Whole-Exome Sequencing Identifies Biallelic IDH3A Variants as a Cause of Retinitis Pigmentosa Accompanied by Pseudocoloboma

Abstract

Purpose To identify the genetic cause and describe the phenotype in four families with autosomal recessive retinitis pigmentosa (arRP) that can be associated with pseudocoloboma. Design Case series. Subjects Seven patients from four unrelated families with arRP of which three patients had bilateral early-onset macular pseudocoloboma. Methods We performed homozygosity mapping and whole-exome sequencing (WES) in five probands and two unaffected family members of four unrelated families. Subsequently, Sanger sequencing and segregation analysis were done in additional family members. We reviewed the medical history of individuals carrying IDH3A variants and performed additional ophthalmic examinations, including full-field electroretinography (ffERG), fundus photography, fundus autofluorescence imaging and optical coherence tomography. Main Outcome Measures IDH3A variants, age at diagnosis, visual acuity, fundus appearance, visual field, ffERG, fundus autofluorescence and OCT findings. Results We identified seven different variants in IDH3A in four unrelated families, i.e. five missense, one nonsense and one frameshift variant. All subjects developed symptoms early in life ranging from night blindness to decreased visual acuity and were diagnosed between the ages of one and 11 years. Four subjects with biallelic IDH3A variants displayed a typical arRP phenotype and three subjects were diagnosed with arRP and pseudocoloboma of the macula. Conclusions IDH3A variants were identified as a novel cause of typical arRP, in some individuals associated with macular pseudocoloboma. We observed both phenotypes in two siblings carrying the same compound heterozygous variants, which could be explained by variable disease expression and warrants caution when making assertions about genotype-phenotype correlations.

A nationwide genetic analysis of inherited retinal diseases in Israel as assessed by the Israeli inherited retinal disease consortium (IIRDC)

“…Since 2012, patients’ DNAs were subjected to NGS, using either T‐NGS and/or WES. Novel IRD genes identified by IIRDC members using this approach include MAK , ARL2BP , CEP250 , CEP78 , IDH3A , SCAPER , ARMC9 , and ARSG (Davidson et al, ; Khateb et al, , ; Namburi et al, ; Özgül et al, ; Pierrache et al, ; Tatour et al, ; van de Weghe et al, ; Table S1). In total, 23% of the families were solved using this approach (41% of solved families).…”

Steeper Macular Curvature in Eyes With Non-Highly Myopic Retinitis Pigmentosa

“…The formation of a posterior staphyloma has been reported to be associated with the mutation of several genes especially in the phenotype of early-onset retinal dystrophy: RDH12, 4 C21orf2, 6 DHX38, 20 IDH3A, 21 and NMNAT1. 22 We included only the patients older than 10 years.…”

A homozygous founder missense variant in arylsulfatase G abolishes its enzymatic activity causing atypical Usher syndrome in humans

“…The development of high-throughput sequencing techniques, including whole-exome sequencing (WES) and wholegenome sequencing (WGS), has contributed tremendously to the identification of novel causative mutations and genes for rare inherited diseases in general and retinal degeneration in particular. 7,8 Nevertheless, despite these advances, the causative gene remains unknown in a large number of cases with inherited retinal disease (IRD). 9,10 Some of the proteins encoded by USH-associated genes interact in complexes that are localized to hair cells of the inner ear and in retinal photoreceptors.…”