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Loss-of-function variants in MYCBP2 cause neurobehavioural phenotypes and corpus callosum defects

AlAbdi, Lama; Desbois, Muriel; Rusnac, Domniţa-Valeria; Sulaiman, Raashda A; Rosenfeld, Jill A; Lalani, Seema; Murdock, David R; Burrage, Lindsay C; Yee Billie Au, Ping; Towner, Shelley; Wilson, William G; Wong, Lawrence; Brunet, Theresa; Strobl-Wildemann, Gertrud; Burton, Jennifer E; Hoganson, George; McWalter, Kirsty; Begtrup, Amber; Zarate, Yuri A; Christensen, Elyse L; Opperman, Karla J; Giles, Andrew C; Helaby, Rana; Kania, Artur; Zheng, Ning; Grill, Brock; Alkuraya, Fowzan S


Lama AlAbdi

Domniţa-Valeria Rusnac

Raashda A Sulaiman

Jill A Rosenfeld

Seema Lalani

David R Murdock

Lindsay C Burrage

Ping Yee Billie Au

Shelley Towner

William G Wilson

Lawrence Wong

Theresa Brunet

Gertrud Strobl-Wildemann

Jennifer E Burton

George Hoganson

Kirsty McWalter

Amber Begtrup

Yuri A Zarate

Elyse L Christensen

Karla J Opperman

Andrew C Giles

Rana Helaby

Artur Kania

Ning Zheng

Brock Grill

Fowzan S Alkuraya


The corpus callosum is a bundle of axon fibres that connects the two hemispheres of the brain. Neurodevelopmental disorders that feature dysgenesis of the corpus callosum as a core phenotype offer a valuable window into pathology derived from abnormal axon development. Here, we describe a cohort of eight patients with a neurodevelopmental disorder characterized by a range of deficits including corpus callosum abnormalities, developmental delay, intellectual disability, epilepsy and autistic features. Each patient harboured a distinct de novo variant in MYCBP2, a gene encoding an atypical really interesting new gene (RING) ubiquitin ligase and signalling hub with evolutionarily conserved functions in axon development. We used CRISPR/Cas9 gene editing to introduce disease-associated variants into conserved residues in the Caenorhabditis elegans MYCBP2 orthologue, RPM-1, and evaluated functional outcomes in vivo. Consistent with variable phenotypes in patients with MYCBP2 variants, C. elegans carrying the corresponding human mutations in rpm-1 displayed axonal and behavioural abnormalities including altered habituation. Furthermore, abnormal axonal accumulation of the autophagy marker LGG-1/LC3 occurred in variants that affect RPM-1 ubiquitin ligase activity. Functional genetic outcomes from anatomical, cell biological and behavioural readouts indicate that MYCBP2 variants are likely to result in loss of function. Collectively, our results from multiple human patients and CRISPR gene editing with an in vivo animal model support a direct link between MYCBP2 and a human neurodevelopmental spectrum disorder that we term, MYCBP2-related developmental delay with corpus callosum defects (MDCD).

Journal Article Type Article
Acceptance Date Aug 22, 2022
Online Publication Date Oct 6, 2022
Publication Date 2023-04
Deposit Date Nov 20, 2023
Journal Brain
Print ISSN 0006-8950
Publisher Oxford University Press
Peer Reviewed Peer Reviewed
Volume 146
Issue 4

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