Abstract：
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, and 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 1060 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.
摘要：
色盲（ACHM）是一种先天性视锥感光障碍，其特征是颜色辨别能力受损，低视力，光敏性,和眼球震颤.迄今为止,六个基因与ACHM相关(CNGA3，CNGB3，GNAT2，PDE6C，PDE6H,和ATF6），其中大多数与视锥光转导级联有关。CNGA3编码视锥光感受器中环核苷酸门控离子通道的CNGA3亚基，是ACHM的主要疾病相关基因之一。在这里，我们提供了一个全面的概述CNGA3变异谱在1060名遗传证实的ACHM患者的队列，其中385例（36.3%）携带CNGA3中的“可能致病”变体。将我们自己的基因数据与文献和公共数据库中报道的数据进行汇编，我们进一步将CNGA3变体谱扩展到总共316个变体，根据ACMG/AMP标准，其中244项我们解释为“可能致病”。我们报告了48个新的“可能致病”变体，其中24个是错义取代,强调了该突变类别在CNGA3变体谱中的主要作用。此外,我们提供了广泛的计算机模拟分析，并总结了以前分析的错义的报告功能数据，无义和剪接变体，以进一步推进所鉴定变体的致病性评估。
