Sistema de Salut de Catalunya
Institut Català de la Salut
[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. University of Melbourne, Parkville, Victoria, Australia. Royal Children's Hospital, Parkville, Victoria, Australia. [Bartos MN] Department of Genetics, University of Alabama at Birmingham, Birmingham, Alabama, USA. [Beatty K] Division of Human Genetics, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA. [Cogné B] CHU Nantes, Service de Génétique Médicale, L'institut du Thorax, University Nantes, Nantes, France. [Braun D] Department of Human Genetics, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland. [Masotto B] Vall d’Hebron Hospital Universitari, Barcelona, Spain
Vall d'Hebron Barcelona Hospital Campus
2024-06-11T10:40:09Z
2024-06-11T10:40:09Z
2024-07
Developmental delay; Intellectual disability; Speech articulation
Retraso en el desarrollo; Discapacidad intelectual; Articulación del habla
Retard del desenvolupament; Discapacitat intel·lectual; Articulació de la parla
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.
Alabama Genomic Health Initiative, Grant/Award Number: F170303004; Dutch Organization for Health Research and Development, Grant/Award Numbers: 917-86-319, 912-12-109; National Human Genome Research Institute, Grant/Award Number: U01HG009599
Article
Published version
English
Fenotip; Trastorns del llenguatge; Malalties congènites; Anomalies cromosòmiques; PHENOMENA AND PROCESSES::Genetic Phenomena::Genetic Variation::Mutation::Allelic Imbalance::Loss of Heterozygosity::Haploinsufficiency; DISEASES::Pathological Conditions, Signs and Symptoms::Signs and Symptoms::Neurologic Manifestations::Neurobehavioral Manifestations::Communication Disorders::Language Disorders::Language Development Disorders; PHENOMENA AND PROCESSES::Genetic Phenomena::Genotype::Genetic Predisposition to Disease; PHENOMENA AND PROCESSES::Genetic Phenomena::Phenotype; FENÓMENOS Y PROCESOS::fenómenos genéticos::variación genética::mutación::desequilibrio alélico::pérdida de heterocigosidad::haploinsuficiencia; ENFERMEDADES::afecciones patológicas, signos y síntomas::signos y síntomas::manifestaciones neurológicas::manifestaciones neuroconductuales::trastornos de la comunicación::trastornos del lenguaje::trastornos del desarrollo del lenguaje; FENÓMENOS Y PROCESOS::fenómenos genéticos::genotipo::predisposición genética a la enfermedad; FENÓMENOS Y PROCESOS::fenómenos genéticos::fenotipo
Wiley
American Journal of Medical Genetics Part A;194(7)
https://doi.org/10.1002/ajmg.a.63559
Attribution-NonCommercial-NoDerivatives 4.0 International
http://creativecommons.org/licenses/by-nc-nd/4.0/
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