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 Bauer; Giovanni Zifarelli; Henry Houlden; Muhannad Daana; Orly Elpeleg; Jeanne Amiel; Stanislas Lyonnet; Christopher T Gordon; Tamar Harel; Katrin Õunap; Maayan Salton; Hagar Mor-Shaked

doi:10.1016/j.ajhg.2023.10.013

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

Am J Hum Genet. 2023 Dec 7;110(12):2112-2119. doi: 10.1016/j.ajhg.2023.10.013. Epub 2023 Nov 13.

Authors

Eden Engal¹, Kaisa Teele Oja², Reza Maroofian³, Ophir Geminder¹, Thuy-Linh Le⁴, Pauline Marzin⁵, Anne Guimier⁶, Evyatar Mor⁷, Naama Zvi⁸, Naama Elefant⁸, Maha S Zaki⁹, Joseph G Gleeson¹⁰, Kai Muru², Sander Pajusalu², Monica H Wojcik¹¹, Divya Pachat¹², Marwa Abd Elmaksoud¹³, Won Chan Jeong¹⁴, Hane Lee¹⁴, Peter Bauer¹⁵, Giovanni Zifarelli¹⁵, Henry Houlden³, Muhannad Daana¹⁶, Orly Elpeleg¹⁷, Jeanne Amiel⁶, Stanislas Lyonnet⁶, Christopher T Gordon⁴, Tamar Harel¹⁷, Katrin Õunap², Maayan Salton¹⁸, Hagar Mor-Shaked¹⁹

Affiliations

¹ Department of Biochemistry and Molecular Biology, The Institute for Medical Research Israel-Canada, Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem 9112102, Israel; Department of Military Medicine and "Tzameret," Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem, Israel.
² Genetics and Personalized Medicine Clinic, Tartu University Hospital, Tartu, Estonia; Institute of Clinical Medicine, University of Tartu, Tartu, Estonia.
³ Department of Neuromuscular Disease, UCL Queen Square Institute of Neurology, London, UK.
⁴ Laboratory of Embryology and Genetics of Human Malformations, Institut National de La Santé et de La Recherche Médicale (INSERM) UMR 1163, Institut Imagine and Université Paris Cité, 75015 Paris, France.
⁵ Service de Médecine Génomique des Maladies Rares, Hôpital Necker-Enfants Malades, AP-HP, 75015 Paris, France.
⁶ Laboratory of Embryology and Genetics of Human Malformations, Institut National de La Santé et de La Recherche Médicale (INSERM) UMR 1163, Institut Imagine and Université Paris Cité, 75015 Paris, France; Service de Médecine Génomique des Maladies Rares, Hôpital Necker-Enfants Malades, AP-HP, 75015 Paris, France.
⁷ Department of Computer Science, Ben-Gurion University of the Negev, Beersheba, Israel.
⁸ Department of Genetics, Hadassah Medical Organization, Jerusalem, Israel.
⁹ Department of Clinical Genetics, Human Genetics and Genome Research Institute, Cairo, Egypt.
¹⁰ Department of Neurosciences, University of California, San Diego, La Jolla, USA; Rady Children's Institute for Genomic Medicine, San Diego, La Jolla, USA.
¹¹ Broad Institute of MIT and Harvard, Cambridge, MA, USA.
¹² Department of Medical Genetics, Aster MIMS (Malabar Institute of Medical Sciences)-Calicut, Kerala, India.
¹³ Neurology Unit, Department of Pediatrics, Faculty of Medicine, Alexandria University, Alexandria, Egypt.
¹⁴ 3billion, Seoul, South Korea.
¹⁵ CENTOGENE GmbH, Am Strande 7, 18055 Rostock, Germany.
¹⁶ Child Development Centers, Clalit Health Care Services, Jerusalem, Israel.
¹⁷ Department of Genetics, Hadassah Medical Organization, Jerusalem, Israel; Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem, Israel.
¹⁸ Department of Biochemistry and Molecular Biology, The Institute for Medical Research Israel-Canada, Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem 9112102, Israel.
¹⁹ Department of Genetics, Hadassah Medical Organization, Jerusalem, Israel; Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem, Israel. Electronic address: [email protected].

Abstract

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.

Keywords: WBP4; abnormal splicing; pre-mRNA splicing; recessive disorder; spliceosome; spliceosomopathy; syndromic neurodevelopmental disorder.

MeSH terms

Humans
Intellectual Disability* / complications
Intellectual Disability* / genetics
Loss of Heterozygosity
Nervous System Malformations* / genetics
Neurodevelopmental Disorders* / genetics
Phenotype
Spliceosomes / genetics
Syndrome

Abstract

MeSH terms

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