GATAD1 – Dilated Cardiomyopathy

GATAD1 has been implicated in autosomal recessive dilated cardiomyopathy (DCM) based on integrated evidence from family-based case studies, multi‐patient analyses, and functional investigations. In the initial study, homozygosity mapping and exome sequencing in a consanguineous family revealed a homozygous mutation that segregated with the disease in affected siblings and additional relatives (17 individuals examined (PMID:21965549)).

Genetic evidence shows that a missense mutation, identified as c.304T>C (p.Ser102Pro), segregates with disease in the affected family. In this report, two affected siblings from the family exhibited the mutation, and 13 heterozygous carriers were identified without any myocardial disease, reinforcing an autosomal recessive model (PMID:21965549). A multi-patient study further supports the association by demonstrating that patients with GATAD1 variants display distinct cardiac functional and morphometric differences relative to non-carriers (PMID:38664609).

The variant spectrum is focused, with the recurrent c.304T>C (p.Ser102Pro) mutation being reported in both the case report and functional studies. This variant represents a complete coding change meeting HGVS guidelines and is central to the genetic evidence linking GATAD1 to DCM (PMID:21965549).

Functional studies provide moderate support for the gene-disease association. An adult zebrafish model expressing the human c.304T>C (p.Ser102Pro) mutation recapitulated key aspects of DCM, including abnormal cardiac morphology under stress conditions (PMID:28955713). Additionally, a separate investigation demonstrated that this mutation disrupts phosphorylation-dependent protein interactions essential for nuclear transport, offering insights into its molecular mechanism (PMID:38605029).

Despite these supportive findings, there is conflicting experimental evidence. A murine study reported that deletion of Gatad1 specifically in cardiomyocytes did not induce cardiomyopathy, suggesting potential species-specific differences or compensatory mechanisms in mammals (PMID:39641830). This discrepancy underscores the need for further research while not detracting from the overall genetic and functional evidence.

In summary, the cumulative evidence establishes a strong association between GATAD1 and autosomal recessive dilated cardiomyopathy. The confluence of robust genetic data, segregation evidence in a consanguineous family, and supportive functional experiments provides clinicians with a valuable diagnostic marker, enhancing patient management and genetic counseling for this severe cardiac disorder.

References

• Circulation. Cardiovascular genetics • 2011 • Homozygosity mapping and exome sequencing reveal GATAD1 mutation in autosomal recessive dilated cardiomyopathy PMID:21965549
• BMC cardiovascular disorders • 2024 • Association of uncertain significance genetic variants with myocardial mechanics and morphometrics in patients with nonischemic dilated cardiomyopathy PMID:38664609
• Journal of cardiovascular development and disease • 2016 • Modeling GATAD1-Associated Dilated Cardiomyopathy in Adult Zebrafish PMID:28955713
• Nature communications • 2024 • Pathogenic mutations of human phosphorylation sites affect protein-protein interactions PMID:38605029
• Journal of molecular histology • 2024 • Loss of GATAD1 in cardiomyocyte does not cause cardiomyopathy in mice PMID:39641830

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