Whole exome sequencing resolves complex phenotype and identifies CC2D2A mutations underlying non‐syndromic rod‐cone dystrophy.

Genetic investigations were performed in three brothers from a consanguineous union, the two oldest diagnosed with rod‐cone dystrophy (RCD), the youngest with early‐onset cone‐rod dystrophy and the two youngest with nephrotic‐range proteinuria. Targeted next‐generation sequencing did not identify homozygous pathogenic variant in the oldest brother. Whole exome sequencing (WES) applied to the family identified compound heterozygous variants in CC2D2A (c.2774G>C p.(Arg925Pro); c.4730_4731delinsTGTATA p.(Ala1577Valfs*5)) in the three brothers with a homozygous deletion in CNGA3 (c.1235_1236del p.(Glu412Valfs*6)) in the youngest correcting his diagnosis to achromatopsia plus RCD. None of the three subjects had cerebral abnormalities or learning disabilities inconsistent with Meckel‐Gruber and Joubert syndromes, usually associated with CC2D2A mutations. Interestingly, an African woman with RCD shared the CC2D2A missense variant (c.2774G>C p.(Arg925Pro); with c.3182+355_3825del p.(?)). The two youngest also carried compound heterozygous variants in CUBN (c.7906C>T rs137998687 p.(Arg2636*); c.10344C>G p.(Cys3448Trp)) that may explain their nephrotic‐range proteinuria. Our study identifies for the first time CC2D2A mutations in isolated RCD and underlines the power of WES to decipher complex phenotypes. Our study identifies for the first time CC2D2A mutations in isolated rod‐cone dystrophy (RCD) and emphasizes the power of whole exome sequencing to elucidate complex phenotypes in the same family including RCD, early‐onset cone‐rod dystrophy which turned out to be achromatopsia with RCD and nephrotic‐range proteinuria inconsistent with nephronophthisis on renal biopsy. [ABSTRACT FROM AUTHOR]