De novo variants predicting haploinsufficiency for DIP2C are associated with expressive speech delay

Ha T, Morgan A, Bartos MN, Beatty K, Cogné B, Braun D, Gerber CB, Gaspar H, Kopps AM, Rieubland C, Hurst AC, Amor DJ, Nizon M, Pasquier L, Pfundt R, Reis A, Siu VM, Tessarech M, Thompson ML, Vincent M, de Vries BB, Walsh MB, Wechsler SB, Zweier C, Schnur RE, Guillen Sacoto MJ, Margot H, Masotto B, Palafoll MIV, Nawaz U, Voineagu I, Slavotinek A (2024)

Publication Type: Journal article

Publication year: 2024

Journal

DOI: 10.1002/ajmg.a.63559

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.

Authors with CRIS profile

Involved external institutions

L'institut Du Thorax France (FR) Cincinnati Children's Hospital Medical Center United States (USA) (US) Centre hospitalier universitaire de Rennes / CHU Rennes France (FR) Inselspital, Universitätsspital Bern Switzerland (CH) Vall d'Hebron University Hospital / Hospital Universitari Vall d'Hebron Spain (ES) University of California San Francisco (UCSF) United States (USA) (US) Murdoch Childrens Research Institute Australia (AU) Cardiology PC United Kingdom (GB) Centre hospitalier universitaire (CHU) d'Angers France (FR) HudsonAlpha United States (USA) (US) Radboud University Nijmegen Medical Centre / Radboudumc of voluit Radboud Universitair Medisch Centrum (UMC) Netherlands (NL) Georgia Institute of Technology United States (USA) (US) GeneDX United States (USA) (US) Western University Canada (CA) Université de Bordeaux France (FR) University of New South Wales (UNSW) Australia (AU) Emory University United States (USA) (US) University of Adelaide Australia (AU)

How to cite

APA:

Ha, T., Morgan, A., Bartos, M.N., Beatty, K., Cogné, B., Braun, D.,... Slavotinek, A. (2024). De novo variants predicting haploinsufficiency for DIP2C are associated with expressive speech delay. American Journal of Medical Genetics Part A. https://dx.doi.org/10.1002/ajmg.a.63559

MLA:

Ha, Thoa, et al. "De novo variants predicting haploinsufficiency for DIP2C are associated with expressive speech delay." American Journal of Medical Genetics Part A (2024).

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