Patterns of Genetic Transmission

Autosomal Dominant Inheritance

Autosomal dominant inheritance is determined by the presence of 1 abnormal gene on 1 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. 80-5) 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. 80-5) 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.

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 2 affected persons (Fig. 80-6). 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.

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. 80-7) 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 incidence may be as high as 50%. 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%).

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:

p2+2pq+q2=1

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. 80-8). 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 because of mutations in GJB2, the gene that encodes Connexin 26.

X-Linked Inheritance

Characteristics of X-linked inheritance (Fig. 80-9) include the following:

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. 80-10). 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.

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. 80-11). Some X-linked dominant conditions are lethal in a high percentage of males. An example is incontinentia pigmenti (see Chapter 596.7). The pedigree shows only affected females and an overall ratio of 2 : 1 females to males with an increased number of miscarriages (Fig. 80-12).

Mitochondrial Inheritance

An individual's mitochondrial genome is entirely derived from the mother because sperm contain few mitochondria, which are typically shed upon fertilization. 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. 80-15). Mitochondrial DNA mutations are often deletions or point mutations; overall, 1 : 400 people has a maternally inherited pathogenic mitochondrial DNA mutation.

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 suggest a mitochondrial basis (Table 80-1).

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 (see Chapters 87.4, 361, 598.2, and 611.4). 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) (see Chapter 598.2 and 611.4).

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 80-2). 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 premutation are at risk for fragile X-associated primary ovarian insufficiency (FXPOI). 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 at onset in subsequent generations is termed genetic anticipation and is a defining characteristic of many triplet-repeat expansion disorders (Fig. 80-16).

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. 80-17). In imprinting, gene expression depends on the parent of origin of the chromosome (see Chapter 81.8). 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.

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. Approximately 30% of cases of Prader-Willi syndrome is caused by paternal UPD15, whereas maternal UPD15 accounts for only 3% of Angelman syndrome (see Chapter 81.8).

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.

Beside 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 UPD 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 deacetylation, with different patterns of (de)methylation noted on paternal or maternal imprintable chromosome regions. Some genes demonstrate tissue-specific imprinting (see Fig. 80-17). 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%.