Biallelic sequence and structural variants in RAX2 are a novel cause for autosomal recessive inherited retinal disease

Abstract

PurposeRAX2 encodes a homeobox-containing transcription factor, in which four monoallelic pathogenic variants have been described in autosomal dominant cone-dominated retinal disease.MethodsExome sequencing in a European cohort with inherited retinal disease (IRD) (n = 2086) was combined with protein structure modeling of RAX2 missense variants, bioinformatics analysis of deletion breakpoints, haplotyping of RAX2 variant c.335dup, and clinical assessment of biallelic RAX2-positive cases and carrier family members.ResultsBiallelic RAX2 sequence and structural variants were found in five unrelated European index cases, displaying nonsyndromic autosomal recessive retinitis pigmentosa (ARRP) with an age of onset ranging from childhood to the mid-40s (average mid-30s). Protein structure modeling points to loss of function of the novel recessive missense variants and to a dominant-negative effect of the reported dominant RAX2 alleles. Structural variants were fine-mapped to disentangle their underlying mechanisms. Haplotyping of c.335dup in two cases suggests a common ancestry.ConclusionThis study supports a role for RAX2 as a novel disease gene for recessive IRD, broadening the mutation spectrum from sequence to structural variants and revealing a founder effect. The identification of biallelic RAX2 pathogenic variants in five unrelated families shows that RAX2 loss of function may be a nonnegligible cause of IRD in unsolved ARRP cases.

Next-Generation Sequencing Applications for Inherited Retinal Diseases

“…Similarly, EYS gene variants were found to be causative in 51% of a RP cohort from Japan [ 36 ]. This discovery is not unique, as several other parallel studies have revealed similar founder mutations in their target populations, for example, Belgium, RAX2 [ 37 ]; Costa Rica, RPE65 [ 38 ]; Finland, CERKL [ 39 ]; Japan, EYS [ 36 ]; Spain, RP1 [ 40 ] and ABCA4 [ 41 ]; Jewish community in Caucasia, PDE6B [ 42 ]; Pakistan, ABCA4 and NMNAT1 [ 43 ]; Guyana, BBS9 [ 44 ]; and Faroe Islands, MERTK [ 45 ]. The enrichment of these variants, several of which are large structural variants, emphasises the value of population-specific TS panels to target and detect mutations and mutational breakpoints that may be missed by commercial generic gene panel sequencing or even WES.…”

Conserved roles of Rax/rx3 genes in hypothalamus and pituitary development

“…Recently, Van de Sompele et al 2019identified five human patients from unrelated families carrying homozygous mutations in RAX2, some of which are predicted to generate proteins with little, if any, activity. The patients present nonsyndromic autosomal recessive retinitis pigmentosa, with an onset age from childhood to late adulthood (Van de Sompele et al, 2019). This study indicates that, as in other species, the role of RAX2 in humans is to maintain the health of the retina throughout life.…”

Novel mutations in the 3-box motif of the BACK domain of KLHL7 associated with nonsyndromic autosomal dominant retinitis pigmentosa

“…Genetic etiologies of retinal dystrophy causing both autosomal dominant and recessive disease have been described in the literature and include RHO , RP1, BEST1 , GUCY2D, RAX2, and RPE65 [17–19, 21–24, 25]. Domain-dependent differences in dominant and recessive disease have been suggested for RP1, but the structural correlation of variants with disease phenotype in the other genes is still a topic of investigation [17–19, 21].…”