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Biallelic loss of function variants in WBP4, encoding a spliceosome protein, result in a variable neurodevelopmental delay syndrome.

ABSTRACT: Over 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 in WBP4. 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 in WBP4 cause a spliceosomopathy. Further functional studies are called for better understanding of the mechanism of pathogenicity.

SUBMITTER: Engal E

PROVIDER: S-EPMC10327195 | biostudies-literature | 2023 Jun

REPOSITORIES: biostudies-literature

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Biallelic loss of function variants in <i>WBP4</i>, encoding a spliceosome protein, result in a variable neurodevelopmental delay syndrome.

Engal Eden E Oja Kaisa Teele KT Maroofian Reza R Geminder Ophir O Le Thuy-Linh TL Mor Evyatar E Tzvi Naama N Elefant Naama N Zaki Maha S MS Gleeson Joseph G JG Muru Kai K Pajusalu Sander S Wojcik Monica H MH Pachat Divya D Elmaksoud Marwa Abd MA Jeong Won Chan WC Lee Hane H Bauer Peter P Zifarelli Giovanni G Houlden Henry H Elpeleg Orly O Gordon Chris C Harel Tamar T Õunap Katrin K Salton Maayan M Mor-Shaked Hagar H

medRxiv : the preprint server for health sciences 20230627

Over 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 d ...[more]

PMID: 37425688

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Dataset Information

Biallelic loss of function variants in WBP4, encoding a spliceosome protein, result in a variable neurodevelopmental delay syndrome.

Publications

Biallelic loss of function variants in <i>WBP4</i>, encoding a spliceosome protein, result in a variable neurodevelopmental delay syndrome.

Similar Datasets

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