Patterns of Inheritance

Autosomal recessive

This pattern is typically seen with a mutation in a gene encoding for an enzyme, resulting in loss of function. Spontaneous new mutations are rare. The allele frequency is usually rare, so a family history is often not present. Heterozygotes generally have enough gene product to get by. Homozygotes generally have too little, but the amount of product and severity of disease may vary. The standard recurrence risk is 25%.

Autosomal dominant

This pattern ttypically occurs when a mutation involves a gene encoding for a structural protein. There can be a "dominant negative" effect in which the product interferes with formation of complex protein structures or a "gain of function" in which the product leads to appearance of abnormal features. Since the genes are large, new mutations can occur, and some variability in phenotypic appearance. Thus, a family history may not be present. The recurrence risk is 50%, but may be less because of reduced penetrance, and a generation may be skipped.

X-linked recessive

In this pattern, females are typically carriers, but because of X-inactivation that leaves some functional genes available to produce product, they do not display the phenotype. Depending upon how much product is needed to be healthy, some females may be mildly affected. Males are typically affected, with some variability in severity. A pedigree typically reveals a "skipped" generation in which there is a female carrier. An affected father cannot transmit the trait to his sons.

X-linked dominant

Theoretically, both males and females will be affected, but a "double dose" of the abnormal gene product may be lethal in utero, so that virtually no males are seen with the disease. Alternatively, fragile X syndrome illustrates how passage of the trait differs between males (no added triple repeats) and females (triple repeats added in each generation) so that males are more severely affected. Otherwise, in a classic X-linked dominant pattern, twice as many females should be affected, though female heterozygotes may be less severely affected. An affected male cannot pass the trait to his male offspring.

Co-dominance

Both alleles lead to expression with a gene product, as in the ABO blood grouping system. Persons with allele A have A antigen on red blood cells; persons with the B allele have B antigen. Persons with both alleles have A and B antigen.

Dosage sensitivity

The amount of gene product depends upon whether none, 1 or 2 functional genes are present. The classic example is familial hypercholesterolemia, where heterozygotes have some LDL receptors and a moderaly increased serum cholesterol, while homozygotes have almost no LDL receptors are a markedly increased serum cholesterol.

Mitochondrial inheritance

There are a few mitochondrial genes involved with oxidative phosphorylation. Mitochondrial DNA is inherited from mother, not father. Diseases related to abnormal mitochondrial genes generally produce myopathy, encephalopathy, or deafness.

Multifactorial inheritance

No one specific gene is involved. Instead, multiple genes and environmental factors interact to produce a phenotype. The recurrence risk is above the average 3%, but the amount is difficult to state precisely.

Pedigree Analysis

In order to better understand inheritance patterns, a pedigree chart of a family can be diagrammed. The symbols used in pedigree analysis are shown below: