The following summary by Hagar Mor-Shaked, who spoke at the European Human Genetics Conference 2023 (ESHG) conference in Glasgow, Scotland. Hagar is also an employee of Geneyx.
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Summary:
Biallelic loss of function variants in WBP4, encoding a spliceosome protein, identified in individuals with syndromic neurodevelopmental delay
Background: The spliceosome is a complex of RNA and proteins responsible for promoting accurate splicing. 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.
Methods: Following informed consent, individuals underwent exome or genome sequencing. Protein analysis included immunoblotting with anti-WBP4. RNA Sequencing and analysis was performed on primary fibroblasts.
Results: Eleven patients, from nine families ascertained through GeneMatcher, were diagnosed 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 four different homozygous loss-of-function variants in WBP4. Immunoblotting on patient fibroblasts from two patients with different genetic variants demonstrated complete loss of protein. 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. Conclusions: Biallelic variants in WBP4 cause a spliceosomopathy. Further functional studies are called for better understanding of the mechanism of pathogenicity.
Funding: PRG471
Article published in MedRxiv below:
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.
Competing Interest Statement
HMS is an employee of Geneyx Genomics. Other authors declare no conflict of interest.
Funding Statement
This work is supported by Estonian Research Council grants PRG471 and PSG774. The Broad Institute Center for Mendelian Genomics (UM1HG008900) is funded by the National Human Genome Research Institute with supplemental funding provided by the National Heart, Lung, and Blood Institute under the Trans-Omics for Precision Medicine (TOPMed) program and the National Eye Institute. MHW is supported by K23HD102589.
