title: De novo missense variants in HECW2 are associated with neurodevelopmental delay and hypotonia.
abstract: The causes of intellectual disability (ID) are diverse and de novo mutations are increasingly recognised to account for a significant proportion of ID.
  
  
  
  In this study, we performed whole exome sequencing on a large cohort of patients with ID or neurodevelopmental delay and identified four novel de novo predicted deleterious missense variants in HECW2 in six probands with ID/developmental delay and hypotonia. Other common features include seizures, strabismus, nystagmus, cortical visual impairment and dysmorphic facial features. HECW2 is an ubiquitin ligase that stabilises p73, a crucial mediator of neurodevelopment and neurogenesis.
  
  
  
  This study implicates pathogenic genetic variants in HECW2 as potential causes of neurodevelopmental disorders in humans.
authors.affiliation: Department of Pediatrics, Columbia University Medical Center, New York, New York, USA.
authors.forename: Esther R
authors.initials: ER
authors.lastname: Berko
authors.affiliation: GeneDx, Gaithersburg, Maryland, USA.
authors.forename: Megan T
authors.initials: MT
authors.lastname: Cho
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA.
authors.forename: Christine
authors.initials: C
authors.lastname: Eng
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA.|Texas Children's Hospital, Houston, Texas, USA.
authors.forename: Yunru
authors.initials: Y
authors.lastname: Shao
authors.affiliation: Massachusetts General Hospital, Boston, Massachusetts, USA.
authors.forename: David A
authors.initials: DA
authors.lastname: Sweetser
authors.affiliation: Massachusetts General Hospital, Boston, Massachusetts, USA.
authors.forename: Jessica
authors.initials: J
authors.lastname: Waxler
authors.affiliation: University of Alabama at Birmingham, Birmingham, Alabama, USA.
authors.forename: Nathaniel H
authors.initials: NH
authors.lastname: Robin
authors.affiliation: University of Alabama at Birmingham, Birmingham, Alabama, USA.
authors.forename: Fallon
authors.initials: F
authors.lastname: Brewer
authors.affiliation: National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Sandra
authors.initials: S
authors.lastname: Donkervoort
authors.affiliation: National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Payam
authors.initials: P
authors.lastname: Mohassel
authors.affiliation: National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Carsten G
authors.initials: CG
authors.lastname: Bönnemann
authors.affiliation: Cohen Children's Medical Center of NY, New Hyde Park, New York, USA.
authors.forename: Martin
authors.initials: M
authors.lastname: Bialer
authors.affiliation: Cohen Children's Medical Center of NY, New Hyde Park, New York, USA.
authors.forename: Christine
authors.initials: C
authors.lastname: Moore
authors.affiliation: Office of the Clinical Director, National Institutes of Health, Bethesda, Maryland, USA.|Undiagnosed Diseases Program, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Lynne A
authors.initials: LA
authors.lastname: Wolfe
authors.affiliation: Office of the Clinical Director, National Institutes of Health, Bethesda, Maryland, USA.|Undiagnosed Diseases Program, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Cynthia J
authors.initials: CJ
authors.lastname: Tifft
authors.affiliation: Departments of Systems Biology and Biomedical Informatics, Columbia University Medical Center, New York, New York, USA.
authors.forename: Yufeng
authors.initials: Y
authors.lastname: Shen
authors.affiliation: GeneDx, Gaithersburg, Maryland, USA.
authors.forename: Kyle
authors.initials: K
authors.lastname: Retterer
authors.affiliation: GeneDx, Gaithersburg, Maryland, USA.
authors.forename: Francisca
authors.initials: F
authors.lastname: Millan
authors.affiliation: Department of Pediatrics, Columbia University Medical Center, New York, New York, USA.|Department of Medicine, Columbia University Medical Center, New York, New York, USA.
authors.forename: Wendy K
authors.initials: WK
authors.lastname: Chung
mesh_terms: D002648:Child; D002675:Child, Preschool; D059472:Exome / Q000235:genetics; D005260:Female; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D008607:Intellectual Disability / Q000235:genetics* / Q000473:pathology; D008297:Male; D009123:Muscle Hypotonia / Q000235:genetics* / Q000473:pathology; D020125:Mutation, Missense / Q000235:genetics; D065886:Neurodevelopmental Disorders / Q000235:genetics* / Q000473:pathology; D000072160:Tumor Protein p73 / Q000235:genetics*; D044767:Ubiquitin-Protein Ligases / Q000235:genetics*
chemical_list: C000606460:TP73 protein, human; D000072160:Tumor Protein p73; C574377:HECW2 protein, human; D044767:Ubiquitin-Protein Ligases
keywords: HECW2; de novo; intellectual disability; neurodevelopmental delay; whole exome sequencing