Biallelic loss of function variants inWBP4, encoding a spliceosome protein, result in a variable neurodevelopmental delay syndrome

Author:

Engal EdenORCID,Oja Kaisa TeeleORCID,Maroofian RezaORCID,Geminder OphirORCID,Le Thuy-Linh,Mor Evyatar,Tzvi Naama,Elefant NaamaORCID,Zaki Maha S.ORCID,Gleeson Joseph G.,Muru KaiORCID,Pajusalu SanderORCID,Wojcik Monica H.ORCID,Pachat DivyaORCID,Elmaksoud Marwa AbdORCID,Jeong Won Chan,Lee Hane,Bauer PeterORCID,Zifarelli GiovanniORCID,Houlden HenryORCID,Elpeleg OrlyORCID,Gordon Chris,Harel TamarORCID,Õunap KatrinORCID,Salton MaayanORCID,Mor-Shaked HagarORCID

Abstract

ABSTRACTOver two dozen spliceosome proteins are involved in human diseases, also referred to as spliceosomopathies. WBP4 (WW Domain Binding Protein 4) is part of the early spliceosomal complex, and was not described before in the context of human pathologies. Ascertained through GeneMatcher we identified eleven patients from eight families, with a severe neurodevelopmental syndrome with variable manifestations. Clinical manifestations included hypotonia, global developmental delay, severe intellectual disability, brain abnormalities, musculoskeletal and gastrointestinal abnormalities. Genetic analysis revealed overall five different homozygous loss-of-function variants inWBP4. Immunoblotting on fibroblasts from two affected individuals with different genetic variants demonstrated complete loss of protein, and RNA sequencing analysis uncovered shared abnormal splicing patterns, including enrichment for abnormalities of the nervous system and musculoskeletal system genes, suggesting that the overlapping differentially spliced genes are related to the common phenotypes of the probands. We conclude that biallelic variants inWBP4cause a spliceosomopathy. Further functional studies are called for better understanding of the mechanism of pathogenicity.

Publisher

Cold Spring Harbor Laboratory

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