Novel C2orf71 mutations account for ∼1% of cases in a large French arRP cohort

Abstract

Autosomal-recessive retinitis pigmentosa (arRP) is a genetically heterogeneous group of disorders to which a novel gene, C2orf71, was recently associated. The purpose of our study was to establish the prevalence and nature of C2orf71 mutations in a clinically well-characterized cohort of 345 sporadic and arRP French cases. Direct sequencing of C2orf71 was performed in 209 subjects for whom mutations had previously been excluded by microarray technology and direct sequencing of EYS. Putative pathogenicity of the identified variants was evaluated through cosegregation analysis, screening of more than 188 control chromosomes and prediction programs. We identified two patients compound heterozygous for mutations predicted to lead to a premature stop codon, 3 of which are novel. In addition, 3 patients carried a single variant of likely pathogenicity. Furthermore a large number of novel putative non-disease causing variants were identified, highlighting the extremely polymorphic nature of C2orf71. To our knowledge, our study provides the first large scale screening of C2orf71 in a French arRP cohort through direct sequencing and suggests that it would account for approximately 1% of arRP cases.

Next-generation sequencing applied to a large French cone and cone-rod dystrophy cohort: mutation spectrum and new genotype-phenotype correlation

“…A total of 19 known and novel mutations were identified in 12 genes not classically associated with CCRD. These mutations were previously reported in RP and LCA ( C2Orf71 [35, 36] , MERTK [37] , RLBP1 [38] , EYS [23, 39] , NMNAT1 [40–42], RDH12 [43, 44]) , RP1 [45, previous 4] , CRB1 [46, 47] and TULP1 [48]) , Senior-Loken ( IQCB1) [49] , ad vitreoretinochoroidopathy ( BEST1 ) [50] and adRP ( ROM1 ) [51]. Although, TULP1 is not a gene that was frequently associated with CCRD (not classified as such in https://sph.uth.edu/retnet/), a recent article revealed TULP1 mutation as a novel cause of cone dysfunction [52].…”

A homozygous nonsense CEP250 mutation combined with a heterozygous nonsense C2orf71 mutation is associated with atypical Usher syndrome

“…Values obtained from patients who are homozygous for the CEP250 mutation and heterozygous for the C2orf71 mutation are shown as a square shape (II:1 in brown, II:5 in blue and II:6 in green) . Values obtained from patients reported previously to have C2orf71 mutations on both alleles22 33 34 are shown as a green triangle.…”

“…In addition, a large number of genes that can cause Bardet–Biedl syndrome (BBS) when mutated encode proteins that interact to produce the BBSome ciliary complex 32. One of the ciliary genes that cause ARRP when mutated is C2orf71 that was identified simultaneously by two groups 22 23 and was reported to cause non-syndromic ARRP with a variable disease severity, but neither deafness nor hearing loss was reported 22 23 33 34. Although the exact localisation of C2orf71 in photoreceptors is unknown, colocalisation assays performed in cell cultures indicate ciliary expression 23…”

Usher syndrome: Hearing loss, retinal degeneration and associated abnormalities

“…They all have a heterozygous C2orf71 nonsense mutation. Although C2orf71is an autosomal recessive RP gene [43–46], it is unclear whether its heterozygous mutation also contributes to the disease development of these atypical USH patients.…”