Unraveling MECP2 structural variants in previously elusive Rett syndrome cases through IGV interpretation.

IF 4.7 2区医学 Q1 GENETICS & HEREDITY NPJ Genomic Medicine Pub Date : 2025-03-13 DOI:10.1038/s41525-025-00481-9

Tomer Poleg, Noam Hadar, Gali Heimer, Vadim Dolgin, Ilana Aminov, Amit Safran, Nadav Agam, Matan M Jean, Ofek Freund, Simran Kaur, John Christodoulou, Bruria Ben-Zeev, Ohad S Birk

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Abstract

Rett syndrome (RTT) is a severe neurodevelopmental disorder, with MECP2 mutations accounting for 90-95% of classic and 50-70% of atypical cases. However, many clinically diagnosed RTT patients remain without molecular diagnoses. While point mutations and large rearrangements in MECP2 are well studied, the role of small-intermediate structural variants (SVs) remains mostly elusive. Using standard short-read whole genome sequencing, we identified novel de novo SVs in three out of three previously unresolved RTT cases: a complex SV with two deletions ( ~ 5Kbp and ~60Kbp) and a ~105Kbp inversion; a ~200Kbp translocation; and a ~3Kbp deletion. These findings suggest that such elusive SVs might be a common cause for "MECP2-negative" RTT. Incorporating SV detection into routine genetic testing through bioinformatic analysis of short-read sequencing or manual review using IGV could improve diagnostic rates and expand our understanding of RTT and similar disorders.

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雷特综合征（RTT）是一种严重的神经发育障碍，MECP2突变占典型病例的90-95%和非典型病例的50-70%。然而，许多经临床诊断的 RTT 患者仍未得到分子诊断。虽然对MECP2的点突变和大重排进行了深入研究，但对小的中间结构变异（SV）的作用大多仍难以捉摸。利用标准短线程全基因组测序，我们在三个先前未解决的 RTT 病例中的三个病例中鉴定出了新的全新 SV：一个复杂 SV，其中有两个缺失（约 5Kbp 和约 60Kbp）和一个约 105Kbp 的倒位；一个约 200Kbp 的易位；以及一个约 3Kbp 的缺失。这些发现表明，这种难以捉摸的 SV 可能是导致 "MECP2 阴性 "RTT 的常见原因。通过对短线程测序进行生物信息学分析或使用 IGV 进行人工复查，将 SV 检测纳入常规基因检测，可提高诊断率并扩大我们对 RTT 和类似疾病的了解。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

NPJ Genomic Medicine Biochemistry, Genetics and Molecular Biology-Molecular Biology

CiteScore

9.40

自引率

1.90%

发文量

审稿时长

17 weeks

期刊介绍： npj Genomic Medicine is an international, peer-reviewed journal dedicated to publishing the most important scientific advances in all aspects of genomics and its application in the practice of medicine. The journal defines genomic medicine as "diagnosis, prognosis, prevention and/or treatment of disease and disorders of the mind and body, using approaches informed or enabled by knowledge of the genome and the molecules it encodes." Relevant and high-impact papers that encompass studies of individuals, families, or populations are considered for publication. An emphasis will include coupling detailed phenotype and genome sequencing information, both enabled by new technologies and informatics, to delineate the underlying aetiology of disease. Clinical recommendations and/or guidelines of how that data should be used in the clinical management of those patients in the study, and others, are also encouraged.