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

Abstract

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.

Atypical, milder presentation in a child with CC2D2A and KIDINS220 variants

“…From the literature search, three brothers from a consanguineous family have been described. They underwent whole-exome sequencing for rod-cone dystrophy and were found to be compound heterozygous for variants in CC2D2A (Méjécase et al, 2019). Similar to our patient, they all have normal brain imaging with absence of the MTS.…”

“…This may be partly due to the fact that initial studies focused on severe developmental delay phenotypes but with wider access to next-generation sequencing, patients with non-distinctive, milder phenotypes are having more advanced genetic testing. Joubert syndrome and its associated genes are no exception (Irfanullah et al, 2016;Méjécase et al, 2019).…”

Mouse Models of Inherited Retinal Degeneration with Photoreceptor Cell Loss

“…Genetic mutations in CC2D2A, which encodes a component of the subdistal appendages of mother centrioles and basal bodies [88], have been observed in patients with Meckel Syndrome [89], Joubert Syndrome [90], and non-syndromic rod-cone dystrophy [91]. Mice with null mutations in Cc2d2a experience embryonic lethality due to the absence of subdistal appendages and nodal cilia [88].…”

Practical guide to genetic screening for inherited eye diseases

“…Moreover, syndromic genes or related gene panels may be considered, for example, if a patient has microphthalmia and anterior segment dysgenesis (ASD), if the MAC panel has no primary findings, the patient could also be screened with the ASD panel. 113 Cytogenetic testing Cytogenetic testing can be used to verify NGS findings or to detect chromosomal abnormalities or CNVs. 114 Cytogenetic testing can include karyotyping, microarray-based comparative genomic hybridisation (array-CGH), fluorescent in situ hybridisation (FISH, used to detect and localise the presence or absence of specific DNA sequences on a chromosome, for example, in ocular lymphoma or melanoma 115,116 ) and qualitative fluorescent polymerase chain reactions (QF-PCR, used to amplify specific regions of DNA to quantify and confirm the copy number in that specific region, previously reported with NGS approaches, and can identify common aneuploidies).…”