Biallelic mutations in G‐Protein coupled receptor kinase 1 (GRK1) cause Oguchi disease, a rare subtype of congenital stationary night blindness (CSNB). The purpose of this study was to identify disease causing GRK1 variants and use in‐depth bioinformatic analyses to evaluate how their impact on protein structure could lead to pathogenicity. Patients’ genomic DNA was sequenced by whole genome, whole exome or focused exome sequencing. Disease associated variants, published and novel, were compared to nondisease associated missense variants. The impact of GRK1 missense variants at the protein level were then predicted using a series of computational tools. We identified twelve previously unpublished cases with biallelic disease associated GRK1 variants, including eight novel variants, and reviewed all GRK1 disease associated variants. Further structure‐based scoring revealed a hotspot for missense variants in the kinase domain. In addition, to aid future clinical interpretation, we identified the bioinformatics tools best able to differentiate disease associated from nondisease associated variants. We identified GRK1 variants in Oguchi disease patients and investigated how disease‐causing variants may impede protein function in‐silico.

中文翻译：

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GRK1 相关 Oguchi 病的新变体和计算机分析

G 蛋白偶联受体激酶 1 (GRK1) 的双等位基因突变导致大口病，这是一种罕见的先天性静止性夜盲症 (CSNB) 亚型。本研究的目的是识别引起疾病的 GRK1 变异体，并使用深入的生物信息学分析来评估它们对蛋白质结构的影响如何导致致病性。通过全基因组、全外显子组或聚焦外显子组测序对患者的基因组 DNA 进行测序。将已发表和新颖的疾病相关变体与非疾病相关的错义变体进行比较。然后使用一系列计算工具预测GRK1错义变体在蛋白质水平上的影响。我们确定了 12 个以前未发表的与双等位基因疾病相关的 GRK1 变体病例，包括 8 个新变体，并回顾了所有GRK1疾病相关变异。进一步基于结构的评分揭示了激酶结构域中错义变体的热点。此外，为了帮助未来的临床解释，我们确定了最能区分疾病相关变异和非疾病相关变异的生物信息学工具。我们在 Oguchi 病患者中鉴定了 GRK1变异体，并研究了致病变异体如何在计算机上阻碍蛋白质功能。