小年
(2024-03-31 17:31):
#paper Fehlings, D.L., Zarrei, M., Engchuan, W. et al. Comprehensive whole-genome sequence analyses provide insights into the genomic architecture of cerebral palsy. Nat Genet (2024). https://doi-org-443.webvpn.las.ac.cn/10.1038/s41588-024-01686-x
本文对超过320名患有脑瘩（CP）的儿童及其生物学父母进行了全基因组测序（WGS）数据分享。研究发现，11.3%的儿童存在致病/可能致病（P/LP）变异，17.7%的儿童存在不确定意义的变异。这些变异类型包括单核苷酸变异/缺失、拷贝数变异以及线粒体变异，其中COL4A1基因发现了最多的P/LP单核苷酸变异（SNVs）。此外，本项研究还将脑瘫患者与儿科对照组进行了比较，以确立新生突变率和遗传负荷分析的基准，发现新生有害变异与与神经系统相关的基因之间存在关联。本篇文章强调，脑瘫是最常见的儿童起始期身体残疾，经常伴随认知和行为障碍等额外发展影响。研究突显了遗传因素对脑瘫的重要影响，尤其是在没有明显产前、产时或产后病理因素、足月出生以及脑部影像学正常的情况下。研究强调了脑瘫的多因素本质，涉及遗传变异与环境因素的复杂交互作用。该研究的结果支持在脑瘫的诊断流程中引入全基因组测序，以识别包括罕见变异和线粒体变异在内的广泛遗传变异。同时表明，遗传测试有助于深入了解脑瘫的病因，改善家庭咨询，并指导针对性治疗。
Comprehensive whole-genome sequence analyses provide insights into the genomic architecture of cerebral palsy
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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.
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