Novel CRELD1 gene mutations in patients with atrioventricular septal defect

Area of Science:

• Genetics
• Cardiology
• Molecular Biology

Background:

• Atrioventricular septal defects (AVSDs) are complex congenital heart malformations with diverse etiologies, including syndromic, autosomal dominant, and sporadic forms.
• Genetic heterogeneity underlies AVSD pathogenesis, with limited understanding of causative genes until recently.
• The CRELD1 gene, encoding a novel cell adhesion molecule, emerged as a candidate gene for AVSD.

Purpose of the Study:

• To investigate the role of the CRELD1 gene in the pathogenesis of atrioventricular septal defects.
• To identify novel mutations within the CRELD1 gene in patients diagnosed with AVSD.

Main Methods:

• Genomic DNA was extracted from peripheral blood samples of 133 patients with AVSD and 200 healthy controls.
• The CRELD1 gene was amplified using polymerase chain reaction (PCR) with specific primers.
• Sequencing of PCR products allowed for comparison of CRELD1 gene sequences between patients and controls.

Main Results:

• Two novel mutations in the CRELD1 gene were identified in patients with AVSD.
• A C-to-G transition at nucleotide 857 in exon 8 resulted in an alanine-to-proline substitution (A286P) in the first calcium-binding EGF domain, found in a patient with isolated partial AVSD.
• A heterozygous c.973G>A transition in exon 9 led to a glutamic acid-to-lysine substitution (E325K) in the second calcium-binding EGF domain, detected in a patient with partial AVSD and Down syndrome.

Conclusions:

• The study identified two novel CRELD1 mutations within the calcium-binding EGF domain of patients with AVSD.
• CRELD1 is implicated as a potential susceptibility gene for AVSD.
• Mutations in CRELD1 may confer an increased risk for developing AVSD rather than being directly causative.