Bi-allelic loss-of-function variants in WBP4, encoding a spliceosome protein, result in a variable neurodevelopmental syndrome

Eden Engal, Kaisa Teele Oja, Reza Maroofian, Ophir Geminder, Thuy Linh Le, Pauline Marzin, Anne Guimier, Evyatar Mor, Naama Zvi, Naama Elefant, Maha S. Zaki, Joseph G. Gleeson, Kai Muru, Sander Pajusalu, Monica H. Wojcik, Divya Pachat, Marwa Abd Elmaksoud, Won Chan Jeong, Hane Lee, Peter BauerGiovanni Zifarelli, Henry Houlden, Muhannad Daana, Orly Elpeleg, Jeanne Amiel, Stanislas Lyonnet, Christopher T. Gordon, Tamar Harel, Katrin Õunap, Maayan Salton, Hagar Mor-Shaked*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

2 Scopus citations


Over two dozen spliceosome proteins are involved in human diseases, also referred to as spliceosomopathies. WW domain-binding protein 4 (WBP4) is part of the early spliceosomal complex and has not been previously associated with human pathologies in the Online Mendelian Inheritance in Man (OMIM) database. Through GeneMatcher, we identified ten individuals from eight families with a severe neurodevelopmental syndrome featuring variable manifestations. Clinical manifestations included hypotonia, global developmental delay, severe intellectual disability, brain abnormalities, musculoskeletal, and gastrointestinal abnormalities. Genetic analysis revealed five different homozygous loss-of-function variants in WBP4. Immunoblotting on fibroblasts from two affected individuals with different genetic variants demonstrated a complete loss of protein, and RNA sequencing analysis uncovered shared abnormal splicing patterns, including in genes associated with abnormalities of the nervous system, potentially underlying the phenotypes of the probands. We conclude that bi-allelic variants in WBP4 cause a developmental disorder with variable presentations, adding to the growing list of human spliceosomopathies.

Original languageAmerican English
Pages (from-to)2112-2119
Number of pages8
JournalAmerican Journal of Human Genetics
Issue number12
StatePublished - 7 Dec 2023

Bibliographical note

Publisher Copyright:
© 2023 American Society of Human Genetics


  • WBP4
  • abnormal splicing
  • pre-mRNA splicing
  • recessive disorder
  • spliceosome
  • spliceosomopathy
  • syndromic neurodevelopmental disorder


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