“…Early studies aimed to determine whether the location of pathogenic variants is able to predict the clinical manifestation of the disease do not support a genotype‐phenotype correlation (Crosnier et al, ; Spinner et al, ). Conversely, a high degree of variable expressivity has been observed, and often significant phenotypic variability is reported in families harboring the same pathogenic variant (Dhorne‐Pollet, Deleuze, Hadchouel, & Bonaiti‐Pellie, ; Elmslie et al, ; Emerick et al, ; Izumi et al, ; Kamath, Bason, Piccoli, Krantz, & Spinner, ; Kamath, Krantz, Spinner, Heubi, & Piccoli, ; Krantz et al, ; Shulman, Hyams, Gunta, Greenstein, & Cassidy, ). These observations have led to the hypothesis that a second gene could act as a modifier, and studies have been carried out to test this theory.…”