Neurological Disorders Associated with WWOX Germline Mutations—A Comprehensive Overview
Ehud Banne,
Baraa Abudiab,
Sara Abu-Swai,
Srinivasa Rao Repudi,
Daniel J. Steinberg,
Diala Shatleh,
Sarah Alshammery,
Leszek Lisowski,
Wendy Gold,
Peter L. Carlen,
Rami I. Aqeilan
Affiliations
Ehud Banne
The Genetic Institute, Kaplan Medical Center, Hebrew University-Hadassah Medical School, Rehovot 76100, Israel
Baraa Abudiab
The Concern Foundation Laboratories, The Lautenberg Center for Immunology and Cancer Research, Department of Immunology and Cancer Research-IMRIC, Hebrew University-Hadassah Medical School, Jerusalem 91120, Israel
Sara Abu-Swai
The Concern Foundation Laboratories, The Lautenberg Center for Immunology and Cancer Research, Department of Immunology and Cancer Research-IMRIC, Hebrew University-Hadassah Medical School, Jerusalem 91120, Israel
Srinivasa Rao Repudi
The Concern Foundation Laboratories, The Lautenberg Center for Immunology and Cancer Research, Department of Immunology and Cancer Research-IMRIC, Hebrew University-Hadassah Medical School, Jerusalem 91120, Israel
Daniel J. Steinberg
The Concern Foundation Laboratories, The Lautenberg Center for Immunology and Cancer Research, Department of Immunology and Cancer Research-IMRIC, Hebrew University-Hadassah Medical School, Jerusalem 91120, Israel
Diala Shatleh
The Concern Foundation Laboratories, The Lautenberg Center for Immunology and Cancer Research, Department of Immunology and Cancer Research-IMRIC, Hebrew University-Hadassah Medical School, Jerusalem 91120, Israel
Sarah Alshammery
Faculty of Medicine and Health, School of Medical Sciences and Discipline of Child and Adolescent Health, The University of Sydney, Westmead 2145, NSW, Australia
Leszek Lisowski
Translational Vectorology Research Unit, Children’s Medical Research Institute, The University of Sydney, Westmead 2145, NSW, Australia
Wendy Gold
Faculty of Medicine and Health, School of Medical Sciences and Discipline of Child and Adolescent Health, The University of Sydney, Westmead 2145, NSW, Australia
Peter L. Carlen
Krembil Research Institute, University Health Network and Department of Medicine, Physiology and BME, University of Toronto, Toronto, ON M5T 1M8, Canada
Rami I. Aqeilan
The Concern Foundation Laboratories, The Lautenberg Center for Immunology and Cancer Research, Department of Immunology and Cancer Research-IMRIC, Hebrew University-Hadassah Medical School, Jerusalem 91120, Israel
The transcriptional regulator WW domain-containing oxidoreductase (WWOX) is a key player in a number of cellular and biological processes including tumor suppression. Recent evidence has emerged associating WWOX with non-cancer disorders. Patients harboring pathogenic germline bi-allelic WWOX variants have been described with the rare devastating neurological syndromes autosomal recessive spinocerebellar ataxia 12 (SCAR12) (6 patients) and WWOX-related epileptic encephalopathy (DEE28 or WOREE syndrome) (56 patients). Individuals with these syndromes present with a highly heterogenous clinical spectrum, the most common clinical symptoms being severe epileptic encephalopathy and profound global developmental delay. Knowledge of the underlying pathophysiology of these syndromes, the range of variants of the WWOX gene and its genotype-phenotype correlations is limited, hampering therapeutic efforts. Therefore, there is a critical need to identify and consolidate all the reported variants in WWOX to distinguish between disease-causing alleles and their associated severity, and benign variants, with the aim of improving diagnosis and increasing therapeutic efforts. Here, we provide a comprehensive review of the literature on WWOX, and analyze the pathogenic variants from published and unpublished reports by collecting entries from the ClinVar, DECIPHER, VarSome, and PubMed databases to generate the largest dataset of WWOX pathogenic variants. We estimate the correlation between variant type and patient phenotype, and delineate the impact of each variant, and used GnomAD to cross reference these variants found in the general population. From these searches, we generated the largest published cohort of WWOX individuals. We conclude with a discussion on potential personalized medicine approaches to tackle the devastating disorders associated with WWOX mutations.
