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Right atrial isomerism (RAI) is a heterotaxy syndrome characterized by bilateral right atrial morphology, complex cardiac malformations, and abnormal visceral lateralization. GDF1 has been identified as the molecular basis of autosomal-recessive RAI. In an initial Caucasian kindred, five siblings with RAI were compound heterozygotes for truncating GDF1 variants, while heterozygous relatives were phenotypically normal (PMID:20413652). Detailed phenotyping confirmed right atrial morphology, asplenia, and associated cardiac lesions. The implicated variants disrupt the mature ligand domain of GDF1, a TGF-β family member essential for left–right axis development. This report established GDF1 as a strong candidate for recessively inherited RAI.
A subsequent study in three unrelated consanguineous Arab-Muslim families uncovered a shared homozygous truncating c.608G>A (p.Trp203Ter) variant in GDF1 among three index cases. Targeted genotyping demonstrated full segregation of this allele with RAI in over fifteen affected individuals, including at least twelve additional affected relatives (PMID:32144877). Phenotypes included right atrial isomerism, malpositioned great vessels, and atrioventricular septal defects. The c.608G>A allele localizes to the growth factor domain and is absent from population databases, reinforcing its pathogenicity in this population.
Collectively, eight probands harbor biallelic loss-of-function GDF1 variants across two independent cohorts, with twelve segregating affected relatives. The inheritance pattern is autosomal recessive. The variant spectrum is dominated by protein-truncating alleles, including frameshift indels (c.289del (p.Val97fs), c.91_98dup (p.Gly34fs)), nonsense mutations (c.189G>A (p.Trp63Ter)), and duplications (c.523_586dup (p.Ala196fs)). A recurrent founder allele (c.608G>A (p.Trp203Ter)) suggests a population-specific risk factor. All reported variants abolish the cystine knot domain required for receptor binding. No pathogenic missense variants have been identified to date.
Functional evidence arises from a Gdf1 knockout mouse model, which recapitulates human laterality defects including RAI, complex cardiac anomalies, and visceral situs abnormalities. In situ hybridization shows Gdf1 expression in left lateral plate mesoderm during gastrulation. Truncated human GDF1 fails to be secreted and cannot activate ALK4 receptor signaling in vitro. The absence of dominant-negative effects supports pure loss-of-function. These data confirm the developmental requirement for GDF1 in left–right patterning (PMID:20413652).
The pathogenic mechanism is loss-of-function of a TGF-β superfamily ligand critical for Nodal signaling. Biallelic truncating variants disrupt the cystine knot structure necessary for receptor engagement, leading to failure of mesodermal signalling during lateralization. The recessive pattern and normal heterozygous carriers argue against haploinsufficiency in a single-allele state. There is no evidence for dominant-negative or gain-of-function effects. Additional studies could explore whether hypomorphic alleles confer milder phenotypes.
In summary, biallelic loss-of-function variants in GDF1 cause autosomal recessive RAI with robust genetic and experimental support, fulfilling ClinGen criteria for a Strong association. Diagnostic testing for GDF1 should be prioritized in individuals with heterotaxy and atrial isomerism to enable genetic counseling and prenatal diagnosis. Key take-home: GDF1 is a clinically actionable recessive gene for right atrial isomerism with high diagnostic yield.
Gene–Disease AssociationStrong8 probands; 12 affected relatives; concordant knockout mouse model Genetic EvidenceStrong8 probands with biallelic LoF variants; segregation in 3 families with 12 affected relatives Functional EvidenceModerateGdf1 knockout mouse model recapitulates RAI phenotype |