Clinical and genetic investigation of a large Tunisian family with complete achromatopsia: identification of a new nonsense mutation in GNAT2 gene

Abstract

Complete achromatopsia is a rare autosomal recessive disease associated with CNGA3, CNGB3, GNAT2 and PDE6C mutations. This retinal disorder is characterized by complete loss of color discrimination due to the absence or alteration of the cones function. The purpose of the present study was the clinical and the genetic characterization of achromatopsia in a large consanguineous Tunisian family. Ophthalmic evaluation included a full clinical examination, color vision testing and electroretinography. Linkage analysis using microsatellite markers flanking CNGA3, CNGB3, GNAT2 and PDE6C genes was performed. Mutations were screened by direct sequencing. A total of 12 individuals were diagnosed with congenital complete achromatopsia. They are members of six nuclear consanguineous families belonging to the same large consanguineous family. Linkage analysis revealed linkage to GNAT2. Mutational screening of GNAT2 revealed three intronic variations c.119À69G4C, c.161+66A4T and c.875À31G4C that co-segregated with a novel mutation p.R313X. An identical GNAT2 haplotype segregating with this mutation was identified, indicating a founder mutation. All patients were homozygous for the p.R313X mutation. This is the first report of the clinical and genetic investigation of complete achromatopsia in North Africa and the largest family with recessive achromatopsia involving GNAT2; thus, providing a unique opportunity for genotype-phenotype correlation for this extremely rare condition.

Mutation spectrum and clinical investigation of achromatopsia patients with mutations in the GNAT2 gene

“…Out of the four different nonsense mutations, two were novel (c.313 C > T;p.[Arg105*] and c.481 C > T;p.[Arg161*]). Similar to the two already published nonsense mutations (Kohl et al, ; Ouechtati et al, ), the mutations will result in the loss of important functional domains, if the mutant transcripts are translated.…”

“…In 2002, we reported five families with patients affected by ACHM caused by mutations in GNAT2 (Kohl et al, ; Rosenberg et al, ). Since then only few reports of single families have been published (Aligianis et al, ; Piña, Baumert, Loyer, & Koenekoop, ; Ouechtati et al, ; Langlo et al, , Taylor et al, ; Carss et al, ; Ueno et al, ). Herein we report the results of our genetic investigation of our complete ACHM cohort over a period of 16 years, in total identifying 23 affected individuals from 19 independent families carrying likely disease‐causing mutations in GNAT2 , of which 12 mutations have never been reported before.…”

Genetic testing for achromatopsia

“…ACHM is a heterogeneous disorder with autosomal recessive inheritance. Pathogenic variants of CNGA3 (OMIM gene: 600053; OMIM disease: 216900), CNGB3 (OMIM gene: 605080; OMIM disease: 262300), GNAT2 (OMIM gene: 139340; OMIM disease 613856), PDE6C (OMIM gene: 600827; OMIM disease: 613093), ATF6 (OMIM gene: 605537; OMIM disease: 616517) and PDE6H (OMIM gene: 601190; OMIM disease: 610024) have been reported to be causative for autosomal recessive ACHM (5,6). CNGA3 and CNGB3 are the major causative genes of ACHM, and account for ~20-30% and 40-50% of the cases, respectively (6,7).…”

Epidemiologic, clinical and pathogenesis features of achromatopsia in the Russian population

“…близительно в 10 % случаев. В последние годы были предприняты значительные усилия для молекулярной характеристики, описания спектра мутаций и диагностики ACHM в различных популяциях, включая голландскую [9], израильскую [10], палестинскую [11], немецкую [12,13], датскую, итальянскую, жителей США [14], шведскую [15], венгерскую [16], французскую, швейцарскую, китайскую [17], польскую [18], европейскую в целом [19] и жителей Туниса [20]. Однако подробных эпидемиологических исследований на территории России и СНГ не было обнаружено.…”