Genomic and phenotypic characterization of 404 individuals with neurodevelopmental disorders caused by CTNNB1 variants.
Genomic and phenotypic characterization of 404 individuals with neurodevelopmental disorders caused by CTNNB1 variants.
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DOI：
10.1016/j.gim.2022.08.006
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发表时间：
2022-11
影响因子：
8.8
通讯作者：
Corbett, Mark A.
中科院分区：
文献类型：
--
作者：
Kayumi, Sayaka;Perez-Jurado, Luis A.;Palomares, Maria;Rangu, Sneha;Sheppard, Sarah E.;Chung, Wendy K.;Kruer, Michael C.;Kharbanda, Mira;Amor, David J.;McGillivray, George;Cohen, Julie S.;Garcia-Minaur, Sixto;van Eyk, Clare L.;Harper, Kelly;Jolly, Lachlan A.;Webber, Dani L.;Barnett, Christopher P.;Santos-Simarro, Fernando;Pacio-Miguez, Marta;del Pozo, Angela;Bakhtiari, Somayeh;Deardorff, Matthew;Dubbs, Holly A.;Izumi, Kosuke;Grand, Katheryn;Gray, Christopher;Mark, Paul R.;Bhoj, Elizabeth J.;Li, Dong;Ortiz-Gonzalez, Xilma R.;Keena, Beth;Zackai, Elaine H.;Goldberg, Ethan M.;de Nanclares, Guiomar Perez;Pereda, Arrate;Llano-Rivas, Isabel;Arroyo, Ignacio;Fernandez-Cuesta, Maria Angeles;Thauvin-Robinet, Christel;Faivre, Laurence;Garde, Aurore;Mazel, Benoit;Bruel, Ange-Line;Tress, Michael L.;Brilstra, Eva;Fine, Amena Smith;Crompton, Kylie E.;Stegmann, Alexander P. A.;Sinnema, Margje;Stevens, Servi C. J.;Nicolai, Joost;Lesca, Gaetan;Lion-Francois, Laurence;Haye, Damien;Chatron, Nicolas;Piton, Amelie;Nizon, Mathilde;Cogne, Benjamin;Srivastava, Siddharth;Bassetti, Jennifer;Muss, Candace;Gripp, Karen W.;Procopio, Rebecca A.;Millan, Francisca;Morrow, Michelle M.;Assaf, Melissa;Moreno-De-Luca, Andres;Joss, Shelagh;Hamilton, Mark J.;Bertoli, Marta;Foulds, Nicola;McKee, Shane;MacLennan, Alastair H.;Gecz, Jozef;Corbett, Mark A.
关键词：
CTNNB 1中的生殖系功能丧失变体导致神经发育障碍伴痉挛性双瘫和视觉缺陷（NEDSDV; OMIM：615075），并且是脑瘫（CP）的最常见、复发性单基因原因。我们研究了由于CTNNB 1破坏引起的临床表型的范围，以确定NEDSDV和CP之间的关联。该研究确定了来自404名个体的遗传信息，共有392种致病性CTNNB 1变体。从中，收集了52个先前未发表的个体的详细表型，并与68个先前发表的具有可比临床信息的个体相结合。通过TOPFlash测定法评估所选CTNNB 1错义变体的功能效应。与致病性CTNNB 1变异体相关的表型相似。CP的诊断与定义特定表型亚组的任何一组性状均不显著相关，表明CP不是NEDSDV的补充。两个CTNNB 1错义变体是WNT信号传导的显性负调控因子，突出了TOPFlash检测在功能评估变体方面的实用性。NEDSDV是一种临床同质性疾病，无论最初的临床诊断，包括CP，或基因检测的切入点。
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 due 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 available. The functional effects of selected CTNNB1 missense variants were assessed by 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 signalling, 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.
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