Familial non syndromic congenital heart disease

Gene: SMAD5

Green List (high evidence)

PMID: 40619738: SMAD5 variants were identified in 7 individuals from 6 unrelated families, all with CHD. Six individuals had predominantly isolated CHD, while one individual (F1.3) had a multisystem phenotype.
Six unique SMAD5 variants were identified: 3 missense variants (p.Thr430Ile, p.Val78Phe, p.Asn361Asp), 2 truncating/LOF variants (p.Ala402Glufs13 and p.Glu261Ter) and 1 copy-number deletion encompassing SMAD5. Four variants were de novo (p.Thr430Ile, p.Val78Phe, p.Asn361Asp and the 5q31.1-q31.2 deletion); p.Ala402Glufs13 was inherited by two affected brothers from a mother who was presumed asymptomatic but was not formally assessed. The authors propose haploinsufficiency as the main mechanism in five of six families, whereas p.Thr430Ile showed functional evidence consistent with a dominant-negative mechanism and was associated with the only multisystem phenotype.

PMID: 39631055: Two unrelated patients with pulmonary arterial hypertension (PAH) carried heterozygous SMAD5 missense variants. The second patient carried p.Trp93Arg and had CHD-associated PAH following surgically repaired VSD; her father also had VSD but was not reported to have PAH.

PMID: 42481704: Two heterozygous SMAD5 variants were identified in association with PDA. The first, p.Lys82*, was identified in a five-generation family with PDA and segregated with the PDA phenotype. The second, p.Arg70Ile, was identified in one sporadic PDA patient among 174 CHD index cases and was reported as de novo.
Sources: Literature

Created: 22 Sep 2026, 11:16 a.m.

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
congenitad heart defect; patent ductus arteriosus; ventricular septal defect; hypoplastic left heart

Publications

• 40619738
• 39631055
• 42481704