Two novel PDE6C gene mutations in Chinese family with achromatopsia

Background: Achromatopsia (ACHM) is an inherited retinal disease affecting the cone cell function. To date, six pathogenic genes of ACHM have been identified. However, the diagnostic and therapeutic methods of this disorder remain limited. Herein, to characterize the clinical features and genetic causes of three affected siblings in a Chinese family with ACHM, we used target next-generation sequencing (NGS) and found new pathogenic factors associated with ACHM in this family. Materials and methods: Three patients with ACHM and three healthy family members were included in this study. All participants received comprehensive ophthalmic tests. NGS approach was performed on the patients to determine the causative mutation for this family. The silico analysis was also applied to predict the pathogenesis of identified mutations. Results: Genetic assessments revealed compound heterozygous mutations of the PDE6C gene (c.1413 + 1 G > C, c.305 G > A), carried by all three patients. Both mutations were novel and predicted to be deleterious by six types of online predictive software. The heterozygous PDE6C missense mutation (c.305 G > A) was found from the mother and the heterozygous PDE6C splice site mutation (c.1413 + 1 G > C) was found in the father and all the children. All patients in the family showed typical signs and symptoms of ACHM. Conclusions: We report novel compound heterozygous PDE6C mutations in causing ACHM and further confirm the clinical diagnosis. Our study extends the genotypic spectrums for PDE6C-ACHM and better illustrates its genotype–phenotype correlations, which would help the ACHM patients with better genetic diagnosis, prognosis, and gene treatment.背景：全色盲（Achromatopsia, ACHM）是一类累及视锥细胞功能的遗传性视网膜疾病。截至目前，已明确6种与全色盲相关的致病基因，但该疾病的诊断与治疗手段仍较为有限。本研究针对一个中国全色盲家系中的3名患病同胞展开，旨在明确其临床特征与遗传病因；我们通过靶向二代测序（target next-generation sequencing, NGS）技术，在该家系中发现了与全色盲相关的全新致病因子。 材料与方法：本研究共纳入3名全色盲患者及3名健康家系成员，所有受试者均接受了全面的眼科检查。对患者实施靶向二代测序，以鉴定该家系的致病突变；同时开展计算机虚拟分析（in silico analysis），对所鉴定突变的致病机制进行预测。 结果：遗传检测结果显示，3名患者均携带PDE6C基因的复合杂合突变（c.1413 + 1 G > C、c.305 G > A）。上述两种突变均为新发突变，经6款在线预测软件分析，均被判定为致病性突变。其中，PDE6C基因的杂合错义突变（c.305 G > A）源自母亲，而杂合剪接位点突变（c.1413 + 1 G > C）则存在于父亲及所有患病子女中。该家系的所有患者均表现出全色盲典型的临床体征与症状。 结论：本研究报道了可导致全色盲的全新PDE6C基因复合杂合突变，进一步验证了该家系的临床诊断。本研究拓展了PDE6C相关性全色盲的基因型谱，并进一步阐明了其基因型与表型之间的关联，可为全色盲患者提供更精准的遗传诊断、预后评估及基因治疗方案。