Children's Hospital Colorado, Aurora, CO, USA.
Department of Pediatrics, University of Colorado, School of Medicine, Aurora, CO, USA.
Dev Med Child Neurol. 2022 May;64(5):633-640. doi: 10.1111/dmcn.15109. Epub 2021 Nov 19.
To identify additional genes associated with infantile spasms using a cohort with defined infantile spasms.
Whole-exome sequencing (WES) was performed on 21 consented individuals with infantile spasms and their unaffected parents (a trio-based study). Clinical history and imaging were reviewed. Potentially deleterious exonic variants were identified and segregated. To refine potential candidates, variants were further prioritized on the basis of evidence for relevance to disease phenotype or known associations with infantile spasms, epilepsy, or neurological disease.
Likely pathogenic de novo variants were identified in NR2F1, GNB1, NEUROD2, GABRA2, and NDUFAF5. Suggestive dominant and recessive candidate variants were identified in PEMT, DYNC1I1, ASXL1, RALGAPB, and STRADA; further confirmation is required to support their relevance to disease etiology.
This study supports the utility of WES in uncovering the genetic etiology in undiagnosed individuals with infantile spasms with an overall yield of five out of 21. High-priority candidates were identified in an additional five individuals. WES provides additional support for previously described disease-associated genes and expands their already broad mutational and phenotypic spectrum.
通过对具有明确婴儿痉挛症的队列进行全外显子测序（WES），鉴定与婴儿痉挛症相关的其他基因。
对 21 名同意参与的婴儿痉挛症患者及其未受影响的父母（基于三亲研究的一组）进行了全外显子测序（WES）。回顾了临床病史和影像学检查。鉴定并分离出潜在的有害外显子变异。为了进一步细化潜在的候选基因，根据这些变异与疾病表型的相关性或与婴儿痉挛症、癫痫或神经疾病的已知关联的证据，对变异进行了进一步的优先排序。
在 NR2F1、GNB1、NEUROD2、GABRA2 和 NDUFAF5 中鉴定出可能具有致病性的新生变异。在 PEMT、DYNC1I1、ASXL1、RALGAPB 和 STRADA 中鉴定出提示显性和隐性候选变异；需要进一步的确认来支持它们与疾病病因的相关性。
这项研究支持 WES 在揭示婴儿痉挛症未确诊个体的遗传病因方面的有效性，在 21 名患者中有 5 名患者得到了明确的结果。在另外 5 名患者中鉴定出高优先级候选基因。WES 为先前描述的与疾病相关的基因提供了额外的支持，并扩展了它们已经广泛的突变和表型谱。
