فهرست نشریات علمی دسترسی آزاد ایران

Tay-Sachs disease (TSD) is a severe autosomal recessive neurodegenerative disorder resulting from mutations in the HEXA gene, leading to β-hexosaminidase A (Hex-A) deficiency. Accurate carrier identification through genetic screening is crucial for reproductive planning. This study aimed to characterize a novel HEXA variant found during preconception screening. A 30-year-old Iranian woman, whose husband is a known HEXA carrier, underwent whole-exome sequencing (WES). A novel heterozygous HEXA variant, c.[649T>C;650G>C] resulting in p.Trp203Pro, was identified in exon 6 and confirmed by Sanger sequencing. Its potential pathogenicity was assessed using in silico prediction tools (SIFT, PolyPhen-2, MutationTaster) and structural stability analysis (Molecular Dynamics and FoldX). Serum Hex-A enzyme activity was measured fluorometrically. The p.Trp203Pro variant was absent from ClinVar, HGMD, and gnomAD databases, indicating its novelty. In silico analyses consistently predicted the variant as "damaging" or "deleterious". Structural analysis predicted significant protein destabilization (ΔΔG +17.03 kcal/mol), comparable to many known pathogenic infantile-onset mutations. The patient serum Hex-A activity was 54.2% of total hexosaminidase activity, falling within the established range for heterozygous carriers. The comprehensive analysis strongly suggests that the novel p.Trp203Pro HEXA variant is likely pathogenic leading to reduced enzyme activity consistent with carrier status. This finding underscores the importance of thorough investigation of novel variants for accurate genetic counseling and highlights the expanding mutational spectrum of HEXA.