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Original research
Delineating the genotypic and phenotypic spectrum of HECW2-related neurodevelopmental disorders
  1. Anushree Acharya1,
  2. Haluk Kavus2,
  3. Patrick Dunn3,
  4. Abdul Nasir4,
  5. Leandra Folk5,
  6. Kara Withrow5,
  7. Ingrid M. Wentzensen5,
  8. Maura R. Z. Ruzhnikov6,
  9. Camille Fallot7,
  10. Thomas Smol8,
  11. Mélanie Rama9,
  12. Kathleen Brown10,
  13. Sandra Whalen11,
  14. Alban Ziegler12,
  15. Magali Barth12,
  16. Anna Chassevent13,
  17. Constance Smith-Hicks14,
  18. Alexandra Afenjar15,
  19. Thomas Courtin16,
  20. Solveig Heide17,
  21. Esperanza Font-Montgomery18,
  22. Caleb Heid18,
  23. J. Austin Hamm19,
  24. Donald R. Love20,
  25. Farouq Thabet21,
  26. Vinod K. Misra22,23,
  27. Mitch Cunningham22,
  28. Suzanne M. Leal1,24,
  29. Irma Jarvela25,
  30. Elizabeth A. Normand5,
  31. Fanggeng Zou5,
  32. Mayada Helal2,
  33. Boris Keren16,
  34. Erin Torti5,
  35. Wendy K. Chung2,26,
  36. Isabelle Schrauwen1
  1. 1Center for Statistical Genetics, Gertrude H. Sergievsky Center and the Department of Neurology, Columbia University Medical Center, New York, New York, USA
  2. 2Department of Pediatrics, Columbia University, New York, New York, USA
  3. 3The George Washington University, Washington, District of Columbia, USA
  4. 4Department of Molecular Science and Technology, Ajou University, Suwon, The Republic of Korea
  5. 5GeneDx, Gaithersburg, Maryland, USA
  6. 6Neurology and Neurological Sciences, Pediatrics, Division of Medical Genetics, Stanford University and Lucile Packard Children's Hospital, Palo Alto, California, USA
  7. 7Clinique de Neuropédiatrie, CHU Lille, Lille, France
  8. 8Institut de Génétique, Univ Lille, EA7364 RADEME, CHU Lille, Lille, France
  9. 9Institut de Génétique, CHU Lille, Lille, France
  10. 10Pediatrics-Clinical Genetics and Metabolism, School of Medicine, University of Colorado—Anschutz Medical Campus, Aurora, Colorado, USA
  11. 11UF de génétique Clinique et Centre de Référence Anomalies du Développement et Syndromes Malformatifs, Assistance Publique-Hôpitaux de Paris (APHP) Sorbonne Université, Hôpital Armand Trousseau, ERN-ITHACA, Paris, France
  12. 12Department of Genetics, Angers University Hospital, Angers, France
  13. 13Division of Neurogenetics, Kennedy Krieger Institute, Baltimore, Maryland, USA
  14. 14Division of Neurogenetics, Kennedy Krieger Institute, Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
  15. 15Assistance Publique-Hôpitaux de Paris (APHP) Sorbonne Université, Centre de Référence Malformations et maladies congénitales du cervelet et déficiences intellectuelles de causes rares, département de génétique et embryologie médicale, Hôpital Trousseau, Paris, France
  16. 16Département de génétique, Hôpital Pitié-Salpêtrière, Assistance Publique-Hôpitaux de Paris (APHP), Paris, France
  17. 17Department of Genetics, Pitié-Salpêtrière Hospital, Referral Center for Intellectual Disabilities of Rare Causes, Assistance Publique-Hôpitaux de Paris (APHP) Sorbonne Université, Paris, France
  18. 18University Hospital Medical Genetics Clinic, University of Missouri, Columbia, Missouri, USA
  19. 19Pediatric Genetics, East Tennessee Children's Hospital, Knoxville, Tennessee, USA
  20. 20Pathology Genetics, Sidra Medicine, Doha, Qatar
  21. 21Pediatric Neurology Division, Sidra Medicine, Doha, Qatar
  22. 22Department of Pediatrics, Division of Genetic, Genomic, and Metabolic Disorders, Children's Hospital of Michigan, Detroit, Michigan, USA
  23. 23Discipline of Pediatrics, Central Michigan University, Mount Pleasant, Michigan, USA
  24. 24Taub Institute for Alzheimer’s Disease and the Aging Brain, Columbia University Medical Center, New York, New York, USA
  25. 25Department of Medical Genetics, University of Helsinki, Helsinki, Finland
  26. 26Department of Medicine, Columbia University, New York, New York, USA
  1. Correspondence to Dr Isabelle Schrauwen, Center for Statistical Genetics, Gertrude H. Sergievsky Center and the Department of Neurology, Columbia University Medical Center, New York, NY, USA; is2632{at}cumc.columbia.edu; Dr Wendy K. Chung, Department of Pediatrics and Medicine, Columbia University Medical Center, New York, NY, USA; wkc15{at}cumc.columbia.edu

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.

  • neurology
  • genetic variation
  • phenotype
  • human genetics

Data availability statement

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.

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Data availability statement

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.

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Footnotes

  • AA, HK and PD contributed equally.

  • Contributors AA, HK, PD and IS: data analysis, data curation, literature review and first draft preparation. AN: homology modelling. IS and WKC: study set-up, supervision and manuscript revision. LF, KW, IMW, MRZR, CF, TS, MR, KB, SW, AZ, MB, AC, CS-H, AA, TC, SH, EF-M, CH, JAH, DRL, FT, VKM, MC, SML, IJ, EAN, FZ, MH, BK and ET: clinical and genetic data organisation. All authors have read and revised the manuscript.

  • Funding WKC is funded by grants from the JPB Foundation and Simons Foundation. IS is supported by a pilot grant from the Columbia University Sergievsky Center.

  • Competing interests LF, KW, IMW, FZ, EAN and ET are employees of GeneDx. All other coauthors have no conflicts of interest related to the work in this manuscript.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.

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