TY - JOUR T1 - Delineating the genotypic and phenotypic spectrum of <em>HECW2</em>-related neurodevelopmental disorders JF - Journal of Medical Genetics JO - J Med Genet DO - 10.1136/jmedgenet-2021-107871 SP - jmedgenet-2021-107871 AU - Anushree Acharya AU - Haluk Kavus AU - Patrick Dunn AU - Abdul Nasir AU - Leandra Folk AU - Kara Withrow AU - Ingrid M. Wentzensen AU - Maura R. Z. Ruzhnikov AU - Camille Fallot AU - Thomas Smol AU - Mélanie Rama AU - Kathleen Brown AU - Sandra Whalen AU - Alban Ziegler AU - Magali Barth AU - Anna Chassevent AU - Constance Smith-Hicks AU - Alexandra Afenjar AU - Thomas Courtin AU - Solveig Heide AU - Esperanza Font-Montgomery AU - Caleb Heid AU - J. Austin Hamm AU - Donald R. Love AU - Farouq Thabet AU - Vinod K. Misra AU - Mitch Cunningham AU - Suzanne M. Leal AU - Irma Jarvela AU - Elizabeth A. Normand AU - Fanggeng Zou AU - Mayada Helal AU - Boris Keren AU - Erin Torti AU - Wendy K. Chung AU - Isabelle Schrauwen Y1 - 2021/07/27 UR - http://jmg.bmj.com/content/early/2021/07/28/jmedgenet-2021-107871.abstract N2 - 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with a HECW2-related neurodevelopmental disorder.Results We identified 13 novel missense variants in HECW2 in 22 unpublished cases, of which 18 were confirmed to have a de novo variant.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. ER -