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

Abstract

Achromatopsia (ACHM) is a hereditary cone photoreceptor disorder characterized by the inability to discriminate colors, nystagmus, photophobia, and low‐visual acuity. Six genes have been associated with this rare autosomal recessively inherited disease, including the GNAT2 gene encoding the catalytic α‐subunit of the G‐protein transducin which is expressed in the cone photoreceptor outer segment. Out of a cohort of 1,116 independent families diagnosed with a primary clinical diagnosis of ACHM, we identified 23 patients with ACHM from 19 independent families with likely causative mutations in GNAT2, representing 1.7% of our large ACHM cohort. In total 22 different potentially disease‐causing variants, of which 12 are novel, were identified. The mutation spectrum also includes a novel copy number variation, a heterozygous duplication of exon 4, of which the breakpoint matches exactly that of the previously reported exon 4 deletion. Two patients carry just a single heterozygous variant. In addition to our previous study on GNAT2‐ACHM, we also present detailed clinical data of these patients.

Photoreceptor Structure inGNAT2-Associated Achromatopsia

“…S3). The observed color vision in our patient was better than previously reported residual color vision in GNAT2, 3,6,8 including the previously reported pedigree included in our study. 7 Despite the milder phenotype observed in patient P4, cone densities at all ROIs were the lowest in the cohort (Fig.…”

“…Felden et al in their genotyping study, reported a patient (CHRO768-II:1) with the same homozygous variant, without, however, any color vision or ERG data available. 8 Interestingly, this patient had undetectable standard light-adapted (LA30Hz; LA3) ERGs, when tested with Internationalstandard full-field ERGs, 54 and undetectable pattern ERG. 55 The recording to short wavelength flashes on an amber background (S-cone ERG; stimulus duration 5 ms) 56 was simplified and subnormal bilaterally ( Supplementary Fig.…”

“…All patients harbored previously reported GNAT2 variants. 1,8,34 Two pedigrees harbor nonsense mutations, leading to premature termination of translation, one pedigree harbored a missense mutation, and one pedigree a 4-bp insertion leading to a frameshift. Demographics and genetics are summarized in Supplementary Table S1.…”

“…3,4 Patients with GNAT2-related achromatopsia (GNAT2-ACHM) exhibit nystagmus beginning at birth / early infancy, photophobia, abnormal color vision, and poor visual acuity (VA). 5 Color vision testing is usually abnormal, with no color discrimination observed in most patients [6][7][8][9] ; although some patients may retain some color vision. 3,7 A study suggested that the retention of color vision may be related to variants that result in some functional protein product.…”

“…32 A recent study from Felden et al estimated the prevalence of GNAT2-ACHM to be 1.7%, in a cohort of 1116 independent ACHM families. 8 Due to its low prevalence, a limited number of studies have focused on phenotyping GNAT2-ACHM, despite the advancements in the field of gene therapy.…”