Adelaide Medical School, The University of Adelaide, Adelaide, South Australia, Australia; Robinson Research Institute, The University of Adelaide, Adelaide, South Australia, Australia.
Genetics Service, Hospital del Mar Medical Research Institute (IMIM), Network Research Centre for Rare Diseases (CIBERER), Barcelona, Spain; Department of Medicine and Life Sciences, Universitat Pompeu Fabra, Barcelona, Spain.
Genet Med. 2022 Nov;24(11):2351-2366. doi: 10.1016/j.gim.2022.08.006. Epub 2022 Sep 9.
Germline loss-of-function variants in CTNNB1 cause neurodevelopmental disorder with spastic diplegia and visual defects (NEDSDV; OMIM 615075) and are the most frequent, recurrent monogenic cause of cerebral palsy (CP). We investigated the range of clinical phenotypes owing to disruptions of CTNNB1 to determine the association between NEDSDV and CP.
Genetic information from 404 individuals with collectively 392 pathogenic CTNNB1 variants were ascertained for the study. From these, detailed phenotypes for 52 previously unpublished individuals were collected and combined with 68 previously published individuals with comparable clinical information. The functional effects of selected CTNNB1 missense variants were assessed using TOPFlash assay.
The phenotypes associated with pathogenic CTNNB1 variants were similar. A diagnosis of CP was not significantly associated with any set of traits that defined a specific phenotypic subgroup, indicating that CP is not additional to NEDSDV. Two CTNNB1 missense variants were dominant negative regulators of WNT signaling, highlighting the utility of the TOPFlash assay to functionally assess variants.
NEDSDV is a clinically homogeneous disorder irrespective of initial clinical diagnoses, including CP, or entry points for genetic testing.
CTNNB1 种系失活变异导致痉挛性双瘫和视觉缺陷的神经发育障碍（NEDSDV；OMIM 615075），是脑瘫（CP）最常见的、反复出现的单基因病因。我们研究了 CTNNB1 中断引起的一系列临床表型，以确定 NEDSDV 与 CP 的关联。
对 404 名个体的遗传信息进行了研究，这些个体共有 392 种致病性 CTNNB1 变异。从这些个体中，收集了 52 名未发表过的个体的详细表型，并与 68 名具有类似临床信息的已发表个体进行了合并。使用 TOPFlash 测定法评估了选定的 CTNNB1 错义变异的功能效应。
与致病性 CTNNB1 变异相关的表型相似。CP 的诊断与定义特定表型亚组的任何一组特征均无显著关联，表明 CP 并非 NEDSDV 的附加症。两种 CTNNB1 错义变异是 WNT 信号的显性负调控因子，突出了 TOPFlash 测定法在功能评估变异方面的效用。
NEDSDV 是一种临床表型均一的疾病，无论初始临床诊断（包括 CP）或遗传检测的切入点如何。
