Autosomal Dominant Inheritance

Autosomal dominant inheritance is determined by the presence of 1 abnormal gene on one of the autosomes (chromosomes 1-22). Autosomal genes exist in pairs, with each parent contributing 1 copy. In an autosomal dominant trait, a change in 1 of the paired genes has an effect on the phenotype; this can refer to physical manifestations, behavioral characteristics, or differences detectable only through laboratory tests, even though the other copy of the gene is functioning correctly.

The pedigree for an autosomal dominant disorder (Fig. 75-5) demonstrates certain characteristics. The disorder is transmitted in a vertical (parent to child) pattern and can appear in multiple generations. This is illustrated by individual I.1 (see Fig 75-5) passing on the changed gene to II.2 and II.5. An affected individual has a 50% (1 in 2) chance of passing on the deleterious gene in each pregnancy and, therefore, of having a child affected by the disorder. This is referred to as the recurrence risk for the disorder. Unaffected individuals (family members who do not manifest the trait) do not pass the disorder to their children. Males and females are equally affected. Although not a characteristic per se, the finding of male-to-male transmission essentially confirms autosomal dominant inheritance. Vertical transmission can also be seen with X-linked traits. However, because a father passes on his Y chromosome to a son, male-to-male transmission cannot be seen with an X-linked trait. Therefore, male-to-male transmission eliminates X-linked inheritance as a possible explanation. Although male-to-male transmission can occur with Y-linked genes as well, there are very few Y-linked disorders compared with thousands having the autosomal dominant inheritance pattern.

Figure 75-5 Autosomal dominant pedigree. Pedigree showing typical inheritance of a form of achondroplasia (FGFR3) inherited as an autosomal dominant trait. Black, affected patients.

Although parent to child transmission is a characteristic of autosomal dominant inheritance, for many patients with an autosomal dominant disorder there is no history of an affected family member. There are several possible reasons: First, the patient may represent a new mutation that occurred in the DNA of the egg or sperm that came together to form that individual. Second, many autosomal dominant conditions demonstrate incomplete penetrance, meaning that not all individuals who carry the mutation have phenotypic manifestations. In a pedigree this can appear as a skipped generation, in which an unaffected individual links two affected persons (Fig. 75-6). There are many potential reasons that a disorder exhibits incomplete penetrance, including the effect of modifier genes, environmental factors, gender, and age. Third, individuals with the same autosomal dominant mutation can manifest the disorder to different degrees. This is termed variable expression and is a characteristic of many autosomal dominant disorders. Fourth, some spontaneous genetic mutations occur not in the egg or sperm that forms a child but rather in a cell in the developing embryo. Such events are referred to as somatic mutations, and because not all cells are affected, the change is said to be mosaic. The resulting phenotype caused by a somatic mutation can be varied, but it is usually milder than if all cells contain the mutation. In germline mosaicism, the mutation occurs in cells that populate the germline that produce eggs or sperm. A germline mosaic might not have any manifestations of the disorder but might produce multiple eggs or sperm that carry the mutation.

Figure 75-6 Incomplete penetrance. This family segregates a familial cancer syndrome, familial adenomatous polyposis. Individual II.3 is an obligate carrier, but there are no findings to suggest the disorder. This disorder is nonpenetrant in this individual.

Autosomal Recessive Inheritance

Autosomal recessive inheritance involves mutations in both copies of a gene. Examples of autosomal recessive diseases are cystic fibrosis and sickle cell disease. Characteristics of autosomal recessive traits (Fig. 75-7) include horizontal transmission, the observation of multiple affected members of a kindred in the same generation, but no affected family members in other generations; recurrence risk of 25% for parents with a previous affected child; males and females being equally affected, although some traits exhibit different expression in males and females and increased incidence, particularly for rare traits, in the offspring of consanguineous parents. Consanguinity refers to the existence of a relationship by a common ancestor and increases the chance that both parents carry a gene affected by an identical mutation that they inherited. Consanguinity between parents of a child with a suspected genetic disorder implies (but does not prove) autosomal recessive inheritance. Although consanguineous unions are uncommon in Western society, in other parts of the world (southern India, Japan, and the Middle East) they are common. The risk of a genetic disorder for the offspring of a first-cousin marriage (6-8%) is about double the risk in the general population (3-4%).

Figure 75-7 Autosomal recessive pedigree with parental consanguinity. Central dot, carriers; black, affected patients.

Every individual probably has several rare, harmful, recessive mutations. Because most mutations carried in the general population occur at a very low frequency, it does not make economic sense to screen the entire population in order to identify the small number of persons who carry these mutations. As a result, these mutations typically remain undetected unless an affected child is born to a couple who both carry mutations affecting the same gene.

However, in some genetic isolates (small populations separated by geography, religion, culture, or language) certain rare recessive mutations are far more common than in the general population. Even though there may be no known consanguinity, couples from these genetic isolates have a greater chance of sharing mutant alleles inherited from a common ancestor. Screening programs have been developed among some such groups to detect persons who carry common disease-causing mutations and therefore are at increased risk for having affected children. For example, a variety of autosomal recessive conditions are more common among Ashkenazi Jews than in the general population. Couples of Ashkenazi Jewish ancestry should be offered prenatal or preconception screening for Gaucher disease type 1 (carrier rate 1 : 14), cystic fibrosis (1 : 25), Tay-Sachs disease (1 : 25), familial dysautonomia (1 : 30), Canavan disease (1 : 40), glycogen storage disease type 1A (1 : 71), maple syrup urine disease (1 : 81), Fanconi anemia type C (1 : 89), Niemann-Pick disease type A (1 : 90), Bloom syndrome (1 : 100), mucolipidosis IV (1 : 120), and possibly neonatal familial hyperinsulinemic hypoglycemia.

The prevalence of carriers of certain autosomal recessive genes in some larger populations is unusually high. In such cases, heterozygote advantage is postulated. For example, the carrier frequencies of sickle cell disease in the African population and of cystic fibrosis in the northern European population are much higher than would be expected from new mutations. It is possible that heterozygous carriers have had an advantage in terms of survival and reproduction over noncarriers. In sickle cell disease, the carrier state might confer some resistance to malaria; in cystic fibrosis, the carrier state has been postulated to confer resistance to cholera or enteropathogenic Escherichia coli infections. Population-based carrier screening for cystic fibrosis is recommended for persons of northern European and Ashkenazi Jewish ancestry; population-based screening for sickle cell disease is recommended for persons of African ancestry.

If the frequency of an autosomal recessive disease is known, the frequency of the heterozygote or carrier state can be calculated from the Hardy-Weinberg formula:

where p is the frequency of one of a pair of alleles and q is the frequency of the other. For example, if the frequency of cystic fibrosis among white Americans is 1 in 2,500 (p²), then the frequency of the heterozygote (2pq) can be calculated: If p² = 1/2,500, then p = 1/50 and q = 49/50; 2pq = 2 × (1/50) × (49/50) = 98/2500 or 3.92%.

Pseudodominant Inheritance

Pseudodominant inheritance refers to the observation of apparent dominant (parent to child) transmission of a known autosomal recessive disorder (Fig. 75-8). This occurs when a homozygous affected individual has a partner who is a heterozygous carrier, and it is most likely to occur for relatively common traits, such as sickle cell anemia or nonsyndromic autosomal recessive hearing loss due to mutations in GJB2, the gene that encodes Connexin 26.

Figure 75-8 Pseudodominant inheritance. Black, affected (deaf); central dot shows carrier who is asymptomatic (unaffected).

X-Linked Inheritance

Characteristics of X-linked inheritance (Fig. 75-9) include the following:

Figure 75-9 Pedigree demonstrating X-linked recessive inheritance.

A female occasionally exhibits signs of an X-linked trait similarly to a male. This occurs rarely owing to homozygosity for an X-linked trait or the presence of a sex chromosome abnormality (45,X or 46,XY female) or skewed or nonrandom X-inactivation. X chromosome inactivation occurs early in development and involves random and irreversible inactivation of most genes on one X chromosome in female cells (Fig. 75-10). In some cases, a preponderance of cells inactivates the same X chromosome, resulting in phenotypic expression of an X-linked mutation if it resides on the active chromosome. This can occur owing to chance, selection against cells that have inactivated the X chromosome carrying the normal gene, or X chromosome abnormalities that result in inactivation of the X chromosome carrying the normal gene.

Figure 75-10 X-inactivation. Black marks the active X chromosome. Color of the cell represents whether it is the paternal-derived X chromosome (Xp active in blue cell) or maternal derived (Xm active in red cell).

Some X-linked disorders are inherited in an X-linked dominant fashion in which female carriers typically manifest abnormal findings. An affected man will have only affected daughters and unaffected sons, and half of the offspring of an affected woman will be affected (Fig. 75-11). Some X-linked dominant conditions are lethal in a high percentage of males. An example is incontinentia pigmenti (see Chapter 589.7). The pedigree shows only affected females and an overall ratio of 2 : 1 females to males with an increased number of miscarriages (Fig. 75-12).

Figure 75-11 Pedigree pattern demonstrating X-linked dominant inheritance. Note there is no father-to-son transmission in this situation, and hemizygosity (i.e., X-linked gene in a male) is not lethal. In some X-linked dominant conditions, X-linked males have a more severe phenotype and might not survive. In that case, only females manifest the disease (see Fig. 75-12).

Figure 75-12 Pedigree of an X-linked dominant disorder with male lethality, such as incontinentia pigmenti.

Mitochondrial Inheritance

An individual’s mitochondrial genome is entirely derived from the mother because sperm contain few mitochondria, which are typically shed upon fertilization (Fig. 75-15). It follows that mitochondrial disorders exhibit maternal inheritance. A woman with a mitochondrial genetic disorder can have affected offspring of either sex, but an affected father cannot pass on the disease to his offspring (Fig. 75-16). mtDNA mutations are often deletions or point mutations; overall, 1 : 400 people has a maternally inherited pathogenic mtDNA mutation.

Figure 75-15 The human mitochondrial DNA molecule, showing the location of genes encoding 22 tRNAs, 2 rRNAs, and 13 proteins of the oxidative phosphorylation (OXPHOA) complex. Some of the most common disease-causing substitutions and deletions in the mtDNA genome are also illustrated. OH and OL are the origins of replication of the two DNA strands, respectively; 12S, 12S ribosomal RNA; 16S, 16S ribosomal RNA. The tRNAs are indicated by the single letter code for their corresponding amino acids (e.g., L for leucine, K for lysine). The 13 OXPHOS polypeptides encoded by mtDNA include components of complex I: NADH dehydrogenase (ND1, ND2, ND3, ND4, ND4L, ND5, and ND6); complex III: cytochrome b (Cyt b); complex IV: cytochrome c oxidase I, or Cyt c (COI, COII, COIII); and complex V: ATPase 6 (ATP-6, ATP-8). See Table 75-1 for representative diseases.

(Adapted from Shoffner JM, Wallace DC: Oxidative phosphorylation disease. In Scriver CR, Beaudet AL, Sly WS, et al, editors: The metabolic and molecular basis of inherited disease, ed 7, New York, 1995, McGraw-Hill; and Johns DR: Mitochondrial DNA and disease, N Engl J Med 333:638–644, 1995. From Nussbaum RL, McInnes RR, Willard HF: Thompson & Thompson genetics in medicine, ed 6, Philadelphia, 2001, WB Saunders.)

Figure 75-16 Pedigree of a mitochondrial disorder, exhibiting maternal inheritance. Black, affected patient.

In individual families, mitochondrial inheritance may be difficult to distinguish from autosomal dominant or X-linked inheritance, but in many cases paying close attention to the sex of the transmitting and nontransmitting parents can suggests a mitochondrial basis (Table 75-1).

The mitochondria are the cell’s suppliers of energy, and it is not surprising that the organs that are most affected by the presence of abnormal mitochondria are those that have the greatest energy requirements, such as the brain, muscle, heart, and liver (Chapters 81.4, 353, and 591). Common manifestations include developmental delay, seizures, cardiac dysfunction, decreased muscle strength and tone, and hearing and vision problems. Examples of mitochondrial disorders include MELAS (myopathy, encephalopathy, lactic acidosis, and strokelike episodes), MERRF (myoclonic epilepsy associated with ragged red fibers), and Kearns-Sayre syndrome (ophthalmoplegia, pigmentary retinopathy, and cardiomyopathy) (Chapter 591).

Mitochondrial diseases can be highly variable in clinical manifestation. This is partly because cells can contain multiple mitochondria, each bearing several copies of the mitochondrial genome. Thus, a cell can have a mixture of normal and abnormal mitochondrial genomes, which is referred to as heteroplasmy. Unequal segregation of mitochondria carrying normal and abnormal genomes and replicative advantage can result in varying degrees of heteroplasmy in the cells of an affected individual, including the individual ova of an affected female. Because of this, a mother may be asymptomatic and yet have children who are severely affected. The level of heteroplasmy at which disease symptoms typically appear can also vary based on the type of mitochondrial mutation. Detection of mitochondrial genome mutations can require sampling of the affected tissue for DNA analysis; testing for mitochondrial DNA mutations may in some tissues, such as blood, be inadequate because the mutation may be found primarily in affected tissues such as muscle.

Triplet Repeat Expansion Disorders

Triplet repeat expansion disorders are distinguished by the special dynamic nature of the disease-causing mutation. Triplet repeat expansion disorders include fragile X syndrome, myotonic dystrophy, Huntington disease, spinocerebellar ataxias, and several others (Table 75-2). These disorders are caused by expansion in the number of 3-bp repeats. The fragile X gene, FMR1, normally has 5-40 CGG triplets. An error in replication can result in expansion of that number, to a level in the gray zone between 41 and 58 repeats, or to a level referred to as premutation, which comprises 59-200 repeats. Some male carriers of the premutation develop fragile X–associated tremor/ataxia syndrome (FXTAS) as adults, and female carriers of the permutation are at risk for FMR1-related premature ovarian failure (POF). Persons with a premutation are also at risk for having the gene expand further in subsequent meiosis, hence crossing into the range of full mutation in offspring. In fragile X, the threshold for clinical diagnosis is above 200 repeats. With this number of repeats, the FMR1 gene becomes hypermethylated, and protein production is lost.

Some triplet expansions associated with other genes can cause disease through a mechanism other than decreased protein production. In Huntington disease, the expansion causes the gene product to have a new, toxic effect on the neurons of the basal ganglia. For most triplet-repeat disorders, there is a clinical correlation to the size of the expansion, with a greater expansion causing more severe symptoms and/or earlier age of onset for the disease. The observation of increasing severity of disease and early age of onset in subsequent generations is termed genetic anticipation and is a defining characteristic of many triplet-repeat expansion disorders (Fig. 75-17).

Figure 75-17 Myotonic dystrophy pedigree illustrating anticipation. In this case, the age of onset for family members affected with an autosomal dominant disease is lower in more recent generations. Black, affected patients.

Genetic Imprinting

The 2 copies of most autosomal genes are functionally equivalent. However, in some cases only 1 copy of a gene is transcribed and the other copy is silenced. This gene silencing is typically associated with methylation of DNA, which is an epigenetic modification, meaning it does not change the nucleotide sequence of the DNA (Fig. 75-18). In imprinting, gene expression depends on the parent of origin of the chromosome (Chapter 76). Imprinting disorders result from an imbalance of active copies of a given gene, which can occur for several reasons. Prader-Willi and Angelman syndromes, two distinct disorders associated with developmental impairment, are illustrative. Both can be caused by microdeletions of chromosome 15q11-12. The microdeletion in Prader-Willi syndrome is always on the paternally derived chromosome 15, whereas in Angelman syndrome it is on the maternal copy. UBE3A is the gene responsible for Angelman syndrome. The paternal copy of UBE3A is transcriptionally silenced in the brain and the maternal copy continues to be transcribed. If an individual has a maternal deletion, an insufficient amount of UBE3A protein is produced in the brain, resulting in the neurologic deficits seen in Angelman syndrome.

Figure 75-18 Tissue-specific DNA methylation and epigenetic heterogeneity among individuals. A subset of the DNA methylation patterns within a cell is characteristic of that cell type. Cell type–specific and tissue-specific DNA methylation are illustrated by organ-to-organ variations in the clusters of methylated CpGs within the same individual. Despite overall consistency in tissue-specific DNA methylation patterns, variations in these patterns exist among different individuals. Methylated CpGs are indicated by a filled circle and unmethylated CpGs by an open circle. SNPs are indicated by the corresponding base.

(Redrawn from Brena RM, Huang THM, Plass C: Toward a human epigenome, Nat Genet 38:1359–1360, 2006.)

Uniparental disomy (UPD), the rare occurrence of a child inheriting both copies of a chromosome from the same parent, is another genetic mechanism that can cause Prader-Willi and Angelman syndromes. Inheriting both chromosomes 15 from the mother is functionally the same as deletion of the paternal 15q12 and results in Prader-Willi syndrome. About 30% of cases of Prader-Willi syndrome is caused by paternal UPD15, whereas maternal UPD15 accounts for only 3% of Angelman syndrome (Chapter 76).

A mutation in an imprinted gene is another cause. Mutations in UBEA3 account for almost 11% of patients with Angelman syndrome and also result in familial transmission. The most uncommon cause is a mutation in the imprinting center, which results in an inability to correctly imprint the UBE3A. In a woman, the inability to reset the imprinting on her paternally inherited chromosome 15 imprint results in a 50% risk of passing on an incorrectly methylated copy of UBE3A to a child who would then develop Angelman syndrome.

Besides 15q12, other imprinted regions of clinical interest include the short arm of chromosome 11, where the genes for Beckwith-Wiedemann syndrome and nesidioblastosis map, and the long arm of chromosome 7 with maternal uniparental disomy of 7q, which has been associated with some cases of idiopathic short stature and Russell-Silver syndrome.

Imprinting of a gene can occur during gametogenesis or early embryonic development (reprogramming). Genes can become inactive or active by various mechanisms including DNA methylation or demethylation or histone acetylation or deacytylation, with different patterns of (de)methylation noted on paternal or maternal imprintable chromosome regions. Some genes demonstrate tissue-specific imprinting (see Fig. 75-18). Several studies suggest that there may be a small but significantly increased incidence of imprinting disorders, specifically Beckwith-Wiedemann and Angelman syndrome, associated with assisted reproductive technologies such as in vitro fertilization and intracytoplasmic sperm injection. However, the overall incidence of these disorders in children conceived using assisted reproductive technologies is likely to be <1%.