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These tests evaluate for specific disease‐causing gene mutations. For completely penetrant simple Mendelian genes, an “affected” test result is 100% accurate in predicting clinical disease. For recessive disorders requiring two copies of the mutation to be affected, these tests allow identification of “carriers” who have one copy of the mutation, while “normal” individuals have no copies of the mutation.

If a direct mutation test does not predict disease 100% of the time, then this is considered incomplete penetrance (i.e., the genotype does not penetrate into the phenotype completely and consistently). This decreased penetrance can be due to the effect of other genes that impact their expression (complex or polygenic inheritance). For late‐onset disorders, variations in age of onset can affect penetrance if the “average” age of onset is close to the average life expectancy of the individual. Examples would be late‐onset cataracts, some forms of progressive retinal atrophy (PRA), and several neurodegenerative disorders.

Some direct genetic tests identify a mutation that causes increased susceptibility to a genetic disease, but is not necessarily associated with disease 100% of the time. These susceptibility or liability genes can be part of complexly inherited diseases or the cause of incomplete penetrance of (assumed) simple Mendelian diseases. Some of these mutations are required for an individual to be affected, and some just provide increased risk (increased odds ratio), if present, but are not required to produce an affected individual. An example is the susceptibility to perianal fistulae/anal furunculosis in German shepherd dogs. Dogs with the susceptibility haplotype (combination of major histocompatibility complex [MHC] genes) have a 5× odds ratio for the disease versus those without the haplotype. This means that individuals with a positive test result are five times more likely to develop the disease than animals that do not test positive. This risk factor occurs whether the susceptibility haplotype is heterozygous or homozygous, though homozygous dogs develop the disease at an earlier age. Another example is the genetic test for pug dog encephalitis, a painful, fatal disease affecting 1–2% of pugs. Dogs homozygous for an MHC susceptibility haplotype have a 15.6× odds ratio for developing the disease, but dogs heterozygous for the susceptibility haplotype have no greater risk.