Department of Ophthalmology, West China Hospital, Sichuan University, Chengdu, China.
Key Laboratory of Epigenetics and Oncology, Research Center for Preclinical Medicine, Southwest Medical University, Luzhou, China.
Br J Ophthalmol. 2019 Mar;103(3):428-435. doi: 10.1136/bjophthalmol-2018-312347. Epub 2018 Oct 26.
BACKGROUND/AIM: Gyrate atrophy of the choroid and retina (GACR) is an extremely rare autosomal recessive inherited disorder characterised by progressive vision loss. To identify the disease-causing gene in a consanguineous Chinese pedigree with GACR, we aimed to accurately diagnose patients with GACR through a combination of next-generation sequencing (NGS) genetic diagnosis, clinical imaging and amino acid metabolic analysis.
A consanguineous Chinese pedigree with GACR, including two patients, was recruited and a comprehensive ophthalmological evaluation was performed. DNA was extracted from a proband and her family members, and the sample from the proband was analysed using targeted NGS. Variants detected by NGS were confirmed by Sanger sequencing and subjected to segregation analysis. Tandem mass spectrometry (MS/MS) was subsequently performed for metabolic assessment.
We identified a novel, deleterious, homologous ornithine aminotransferase () variant, c.G248A: p.S83N, which contributes to the progression of GACR in patients. Our results showed that the p.S83N autosomal recessive variant of OAT is most likely pathogenic, with changes in protein stability drastically decreasing functionality. MS/MS verified that ornithine levels in patients were significantly elevated.
Recruitment of a third-degree first cousin consanguineous marriage family with GACR allowed us to identify a novel pathogenic variant in the Chinese population, broadening the mutation spectrum. Our findings reported the diagnostic value of a combination of NGS, retinal imaging and metabolic analysis of consanguineous marriage pedigrees in low-income/middle-income and low-incidence countries, including China, and may help to guide accurate diagnosis and treatment of this disease.
背景/目的：脉络膜和视网膜鸟氨酸氨甲酰基转移酶缺乏症（GACR）是一种极其罕见的常染色体隐性遗传疾病，其特征是进行性视力丧失。为了确定一个有 GACR 家族史的中国近亲家庭中的致病基因，我们旨在通过下一代测序（NGS）遗传诊断、临床成像和氨基酸代谢分析相结合，准确诊断 GACR 患者。
我们招募了一个有 GACR 的中国近亲家族，包括两名患者，并进行了全面的眼科评估。从先证者及其家庭成员中提取 DNA，并对先证者的样本进行靶向 NGS 分析。通过 NGS 检测到的变体通过 Sanger 测序进行确认，并进行分离分析。随后进行串联质谱（MS/MS）进行代谢评估。
我们发现了一种新的、有害的、同源的鸟氨酸转氨酶（OAT）变体，c.G248A：p.S83N，该变体导致患者 GACR 的进展。我们的结果表明，OAT 的 p.S83N 常染色体隐性变体很可能是致病性的，其蛋白稳定性的变化大大降低了功能。MS/MS 验证了患者的鸟氨酸水平明显升高。
招募一个有 GACR 的第三代表亲近亲结婚家庭，使我们能够在中国人群中发现一种新的致病变体，扩大了突变谱。我们的研究结果报告了 NGS、视网膜成像和代谢分析相结合在低收入/中等收入和低发病率国家（包括中国）的近亲婚姻家族中的诊断价值，可能有助于指导这种疾病的准确诊断和治疗。
