An autosomal-dominant childhood-onset disorder associated with pathogenic variants in VCP

Creators: Mah-Som, Annelise Y.; Daw, Jil; Huynh, Diana; Wu, Mengcheng; Creekmore, Benjamin C.; Burns, William; Skinner, Steven A.; Holla, Øystein L.; Smeland, Marie F.; Planes, Marc; Uguen, Kevin; Redon, Sylvia; Bierhals, Tatjana; Scholz, Tasja; Denecke, Jonas; Mensah, Martin A.; Sczakiel, Henrike L.; Tichy, Heidelis; Verheyen, Sarah; Blatterer, Jasmin; Schreiner, Elisabeth; Thies, Jenny; Lam, Christina; Spaeth, Christine G.; Pena, Loren; Ramsey, Keri; Narayanan, Vinodh; Seaver, Laurie H.; Rodriguez, Diana; Afenjar, Alexandra; Burglen, Lydie; Lee, Edward B.; Chou, Tsui-Fen¹; Weihl, Conrad C.; Shinawi, Marwan S.

1. California Institute of Technology

Abstract

Valosin-containing protein (VCP) is an AAA⁺ ATPase that plays critical roles in multiple ubiquitin-dependent cellular processes. Dominant pathogenic variants in VCP are associated with adult-onset multisystem proteinopathy (MSP), which manifests as myopathy, bone disease, dementia, and/or motor neuron disease. Through GeneMatcher, we identified 13 unrelated individuals who harbor heterozygous VCP variants (12 de novo and 1 inherited) associated with a childhood-onset disorder characterized by developmental delay, intellectual disability, hypotonia, and macrocephaly. Trio exome sequencing or a multigene panel identified nine missense variants, two in-frame deletions, one frameshift, and one splicing variant. We performed in vitro functional studies and in silico modeling to investigate the impact of these variants on protein function. In contrast to MSP variants, most missense variants had decreased ATPase activity, and one caused hyperactivation. Other variants were predicted to cause haploinsufficiency, suggesting a loss-of-function mechanism. This cohort expands the spectrum of VCP-related disease to include neurodevelopmental disease presenting in childhood.

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Acknowledgement

This research would be impossible without the generosity of our probands and their families, and we thank them from the bottom of our hearts. We were not able to recognize as authors all clinical and research team members who helped care for these individuals, but their contributions were invaluable. We would also like to thank Kathryn Russell and Moriel Singer-Berk of the Broad Institute for their assistance with variant classification. E.B.L. is supported by National Institutes of Health grant RF1AG065341. T.-F.C. is supported by National Institute of Neurological Disorders and Stroke grant R01NS102279. C.C.W. is supported by National Institute on Aging grant R01AG031867 and National Institute of Arthritis and Musculoskeletal and Skin Diseases grant K24AR073317.

Contributions

Conceptualization, M.S.S.; writing – original draft, A.Y.M. with proband supplements contributed by W.B., M.F.S., K.U., T.S., H.L.S., H.T., S.V., J.T., C.G.S., K.R., L.H.S., and A.A.; writing – review & editing, A.Y.M.-S., B.C.C., L.P., E.B.L., C.C.W., and M.S.S.; investigation – clinical & variant analysis, W.B., S.A.S., Ø.L.H., M.F.S., M.P., K.U., S.R., T.B., T.S., M.A.M, H.L.S., H.T., S.V., J.B., E.S., J.T., C.L., C.G.S, L.P., K.R., V.N., L.H.S, D.R., A.A., L.B., and M.S.S.; supervision – clinical, C.L., J.D., and M.S.S.; investigation – in vitro, J.D., D.H., and M.W. with supervision by T.-F.C. and C.C.W.; visualization, A.Y.M.-S. and B.C.C.

Data Availability

We, or the sequencing laboratory, have submitted these variants and associated phenotypes to ClinVar under accession numbers 1331681, 2582677, 1303410, 2582678, 2582679, 1913089, 2429745, 2582680, 2582681, 2582682, 2444456, 1303647, and 2575609. Anonymized data will be shared by request from any qualified investigator.

Document S1. Figures S1–S4, Tables S1–S5, and supplemental note

Conflict of Interest

The authors declare no competing interests.

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