University of Lausanne, Lausanne, Switzerland.
Service of Endocrinology, Diabetology and Metabolism, Lausanne University Hospital, Avenue de La Sallaz 8, Lausanne, CH-1011, Switzerland.
BMC Genomics. 2024 Aug 14;25(1):787. doi: 10.1186/s12864-024-10598-3.
BACKGROUND/OBJECTIVES: This study aims to elucidate the genetic causes of congenital hypogonadotropic hypogonadism (CHH), a rare genetic disorder resulting in GnRH deficiency, in six families from Pakistan.
Eighteen DNA samples from six families underwent genome sequencing followed by standard evaluation for pathogenic single nucleotide variants (SNVs) and small indels. All families were subsequently analyzed for pathogenic copy number variants (CNVs) using CoverageMaster.
Novel pathogenic homozygous SNVs in known CHH genes were identified in four families: two families with variants in GNRHR, and two others harboring KISS1R variants. Subsequent investigation of CNVs in the remaining two families identified novel unique large deletions in ANOS1.
A combined, systematic analysis of single nucleotide and CNVs helps to improve the diagnostic yield for variants in patients with CHH.
背景/目的：本研究旨在阐明导致促性腺激素释放激素缺乏的罕见遗传性疾病——先天性低促性腺激素性性腺功能减退症（CHH）的遗传原因。该研究共纳入来自巴基斯坦的六个家庭的 18 个 DNA 样本，对这些样本进行了基因组测序，并对致病性单核苷酸变异（SNV）和小插入缺失进行了标准评估。随后使用 CoverageMaster 对所有家庭进行致病性拷贝数变异（CNV）分析。
在四个家庭中发现了已知 CHH 基因中的新的致病性纯合 SNV：两个家庭存在 GNRHR 变异，另外两个家庭存在 KISS1R 变异。对其余两个家庭的 CNV 进行进一步研究，发现了 ANOS1 中的新型独特大片段缺失。
对单核苷酸和 CNV 的综合、系统分析有助于提高 CHH 患者变异的诊断率。
