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De novo variants predicting haploinsufficiency for DIP2C are associated with expressive speech delay.
Ha, Thoa; Morgan, Angela; Bartos, Meghan N; Beatty, Katelyn; Cogné, Benjamin; Braun, Dominique; Gerber, Céline B; Gaspar, Harald; Kopps, Anna M; Rieubland, Claudine; Hurst, Anna C E; Amor, David J; Nizon, Mathilde; Pasquier, Laurent; Pfundt, Rolph; Reis, André; Siu, Victoria Mok; Tessarech, Marine; Thompson, Michelle L; Vincent, Marie; de Vries, Bert B A; Walsh, Matthew B; Wechsler, Stephanie Burns; Zweier, Christiane; Schnur, Rhonda E; Guillen Sacoto, Maria J; Margot, Henri; Masotto, Barbara; Palafoll, Maria Irene Valenzuela; Nawaz, Urwah; Voineagu, Irina; Slavotinek, Anne.
Afiliación
  • Ha T; Division of Medical Genetics, Department of Pediatrics, University of California, San Francisco, San Francisco, USA.
  • Morgan A; Murdoch Children's Research Institute, Parkville, Victoria, Australia.
  • Bartos MN; University of Melbourne, Parkville, Victoria, Australia.
  • Beatty K; Royal Children's Hospital, Parkville, Victoria, Australia.
  • Cogné B; Department of Genetics, University of Alabama at Birmingham, Birmingham, Alabama, USA.
  • Braun D; Division of Human Genetics, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA.
  • Gerber CB; CHU Nantes, Service de Génétique Médicale, L'institut du Thorax, University Nantes, Nantes, France.
  • Gaspar H; Department of Human Genetics, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland.
  • Kopps AM; Department of Human Genetics, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland.
  • Rieubland C; Department of Human Genetics, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland.
  • Hurst ACE; Department of Human Genetics, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland.
  • Amor DJ; Department of Human Genetics, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland.
  • Nizon M; Department of Genetics, University of Alabama at Birmingham, Birmingham, Alabama, USA.
  • Pasquier L; Murdoch Children's Research Institute, Parkville, Victoria, Australia.
  • Pfundt R; University of Melbourne, Parkville, Victoria, Australia.
  • Reis A; Royal Children's Hospital, Parkville, Victoria, Australia.
  • Siu VM; CHU Nantes, Service de Génétique Médicale, L'institut du Thorax, University Nantes, Nantes, France.
  • Tessarech M; Service de Génétique Médicale, Hôpital Sud, Rennes, France.
  • Thompson ML; Department of Human Genetics, Radboud University Medical Center and Donders Institute for Brain, Cognition and Behavior, Nijmegen, The Netherlands.
  • Vincent M; Institute of Human Genetics, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany.
  • de Vries BBA; Centre for Rare Diseases Erlangen (ZSEER), Erlangen, Germany.
  • Walsh MB; London Health Sciences Center and Department of Pediatrics, Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada.
  • Wechsler SB; Department of Biochemistry and Genetics, Angers University Hospital, Angers, France.
  • Zweier C; HudsonAlpha Institute for Biotechnology, Huntsville, Alabama, USA.
  • Schnur RE; CHU Nantes, Service de Génétique Médicale, L'institut du Thorax, University Nantes, Nantes, France.
  • Guillen Sacoto MJ; Department of Human Genetics, Radboud University Medical Center and Donders Institute for Brain, Cognition and Behavior, Nijmegen, The Netherlands.
  • Margot H; Emory Healthcare, Atlanta, Georgia, USA.
  • Masotto B; Departments of Pediatrics and Human Genetics, Emory University School of Medicine, Atlanta, Georgia, USA.
  • Palafoll MIV; Department of Human Genetics, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland.
  • Nawaz U; Institute of Human Genetics, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany.
  • Voineagu I; GeneDx, Gaithersburg, Maryland, USA.
  • Slavotinek A; GeneDx, Gaithersburg, Maryland, USA.
Am J Med Genet A ; 194(7): e63559, 2024 07.
Article en En | MEDLINE | ID: mdl-38421105
ABSTRACT
The disconnected (disco)-interacting protein 2 (DIP2) gene was first identified in D. melanogaster and contains a DNA methyltransferase-associated protein 1 (DMAP1) binding domain, Acyl-CoA synthetase domain and AMP-binding sites. DIP2 regulates axonal bifurcation of the mushroom body neurons in D. melanogaster and is required for axonal regeneration in the neurons of C. elegans. The DIP2 homologues in vertebrates, Disco-interacting protein 2 homolog A (DIP2A), Disco-interacting protein 2 homolog B (DIP2B), and Disco-interacting protein 2 homolog C (DIP2C), are highly conserved and expressed widely in the central nervous system. Although there is evidence that DIP2C plays a role in cognition, reports of pathogenic variants in these genes are rare and their significance is uncertain. We present 23 individuals with heterozygous DIP2C variants, all manifesting developmental delays that primarily affect expressive language and speech articulation. Eight patients had de novo variants predicting loss-of-function in the DIP2C gene, two patients had de novo missense variants, three had paternally inherited loss of function variants and six had maternally inherited loss-of-function variants, while inheritance was unknown for four variants. Four patients had cardiac defects (hypertrophic cardiomyopathy, atrial septal defects, and bicuspid aortic valve). Minor facial anomalies were inconsistent but included a high anterior hairline with a long forehead, broad nasal tip, and ear anomalies. Brainspan analysis showed elevated DIP2C expression in the human neocortex at 10-24 weeks after conception. With the cases presented herein, we provide phenotypic and genotypic data supporting the association between loss-of-function variants in DIP2C with a neurocognitive phenotype.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Haploinsuficiencia / Trastornos del Desarrollo del Lenguaje Límite: Child / Child, preschool / Female / Humans / Infant / Male Idioma: En Revista: Am J Med Genet A Asunto de la revista: GENETICA MEDICA Año: 2024 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Estados Unidos
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Haploinsuficiencia / Trastornos del Desarrollo del Lenguaje Límite: Child / Child, preschool / Female / Humans / Infant / Male Idioma: En Revista: Am J Med Genet A Asunto de la revista: GENETICA MEDICA Año: 2024 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Estados Unidos