Achromatopsia (ACHM) is a congenital cone photoreceptor disorder characterized by
impaired color discrimination, low visual acuity, photosensitivity, and nystagmus.
To date, six genes have been associated with ACHM (CNGA3, CNGB3, GNAT2, PDE6C, PDE6H,
ATF6), the majority of these being implicated in the cone phototransduction cascade.
CNGA3 encodes the CNGA3 subunit of the cyclic nucleotide-gated ion channel in cone
photoreceptors and is one of the major disease-associated genes for ACHM. Herein,
we provide a comprehensive overview of the CNGA3 variant spectrum in a cohort of 1,060
genetically confirmed ACHM patients, 385 (36.3%) of these carrying "likely disease-causing"
variants in CNGA3. Compiling our own genetic data with those reported in the literature
and in public databases, we further extend the CNGA3 variant spectrum to a total of
316 variants, 244 of which we interpreted as "likely disease-causing" according to
ACMG/AMP criteria. We report 48 novel "likely disease-causing" variants, 24 of which
are missense substitutions underlining the predominant role of this mutation class
in the CNGA3 variant spectrum. In addition, we provide extensive in silico analyses
and summarize reported functional data of previously analyzed missense, nonsense and
splicing variants to further advance the pathogenicity assessment of the identified
variants. This article is protected by copyright. All rights reserved.
