Division of Molecular Biology and Human Genetics, Stellenbosch University, Cape Town, South Africa.
Medical Genetics, Tygerberg Hospital, Cape Town, South Africa.
Am J Med Genet A. 2022 Sep;188(9):2684-2692. doi: 10.1002/ajmg.a.62847. Epub 2022 May 26.
The Undiagnosed Disease Program in South Africa (UDP) sought to prospectively evaluate the clinical utility of exome sequencing (ES) in a phenotypically diverse, multi-ethnic cohort of South African patients with suspected rare genetic disorders. ES was undertaken in 100 sequential patients (93 singletons, 3 duos, and 4 trios) recruited to the UDP at Stellenbosch University. The data were analyzed through two separate bioinformatics pipelines (EVIDENCE from 3 billion and our in-house pipeline). A definitive diagnosis could be reached in 51% (51/100) patients, with 46% (46/100) patients having either pathogenic or likely pathogenic single-nucleotide variants/indels (SNVs/indels), and 5 patients with likely-pathogenic copy number variants (CNVs) (5/100). The CNVs were subsequently confirmed on microarray or MLPA analysis. Detailed phenotyping and HPO terms enabled analysis and variant identification. Twenty-five novel variants in 22 genes are reported here. We provide data from the first year of this UDP and show that even amongst mainly singletons from an understudied, diverse African population, ES is a valuable diagnostic tool, especially if it includes CNV analysis. The remaining undiagnosed patients present a unique opportunity for further research and novel gene discovery.
南非未确诊疾病计划（UDP）旨在前瞻性评估外显子组测序（ES）在南非疑似罕见遗传疾病的表型多样、多种族队列中的临床应用价值。在斯泰伦博斯大学的 UDP 中，对 100 名连续患者（93 名单胎、3 对双胞胎和 4 对三胞胎）进行了 ES 检测。通过两个独立的生物信息学管道（来自 30 亿的 EVIDENCE 和我们内部的管道）对数据进行了分析。在 51%（51/100）的患者中可以明确诊断，其中 46%（46/100）的患者存在致病性或可能致病性的单核苷酸变异/插入（SNVs/indels），5 名患者存在可能致病性的拷贝数变异（CNVs）（5/100）。随后在微阵列或 MLPA 分析中确认了 CNVs。详细的表型和 HPO 术语使分析和变异鉴定成为可能。在 22 个基因中报告了 25 个新的变异。我们提供了 UDP 第一年的数据，表明即使在主要来自研究不足、多样化的非洲人群的单胎中，ES 也是一种有价值的诊断工具，特别是如果它包括 CNV 分析。其余未确诊的患者为进一步研究和新基因发现提供了独特的机会。
