risk of affected offspring only if their partners are also carriers of pathogenic variants in the same gene.
Both males and females may be affected in equal proportions.
Carriers of single recessive pathogenic variants do not manifest the disease, are healthy (in some cases they may have changes at the biochemical or cellular level).
Carriers of recessive pathogenic variants may be recognized after the birth of an affected child, after the diagnosis of an affected family member, or as the result of a genetic screening program.
Males will usually manifest the fullest expression of the disorder, whereas random X inactivation will largely influence expression in females.
Affected men will produce carrier daughters, while their sons will be healthy.
The male-to-male transmission does not occur because a male never contributes his X chromosome to a son.
Females heterozygotes have a risk of 50% of male children affected in each conception, while half of the female daughters will be carriers.
Females heterozygotes are generally asymptomatic but may manifest some sign(s) of the disease in question (eg, female carriers of DMD are generally asymptomatic but may manifest cardiomyopathy or cardiac conduction defects).
daughters and none of his sons; an affected female has a 50% likelihood of transmitting the disorder to her sons or daughters. Rarely, an X-linked dominant trait may be lethal in affected males, resulting in a disorder that appears to occur, clinically, only in females and in which an affected female has a 50% likelihood of transmitting the trait to her daughters. These affected women have an increased frequency of miscarriage due to affected male fetuses.
The mother transmits mitochondrial DNA because only maternal mitochondria are transmitted to the offspring (sperm mitochondria are eliminated during fertilization).
Males and females can be equally affected.
The phenotype will be affected by mitochondrial heteroplasmy, which is the coexistence of normal and abnormal mitochondrial DNA molecules within each cell (each cell contains multiple mitochondria, and each mitochondrion contains multiple copies of mitochondrial DNA). Mitochondria divide through mitosis and segregate to daughter cells during cell division. An mtDNA pathogenic variant present in one mitochondrion will generate more abnormal mitochondria that will segregate to daughter cells. The proportion of normal and abnormal mitochondria will vary in different cells and different tissues, therefore affecting the expression and severity of the disorder depending on the eventual abnormal mitochondrial load in various tissues.
The mother of an affected individual has the mtDNA pathogenic variant and may or may not have symptoms.
Males with an mtDNA pathogenic variant will not transmit the variant to offspring.
Females with an mtDNA will transmit the variant to all her offspring, and the phenotype will vary according to the number of abnormal mitochondria in different tissues.
An individual is unique in the proportion of normal and abnormal mitochondrial DNA in different organs.
Table 11.3 Uniparental Disomy-Associated Syndromes
Intermediate allele: offspring are not at increased risk for fragile X syndrome, although almost 14% may expand into the premutation range when transmitted by the mother.16 They are not known to expand to full mutations.
Premutation alleles: Premutation carriers do not have fragile X syndrome. Women with alleles in this range have a 50% risk of transmitting a premutation in each pregnancy. They are also at risk to repeat expansion and having children with fragile X syndrome. The risk of a maternal premutation becoming a full mutation in her offspring depends on the number of CGG trinucleotide repeats. The larger the size of the premutation repeat, the more likely the expansion to a fully expanded CGG repeat. For small premutations, AGG interrupters in the FMR1 gene may help
evaluate the risk of expansion. The presence of AGG decreases the risk of expansion of a premutation allele to a full mutation allele during maternal transmission. Premutation carriers also have an increased risk of FMR1-related primary ovarian insufficiency (POI), and fragile X-associated tremor/ataxia syndrome (FXTAS) (both males and females). Males are considered “transmitting males” because the father does not expand to full mutations (the premutation is inherited by all of his daughters and none of his sons).28
Table 11.4 FMR1 Alleles Classified According to the Number of Repeats
United States and Canada, board-certified genetic counselors are available for referral, but this career does not exist in all countries.34 Genetic counselors are professionals who have specialized education in genetics and counseling and provide personalized help to patients so as they can make informed decisions about their genetic health. They are used to interpret genetic disease etiology and clinical consequences, to incorporate new technologic information for pretest counseling, to deal with posttest result interpretation, and to provide an assessment based on patient knowledge, values, and concerns, supporting autonomy.31,33,37,38