Figure 1.

Different genetic phenomena in combination with Mendelian disorders, can make disease characterization challenging. (A) This is a case of a digenic disorder. Two individually healthy variants combinedly produce the disease (e.g., Bardet-Biedl syndrome caused by BBS1 and BBS10 [35]). (B) Two different monogenic disorders may produce a blended or composite representation of both diseases (e.g., Mutation in NPL (causing sialic acid disorder) and GJB2 (causing deafness) creating composite disease phenotype for a patient [36]). (C) A case for a genetic modifier. Disease variant is modified by the modifier variant (circled) that enhances or suppresses the severity of the disease (i.e., Spinal Muscular Atrophy modified by SMN2 variants [37]). (D) An oligogenic disease can be modified by a modifier variant as well (i.e., Digenic Usher syndrome modified by PDZD7 [38]). More complex scenarios are also possible, such as multiple modifier alleles that can act independently or together (joint effect) [31].