Identification of a Novel Homozygous Nonsense Mutation Confirms the Implication of GNAT1 in Rod-Cone Dystrophy

Abstract

GNAT1, encoding the transducin subunit Gα, is an important element of the phototransduction cascade. Mutations in this gene have been associated with autosomal dominant and autosomal recessive congenital stationary night blindness. Recently, a homozygous truncating GNAT1 mutation was identified in a patient with late-onset rod-cone dystrophy. After exclusion of mutations in genes underlying progressive inherited retinal disorders, by targeted next generation sequencing, a 32 year-old male sporadic case with severe rod-cone dystrophy and his unaffected parents were investigated by whole exome sequencing. This led to the identification of a homozygous nonsense variant, c.963C>A p.(Cys321*) in GNAT1, which was confirmed by Sanger sequencing. The mother was heterozygous for this variant whereas the variant was absent in the father. c.963C>A p.(Cys321*) is predicted to produce a shorter protein that lacks critical sites for the phototransduction cascade. Our work confirms that the phenotype and the mode of inheritance associated with GNAT1 variants can vary from autosomal dominant, autosomal recessive congenital stationary night blindness to autosomal recessive rod-cone dystrophy.

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

“…2 Next-generation sequencing (NGS) delivers comprehensive tools to encompass genetic heterogeneity, resolve complex phenotypes and identify novel gene defects. 3,4 We report the genetic characterization of three brothers with IRD from consanguineous Senegalese parents applying targeted NGS and whole exome sequencing (WES) and show the relevance of these techniques to decipher phenotypic complexity. All research procedures followed the tenets of the Declaration of Helsinki, were approved by the local Ethics Committee with informed consent prior to genetic testing.…”

A novel nonsense variant in REEP6 is involved in a sporadic rod‐cone dystrophy case

“…WES data analyses identified 4 presumably homozygous variants in 4 genes, TTC1 (MIM*601963), APC2 (MIM*612034), THOC3 (MIM*606929) and REEP6 (MIM*609346) (Table ). While variants in TTC1 , APC2 and THOC3 are missense, a nonsense variant in REEP6 (c.267G>A rs761786834 p.(Trp89*)) was identified in a homozygous region (1.8 Mb), as shown by homozygosity mapping, and never reported at homozygous state (gnomAD, Table ). Variants identified in TTC1 and APC2 , coding for tetratricopeptide repeat domain‐containing protein 1 and adenomatous polyposis coli protein 2, respectively, were predicted to be pathogenic only by 1 program, and THOC3 , coding for THO complex subunit 3, was not found in a homozygous region.…”

“…Considering the reported consanguinity only homozygous variants were kept. Stringent filtering was applied as previously reported with Genome Aggregation Database (gnomAD) (http://gnomad.broadinstitute.org/) and Bravo (https://bravo.sph.umich.edu/freeze3a/hg19). Retinal expression profiles were evaluated with mouse and human transcriptomic databases in case of a variant in a gene not previously reported to be mutated in IRD .…”

“…1 RCD is associated with mutations in 84 distinct genes (RetNet, updated May 23, 2017; https://sph.uth.edu/retnet/sum-dis.htm) encoding proteins involved in various cellular functions including the phototransduction cascade, protein biogenesis or trafficking, especially in photoreceptors. 2,3 To cover the genetic heterogeneity and identify new gene defects, highthroughput sequencing strategies including targeted next-generation sequencing (NGS), whole exome sequencing (WES) and whole genome sequencing [4][5][6][7][8][9][10][11] have been successfully developed. We report here the gene defect identified through WES of a RCD case, previously excluded for known gene defects by targeted NGS.…”

“…5,6 Considering the reported consanguinity only homozygous variants were kept. Stringent filtering was applied as previously reported 10 (Trp89*)) was identified in a homozygous region (1.8 Mb), as shown by homozygosity mapping, 10 and never reported at homozygous state (gno-mAD, Table 1). Variants identified in TTC1 and APC2, coding for tetratricopeptide repeat domain-containing protein 1 and adenomatous polyposis coli protein 2, respectively, were predicted to be pathogenic only by 1 program, and THOC3, coding for THO complex subunit 3, was not found in a homozygous region.…”