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The average human has approximately 4 million germline variants, that is, positions in their genome that differ from the reference genome (see Appendix 2 for a discussion of the reference genome). For the most part, this variation is not harmful and makes us distinct individuals, but some variants have been linked to diseases and health-related traits. The presence of some disease-causing variants means a high degree of certainty that the person with the variant will develop the disease. This is true for so-called Mendelian diseases. For other disease-causing variants, the relationship with disease is complex and the variants not very predictive of disease. Establishing the relationship between a genetic variant and disease is accomplished through different research methods. Mendelian and complex diseases differ in terms of the location of disease-causing variants, their frequency in the population, their penetrance, and their utility as diagnostic/predisposition tests.


Mendelian genetic disorders are individually rare, but in aggregate are present in about 2–3% of all newborns, although disease may not be manifest for years to decades, or ever. They are characterized by a clear pattern of inheritance, typically autosomal dominant, autosomal recessive, or X-linked.

Modes of inheritance

Autosomal dominant

A disease-causing variant in one of the two copies of a gene is sufficient to cause disease. Typical inheritance is from one affected parent who passes the variant to 50% of his or her offspring (Fig. A3-1). These tend to be diseases that occur in adulthood. Both sexes are affected equally. Some common examples include familial hypercholesterolemia (1 in 200), hereditary breast and ovarian cancer (1 in 400), and Lynch syndrome (1 in 400).

Figure A3-1.

Pedigree illustrating autosomal dominant inheritance. The most common situation is one affected parent carrying the disease mutation and passing it on to half of their offspring, who also become affected by the disease.

Autosomal recessive

Autosomal recessive diseases are the result of two unaffected parents who are each carriers of a mutation in one copy of the gene, and disease results when their child inherits both abnormal copies (Fig. A3-2). These may be two copies of the same variant (homozygote) or two different variants (compound heterozygote). Individuals with only one copy of a disease-causing variant are carriers, but will not develop the disease. When two carriers reproduce, one quarter of their offspring are expected to inherit both disease-causing variants and will manifest the disease, one quarter of offspring inherit two normal copies of the gene, and half will inherit just one and be carriers. Recessive diseases affect both sexes equally and are more prevalent in consanguineous populations. Carrier rates are highest in the United States for sickle cell anemia (1 in ...

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