Patterns of Genetic Transmission

Autosomal Dominant Inheritance

Autosomal dominant inheritance is determined by the presence of one 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 affects the phenotype of an individual, even though the other copy of the gene is functioning correctly. A phenotype can refer to a physical manifestation, a behavioral characteristic, or a difference detectable only through laboratory tests.

The pedigree for autosomal dominant disorders demonstrates certain characteristics. These disorders show a vertical transmission (parent-to-child) pattern and can appear in multiple generations. In Fig. 97.5 , this is illustrated by individual I.1 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 and do not harbor a copy of the deleterious gene) 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, many patients with an autosomal dominant disorder have no history of an affected family member, for several possible reasons. First, the patient may have the disorder due to a de novo (new) mutation that occurred in the DNA of the egg or sperm that formed 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. 97.6 ). There are many potential reasons that a disorder might exhibit incomplete penetrance, including the effect of modifier genes, environmental factors, gender, and age. Third, individuals with the same autosomal dominant variant 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 phenotype caused by a somatic mutation can vary but is usually milder than if all cells were affected by the mutation. In germline mosaicism the mutation occurs in cells that populate the germline that produces eggs or sperm. An individual who is germline mosaic might not have any manifestations of the disorder but may produce multiple eggs or sperm that are affected by the mutation.

Autosomal Recessive Inheritance

Autosomal recessive inheritance requires deleterious variants in both copies of a gene to cause disease. Examples include cystic fibrosis and sickle cell disease. Autosomal recessive disorders are characterized by horizontal transmission , the observation of multiple affected members of a kindred in the same generation, but no affected family members in other generations ( Fig. 97.7 ). They are associated with a recurrence risk of 25% for carrier parents who have had a previous affected child. Male and female offspring are equally likely to be affected, although some traits exhibit differential expression between sexes. The offspring of consanguineous parents are at increased risk for rare, autosomal recessive traits due to the increased chance that that both parents may carry a gene affected by a deleterious mutation that they inherited from a common ancestor. Consanguinity between parents of a child with a suspected genetic disorder implies, but certainly 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) as high as 50% of all children may be conceived in consanguineous unions. The risk of a genetic disorder for the offspring of a first-cousin union (6–8%) is about double the risk in the general population (3–4%).

Every individual probably has several rare, deleterious recessive pathogenic sequence variants. Because most pathogenic variants 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 variants. As a result, these variants typically remain undetected unless an affected child is born to a couple who both carry pathogenic variants affecting the same gene.

However, in some genetic isolates (small populations isolated by geography, religion, culture, or language), certain rare recessive pathogenic variants are much 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 pathogenic alleles inherited from a common ancestor. Screening programs have been developed among some such groups to detect persons who carry common disease-causing variants and therefore are at increased risk for having affected children. 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 variants in some larger populations is unusually high. In such cases, heterozygote advantage is postulated. 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 the rate of new mutations. In these populations, heterozygous carriers may have had an advantage in terms of survival and reproduction over noncarriers. In sickle cell disease the carrier state is thought to 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 (p ² ), then the frequency of the heterozygote (2pq) can be calculated: If p ² = 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. 97.8 ). This occurs when a homozygous affected individual has a partner who is a heterozygous carrier. This is most likely to occur for relatively common recessive traits within a population, such as sickle cell anemia or nonsyndromic autosomal recessive hearing loss caused by deleterious mutations in the GJB2 , the gene that encodes connexin 26.