@article {Acharya669, author = {Anushree Acharya and Haluk Kavus and Patrick Dunn and Abdul Nasir and Leandra Folk and Kara Withrow and Ingrid M. Wentzensen and Maura R. Z. Ruzhnikov and Camille Fallot and Thomas Smol and M{\'e}lanie Rama and Kathleen Brown and Sandra Whalen and Alban Ziegler and Magali Barth and Anna Chassevent and Constance Smith-Hicks and Alexandra Afenjar and Thomas Courtin and Solveig Heide and Esperanza Font-Montgomery and Caleb Heid and J. Austin Hamm and Donald R. Love and Farouq Thabet and Vinod K. Misra and Mitch Cunningham and Suzanne M. Leal and Irma Jarvela and Elizabeth A. Normand and Fanggeng Zou and Mayada Helal and Boris Keren and Erin Torti and Wendy K. Chung and Isabelle Schrauwen}, title = {Delineating the genotypic and phenotypic spectrum of HECW2-related neurodevelopmental disorders}, volume = {59}, number = {7}, pages = {669--677}, year = {2022}, doi = {10.1136/jmedgenet-2021-107871}, publisher = {BMJ Publishing Group Ltd}, abstract = {Background Variants in HECW2 have recently been reported to cause a neurodevelopmental disorder with hypotonia, seizures and impaired language; however, only six variants have been reported and the clinical characteristics have only broadly been defined.Methods Molecular and clinical data were collected from clinical and research cohorts. Massive parallel sequencing was performed and identified individuals with a HECW2-related neurodevelopmental disorder.Results We identified 13 novel missense variants in HECW2 in 22 unpublished cases, of which 18 were confirmed to have a de novo variant. In addition, we reviewed the genotypes and phenotypes of previously reported and new cases with HECW2 variants (n=35 cases). All variants identified are missense, and the majority of likely pathogenic and pathogenic variants are located in or near the C-terminal HECT domain (88.2\%). We identified several clustered variants and four recurrent variants (p.(Arg1191Gln);p.(Asn1199Lys);p.(Phe1327Ser);p.(Arg1330Trp)). Two variants, (p.(Arg1191Gln);p.(Arg1330Trp)), accounted for 22.9\% and 20\% of cases, respectively. Clinical characterisation suggests complete penetrance for hypotonia with or without spasticity (100\%), developmental delay/intellectual disability (100\%) and developmental language disorder (100\%). Other common features are behavioural problems (88.9\%), vision problems (83.9\%), motor coordination/movement (75\%) and gastrointestinal issues (70\%). Seizures were present in 61.3\% of individuals. Genotype-phenotype analysis shows that HECT domain variants are more frequently associated with cortical visual impairment and gastrointestinal issues. Seizures were only observed in individuals with variants in or near the HECT domain.Conclusion We provide a comprehensive review and expansion of the genotypic and phenotypic spectrum of HECW2 disorders, aiding future molecular and clinical diagnosis and management.All data relevant to the study are included in the article or uploaded as supplementary information. HECW2 variants reported in this study were deposited into ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/) under accession numbers: SCV001519450, SCV001519452-SCV001519463, SCV000741462 and SCV001444913.}, issn = {0022-2593}, URL = {https://jmg.bmj.com/content/59/7/669}, eprint = {https://jmg.bmj.com/content/59/7/669.full.pdf}, journal = {Journal of Medical Genetics} }