CRELD1 – Congenital Heart Disease

CRELD1 encodes a cell adhesion molecule that regulates calcineurin/NFAT signaling during cardiac development. Heterozygous missense variants in CRELD1 have been reported in both syndromic and non-syndromic congenital heart disease (CHD), particularly atrioventricular septal defects (AVSD), suggesting a dosage-sensitive role in septal morphogenesis. Mouse and cellular models corroborate these findings by demonstrating synergistic effects with other genetic modifiers.

Genetic evidence includes identification of the missense variant c.985C>T (p.Arg329Cys) in two unrelated Indian CHD probands (PMID:21413875) and the variant c.973G>A (p.Glu325Lys) in a Down syndrome cohort with AVSD (PMID:29054759). Rare CRELD1 variants were also significantly enriched in Turner syndrome patients with bicuspid aortic valve (PMID:36929416). Conversely, no pathogenic CRELD1 variants were observed in a Mexican Down syndrome CHD cohort (PMID:25524324).

Functional studies demonstrate that Creld1 haploinsufficiency interacts with a functional VEGFA c.-634C allele to disrupt atrioventricular canal morphogenesis in Creld1-deficient mice and in vitro assays (PMID:25328912). Furthermore, loss-of-function Creld1 alleles on the trisomic Ts65Dn background significantly increase CHD penetrance, supporting a threshold model of additive genetic modifiers in Down syndrome (PMID:22523272).

The mechanism of pathogenicity is best described as haploinsufficiency with incomplete penetrance, where single-allele missense changes predispose to CHD in sensitized genetic backgrounds. Key assays include in vivo mouse crosses, in vitro calcineurin/NFAT signaling measurements, and genetic interaction studies.

Conflicting evidence arises from copy number variation screens in Chinese and Romanian CHD cohorts, where no CNVs affecting CRELD1 were detected (PMID:30221396; PMID:38397197), and from the absence of CRELD1 coding variants in a Mexican Down syndrome CHD sample (PMID:25524324). These discrepancies highlight population-specific variant spectra and the need for larger studies.

In summary, CRELD1 has moderate clinical validity as a genetic modifier of CHD. Heterozygous missense variants have been reported in at least three unrelated probands, and multiple functional models support a haploinsufficiency mechanism. Genetic testing for CRELD1 variants can inform risk assessment in families with AVSD and related septal defects.

References

• Genetic testing and molecular biomarkers • 2011 • A maiden report on CRELD1 single-nucleotide polymorphism association in congenital heart disease patients of Mysore, South India. PMID:21413875
• Gene • 2018 • CRELD1 gene variants and atrioventricular septal defects in Down syndrome. PMID:29054759
• Human genetics • 2023 • CRELD1 variants are associated with bicuspid aortic valve in Turner syndrome. PMID:36929416
• Pediatric cardiology • 2015 • Germline mutations in NKX2-5, GATA4, and CRELD1 are rare in a Mexican sample of Down syndrome patients with endocardial cushion and septal heart defects. PMID:25524324
• AIMS genetics • 2014 • Allelic Interaction between CRELD1 and VEGFA in the Pathogenesis of Cardiac Atrioventricular Septal Defects. PMID:25328912
• Circulation. Cardiovascular genetics • 2012 • Genetic modifiers predisposing to congenital heart disease in the sensitized Down syndrome population. PMID:22523272
• Journal of clinical laboratory analysis • 2019 • Copy number variations in the GATA4, NKX2-5, TBX5, BMP4 CRELD1, and 22q11.2 gene regions in Chinese children with sporadic congenital heart disease. PMID:30221396
• Genes • 2024 • A Pilot Study of Multiplex Ligation-Dependent Probe Amplification Evaluation of Copy Number Variations in Romanian Children with Congenital Heart Defects. PMID:38397197

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