加拿大病童医院Stephen W. Scherer研究组发现，全面的全基因组序列分析有助于深入了解脑瘫的基因组结构。这一研究成果于2024年3月29日在线发表在国际学术期刊《自然—遗传学》上。

研究人员对327名脑瘫（CP）儿童及其亲生父母进行了全基因组测序（WGS）。研究人员将327名儿童中的37名（11.3%）归类为致病/可能致病（P/LP）变异，将327名儿童中的58名（17.7%）归类为意义不确定的变异。多类P/LP变异包括单核苷酸变异（SNV）/indels（6.7%）、拷贝数变异（3.4%）和线粒体突变（1.5%）。COL4A1基因的P/LP SNV最多。

研究人员还分析了两个儿科对照队列（n=203个三人家庭和n=89个兄弟姐妹家庭），为新发突变率和遗传负荷分析提供了基线，后者显示了新发有害变异与神经系统相关基因之间的关联。富集分析发现了以前未曾描述过的疑似CP候选基因（SMOC1、KDM5B、BCL11A和CYP51A1）。多因素CP风险概况和P/LP变异的大量存在，共同支持了WGS在所有CP和相关表型的诊断工作中的应用。

附：英文原文

Title: Comprehensive whole-genome sequence analyses provide insights into the genomic architecture of cerebral palsy

Author: Fehlings, Darcy L., Zarrei, Mehdi, Engchuan, Worrawat, Sondheimer, Neal, Thiruvahindrapuram, Bhooma, MacDonald, Jeffrey R., Higginbotham, Edward J., Thapa, Ritesh, Behlim, Tarannum, Aimola, Sabrina, Switzer, Lauren, Ng, Pamela, Wei, John, Danthi, Prakroothi S., Pellecchia, Giovanna, Lamoureux, Sylvia, Ho, Karen, Pereira, Sergio L., de Rijke, Jill, Sung, Wilson W. L., Mowjoodi, Alireza, Howe, Jennifer L., Nalpathamkalam, Thomas, Manshaei, Roozbeh, Ghaffari, Siavash, Whitney, Joseph, Patel, Rohan V., Hamdan, Omar, Shaath, Rulan, Trost, Brett, Knights, Shannon, Samdup, Dawa, McCormick, Anna, Hunt, Carolyn, Kirton, Adam, Kawamura, Anne, Mesterman, Ronit, Gorter, Jan Willem, Dlamini, Nomazulu, Merico, Daniele, Hilali, Murto, Hirschfeld, Kyle, Grover, Kritika, Bautista, Nelson X., Han, Kara, Marshall, Christian R., Yuen, Ryan K. C., Subbarao, Padmaja, Azad, Meghan B., Turvey, Stuart E., Mandhane, Piush, Moraes, Theo J., Simons, Elinor, Maxwell, George, Shevell, Michael, Costain, Gregory, Michaud, Jacques L., Hamdan, Fadi F., Gauthier, Julie, Uguen, Kevin, Stavropoulos, Dimitri J.

Issue&Volume: 2024-03-29

Abstract: We performed whole-genome sequencing (WGS) in 327 children with cerebral palsy (CP) and their biological parents. We classified 37 of 327 (11.3%) children as having pathogenic/likely pathogenic (P/LP) variants and 58 of 327 (17.7%) as having variants of uncertain significance. Multiple classes of P/LP variants included single-nucleotide variants (SNVs)/indels (6.7%), copy number variations (3.4%) and mitochondrial mutations (1.5%). The COL4A1 gene had the most P/LP SNVs. We also analyzed two pediatric control cohorts (n=203 trios and n=89 sib-pair families) to provide a baseline for de novo mutation rates and genetic burden analyses, the latter of which demonstrated associations between de novo deleterious variants and genes related to the nervous system. An enrichment analysis revealed previously undescribed plausible candidate CP genes (SMOC1, KDM5B, BCL11A and CYP51A1). A multifactorial CP risk profile and substantial presence of P/LP variants combine to support WGS in the diagnostic work-up across all CP and related phenotypes.

DOI: 10.1038/s41588-024-01686-x

Source: https://www.nature.com/articles/s41588-024-01686-x