Phenotype and genotype of 87 patients with Mowat†"Wilson syndrome and recommendations for care

Mowat†"Wilson syndrome (MWS) (OMIM # 235730) is characterized by distinctive facial appearance in association with variable moderate-to-severe intellectual disability (ID), epilepsy, Hirschsprung disease (HSCR), and multiple con-genital anomalies, including genital anomalies (in particular hypospadias), congenital heart disease, agenesis of the corpus callosum, and eye defects. MWS is caused by deleterious de novo heterozygous variations in the ZEB2 gene. The majority of variants lead to haploinsufficiency through premature stop codons or large deletions. MWS was first delineated in 1998. by Mowat et al. as a syndromic condition characterized by distinctive facial phenotype, ID, and Hirschsprung disease in four of six reported individuals. The causative genetic defect was mapped to chromosome 2q21-q23 based on cytogenetic deletions in two patients, and narrowed to heterozygous mutations of the ZEB2 gene by subsequent literature reports. In 2002 Zweier et al. further delineated the phenotype of MWS with or without HSCR, invariably characterized by ZEB2 gene defects, and proposed that the condition be named Mowat†"Wilson syndrome. More than 300 patients have been reported so far. We carried out a collaborative international study to further characterize and delineate the phenotype, natural history, and genotype†"phenotype correlation of MWS. We analyzed clinical data for 87 patients with a molecularly confirmed diagnosis of MWS, including 62 previously reported patients and 25 unpublished cases, and compared them with patients previously reported by other authors. We obtained these data through collaborations involving clin- icians from various countries. Such primary data have never been collated from a large cohort of affected individuals. In this thesis we present a comprehensive study of MWS features underlining a highly consistent phenotype for the disease, its genotype†"phenotype correlations, and the phenotypic and clinical evolution taking place with age. The purpose of the thesis is to assist clinicians to identify the disease and to provide them with updated care recommendations for patient management.