Whole Exome Sequencing Reveals Novel Genetic Variants Associated with Atrial Septal Defect in a Tibetan Patient...

Atrial septal defect (ASD) is a common congenital heart defect with incompletely understood genetic underpinnings, particularly in specific ethnic groups. This study aimed to identify novel genetic variants related to ASD within the Tibetan population using whole exome sequencing (WES).

Genomic DNA was extracted from blood samples of 17 Tibetan ASD patients. WES was performed using the Illumina HiSeq platform. After rigorous filtering, detection, and annotation of single nucleotide variations (SNVs) and insertion-deletions (InDels), potentially pathogenic variants were prioritized. Functional impact predictions were conducted using SIFT, PolyPhen V2, MutationTaster, and CADD databases to identify variants likely contributing to ASD etiology.

We identified nine high-confidence candidate variants in Tibetan ASD patients, including rs145116532 (ALKAL1, c.287G >A: p. R96Q), rs374798430 (AVL9, c.1267G >A: p.D423N), rs138933092 (C5, c.4432C >T: p.R1478W), rs141638421 (CRYAB, c.470G>A: p.R157H), rs147287319 (DOCK8, c.989G>A: c.1193G>A: p.R330Q, p.R398Q), rs141616597 (NTN3, c.1243C>T: p.R415C), rs117506395 (PIWIL1, c.2207C>T: p.T736M), rs142533677 (PLEKHG4, c.2246G>A: p.R749Q), and rs118203532 (TSC1, c.1460C>G: p.S487C). Function annotation further suggested potential associations of C5, CRYAB, PIWIL1, and TSC1 with congenital heart diseases.

This first WES-based study of Tibetan ASD patients reveals population-specific genetic determinants. The nine novel candidate variants, particularly in C5, CRYAB, PIWIL1, and TSC1, provide preliminary insights into ASD etiology in high-altitude populations and highlight potential targets for future diagnostic biomarker development.