PDF(Pubmed)
Abstract：
While short-read sequencing currently dominates genetic research and diagnostics, it frequently falls short of capturing certain structural variants (SVs), which are often implicated in the etiology of neurodevelopmental disorders (NDDs). Optical genome mapping (OGM) is an innovative technique capable of capturing SVs that are undetectable or challenging-to-detect via short-read methods. This study aimed to investigate NDDs using OGM, specifically focusing on cases that remained unsolved after standard exome sequencing. OGM was performed in 47 families using ultra-high molecular weight DNA. Single-molecule maps were assembled de novo, followed by SV and copy number variant calling. We identified 7 variants of interest, of which 5 (10.6%) were classified as likely pathogenic or pathogenic, located in BCL11A, OPHN1, PHF8, SON, and NFIA. We also identified an inversion disrupting NAALADL2, a gene which previously was found to harbor complex rearrangements in two NDD cases. Variants in known NDD genes or candidate variants of interest missed by exome sequencing mainly consisted of larger insertions (> 1kbp), inversions, and deletions/duplications of a low number of exons (1-4 exons). In conclusion, in addition to improving molecular diagnosis in NDDs, this technique may also reveal novel NDD genes which may harbor complex SVs often missed by standard sequencing techniques.
摘要：
虽然短读测序目前主导着基因研究和诊断，它经常无法捕获某些结构变体(SV)，这通常与神经发育障碍（NDD）的病因有关。光学基因组作图（OGM）是一种创新技术，能够通过短阅读方法捕获无法检测或难以检测的SV。本研究旨在研究使用OGM的NDD，特别关注标准外显子组测序后仍未解决的病例。使用超高分子量DNA在47个家族中进行OGM。单分子图谱从头组装，其次是SV和拷贝数变异调用。我们确定了7个感兴趣的变体，其中5人(10.6%)被归类为可能致病或致病，位于BCL11A,OPHN1,PHF8,SON,NFIA。我们还确定了破坏NAALADL2的倒位，该基因先前在两个NDD病例中被发现具有复杂的重排。已知NDD基因的变异体或外显子组测序遗漏的候选变异体主要由较大的插入体（>1kbp）组成。倒置,以及少量外显子（1-4个外显子）的缺失/重复。总之,除了改善NDD的分子诊断，该技术还可能揭示新的NDD基因,这些基因可能含有标准测序技术经常遗漏的复杂SVs.
