De novo variants predicting haploinsufficiency for DIP2C are associated with expressive speech delay.
Thoa HaAngela MorganMeghan N BartosKatelyn BeattyBenjamin CognéDominique BraunCéline B GerberHarald GasparAnna M KoppsClaudine RieublandAnna C E HurstDavid J AmorMathilde NizonLaurent PasquierRolph PfundtAndré ReisVictoria Mok SiuMarine TessarechMichelle L ThompsonMarie VincentBert B A de VriesMatthew B WalshStephanie Burns WechslerChristiane ZweierRhonda E SchnurMaria J Guillen SacotoHenri MargotBarbara MasottoMaria Irene Valenzuela PalafollUrwah NawazIrina VoineaguAnne M SlavotinekPublished in: American journal of medical genetics. Part A (2024)
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.
Keyphrases
- copy number
- end stage renal disease
- mitochondrial dna
- aortic valve
- hypertrophic cardiomyopathy
- ejection fraction
- chronic kidney disease
- newly diagnosed
- genome wide
- stem cells
- prognostic factors
- spinal cord injury
- spinal cord
- left ventricular
- peritoneal dialysis
- emergency department
- patient reported outcomes
- atrial fibrillation
- heart failure
- bipolar disorder
- multiple sclerosis
- poor prognosis
- electronic health record
- machine learning
- amino acid
- big data
- genome wide identification
- mitral valve
- fatty acid
- patient reported
- gestational age