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CRELD1 gene variants and atrioventricular septal defects in Down syndrome
Ambreen Asim1, Sarita Agarwal1, Inusha Panigrahi2
1Department of Genetics, Sanjay Gandhi Postgraduate Institute of Medical Sciences (SGPGIMS), Lucknow 226014, India.
Insights
Congenital heart defects, specifically Atrioventricular Septal Defect, are common in Down syndrome (DS). This study links CRELD1 gene variants to AVSD in DS patients, suggesting a role in cardiac development.
Area of Science:
- Genetics
- Cardiology
- Developmental Biology
Background:
- Congenital heart defects (CHD) affect approximately 40% of individuals with Down syndrome (DS).
- Atrioventricular Septal Defect (AVSD), a form of CHD, is particularly prevalent in children with DS.
- The CRELD1 gene has been previously associated with sporadic AVSD cases.
Purpose of the Study:
- To investigate the association and significance of CRELD1 gene variants in Down syndrome patients with AVSD.
- To identify specific CRELD1 variants contributing to AVSD in the DS population.
Main Methods:
- DNA sequencing of the CRELD1 gene in blood samples from three groups: DS with AVSD, DS without AVSD, and non-syndromic AVSD.
- Sequence and structural analysis of identified CRELD1 variants.
- Prediction of the functional impact of variants on CRELD1 protein.
Main Results:
- Twenty-two variants in the CRELD1 gene were identified, including 16 novel and 6 previously reported variants.
- A specific variant, c.973G>A (p.Glu325Lys), was found exclusively in DS patients with AVSD.
- This variant is predicted to significantly affect the calcium-binding ability of the CRELD1 protein.
Conclusions:
- The CRELD1 gene plays a likely significant role in the causation of the AVSD phenotype in specific Down syndrome patients.
- Alterations in the calcium-binding domain of CRELD1 may lead to pathogenic consequences in cardiac development.
- CRELD1's role in regulating calcineurin/NFATc1 signaling is crucial for cardiac development, and its disruption by variants can impact this pathway.
Abstract:
Congenital heart defects (CHD) are seen in around 40% of the Down syndrome patients. Atrioventricular Septal Defect (AVSD) or endocardial cushion defect is commonest form of CHD in these children. CRELD1 gene is implicated in causation of sporadic AVSD. In the present study, we evaluated the association and significance of CRELD1 variants with AVSD in Down syndrome (DS) patients. Sequencing was done in blood samples from 3 groups: group I (DS with AVSD), group II (DS without AVSD) and group III (non-syndromic AVSD cases). Twenty two variants in CRELD1 gene were identified, comprising of sixteen novel and six previously reported variants. However, on the basis of sequence, as well as structure analysis, the variant c.973G>A(p.Glu325Lys) variant was identified only in DS having AVSD group which was predicted to have significant effects on calcium binding of putative CRELD1 protein. Since CRELD1 gene acts as a regulator of calcineurin/NFATc1 signaling which is crucial for the regulation of cardiac development by dephosphorylation of the transcription factor, NFAT(nuclear factor of activated T cells),in cytoplasm, the variation in cb-EGF-like calcium binding domain in CRELD1 protein is likely to have pathogenic consequences. Thus, we conclude that the CRELD1 gene is likely to have a major role in causation of AVSD phenotype in selected DS patients.
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