Congenital Heart Defect

Gene: ARID1B

Green List (high evidence)

Mode of pathogenicity
Heterozygous, de novo mutation in the ARID1B gene has been found to result in haploinsufficiency (OMIM).
Truncating (nonsense or frameshift) variants associated with loss of function and haploinsufficiency have been found in individuals with Coffin-Siris syndrome (OMIM).
 
PMID: 35579625
19/44 of prenatal testing of Coffin-Siris syndrome found a variant in the ARID1B gene. Prenatal ultrasound and postnatal examination displayed a spectrum of clinical characteristics. The relevant clinical features found on ultrasound include cardiovascular anomaly (n=16), aortic arch (n=14), cardiac anomaly (n=15), hypoplastic left heart (n=16), hypoplastic right heart (n=16), atrioventricular canal (n=14), double outlet right ventricle (n=14), septal defect (n=14), valve defect (n=14), and cardiovascular intervention (n=14).

PMID: 35445787
Cardiac assessments based on the Bayessian model of ARID1B single gene mutation mouse model (Arid1b(+/−)) found a decrease in aorta diameter and LV chamber diameter. Arid1b loss‐of‐function mutations have been found to upregulate the Wnt/β‐catenin signalling pathway. Studies in the mouse have shown β‐catenin contributes to the regulation of postnatal hypertrophic growth by acting upstream of fibroblast growth factor signalling. Fibroblast growth factor signalling regulates second heart field progenitors, which give rise to the atrial, ventricular and outflow tract structures.

PMID: 29549119
WGS of a 7-month-old girl with a prenatal diagnosis of aortic arch hypoplasia, small left-sided cardiac structures, and ventricular septal defect found a de novo variant in the ARID1B gene - c.3096_3100delCAAAG (p.Lys1033ArgfsTer32), following genetic analysis of proband and both parents.

PMID: 34324492
A large case/control study of individuals with non-syndromic congenital heart disease, syndromic congenic heart disease and thoracic aortic aneurysm demonstrated a statistical significance in the association between ARID1B gene and congenital heart disease.

Created: 21 Nov 2023, 12:18 a.m. | Last Modified: 21 Nov 2023, 12:18 a.m.

Panel Version: 0.315

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
Coffin-Siris syndrome 1; intellectual disability with or without nonspecific dysmorphic features

Publications

• PMID: 35579625
• 35445787
• 29549119
• 34324492

Mode of pathogenicity
Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments