Fig. 1

Complex modes of inheritance. Digenic inheritance involves variation at 2 loci that are required for expression of a single Mendelian condition. Most often, both variants are rare, but there have been examples of one rare variant and one common variant at distinct loci leading to expression of a single Mendelian condition. Dual molecular diagnoses occur when an individual has two Mendelian conditions resulting from rare variants at two typically unlinked loci. Mendelian condition pairs can involve one or more modes of inheritance, for example, AD+AD, AD+AR, or AR + AR. Mutational burden is observed when the phenotype associated with a highly penetrant variant is modified by the presence of one or more additional variants which by themselves are not penetrant. Incomplete penetrance can be observed when disease expression requires compound inheritance of one rare and one common variant, either at the same locus, or at unlinked loci. Distinct chromosomes are represented in blue. Rare variants of high penetrance are indicated by red ovals. Common and/or low penetrance variants are indicated by grey ovals. AD – autosomal dominant; AR – autosomal recessive