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Cécile Méjécase, Saddek Mohand-Said, Camille Andrieux, Aurélie Hummel, Saïd El Shamieh, Aline Antonio, Fiona Boyard, Christel Condroyer, Christelle Michiels, Steven Blanchard, Mélanie Letexier, Jean-Paul Saraiva, Jose Alain Sahel, Christina Zeitz, Isabelle S Audo; CC2D2A mutations lead to variable phenotypes in a family with retinal dystrophy. Invest. Ophthalmol. Vis. Sci. 2017;58(8):573.
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© ARVO (1962-2015); The Authors (2016-present)
Inherited retinal dystrophies (IRDs) are a heterogeneous group of disorders characterized by progressive degeneration of photoreceptors. Many gene defects have been identified but they only account for 60% of the cases. The purpose of this study was to identify the gene defect(s) underlying IRD in three affected brothers from a consanguineous family.
Patients were clinically examined by standard methods. Targeted next-generation sequencing (NGS) covering 120 genes known to be mutated in IRD and subsequent whole exome sequencing (WES) were performed. Putative disease-causing variants identified after stringent filtering were confirmed by Sanger sequencing. Additional 960 probands with IRDs were analyzed by targeted NGS.
Ophthalmic examination of the eldest brothers was in keeping with rod-cone dystrophy whereas the younger brother had early-onset cone-rod dystrophy. Renal function and ultrasound was normal in the eldest brothers whereas the youngest had high blood pressure, hematuria and proteinuria but no sign of glomerulonephritis on renal biopsy. Brain magnetic resonance imaging was normal for the three siblings. In addition, none of the siblings had learning disabilities and all were otherwise fit and well. Initial targeted NGS and subsequent WES did not identify any homozygous disease-causing variant. However, two heterozygous variants were identified in CC2D2A (c.2774G>C p.(Arg925Pro) and c.4730_4731delinsTGTATA p.(Ala1577Valfs*5)), confirmed by direct sequencing. Of note, CC2D2A was covered by targeted NGS approach, but the two variants were missed due to the expectation of homozygous mutations related to the reported consanguinity. Additional 960 probands with IRD screened by targeted NGS did not have CC2D2A mutations.
Mutations in CC2D2A were previously reported in Meckel-Gruber and Joubert Syndromes. Here we report new phenotypes associated with CC2D2A mutations in the same sibship including non-syndromic rod-cone dystrophy and cone-rod dystrophy with atypical renal feature. The link between renal and retinal abnormalities is not established in the later case and warrant further investigations. Mutations in CC2D2A underlying non-syndromic IRD account for less than 0.1%. Further studies are needed to understand the phenotype-genotype correlations in Meckel-Gruber Syndrome, Joubert Syndrome and in non-syndromic retinal dystrophy.
This is an abstract that was submitted for the 2017 ARVO Annual Meeting, held in Baltimore, MD, May 7-11, 2017.
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