Unraveling CBS Mutations and Their Clinical Impact in a Chinese Family With Classical Homocystinuria

Classical homocystinuria (HCU), caused by cystathionine beta-synthase (CBS) deficiency, exhibits significant geographic variability in its mutational spectrum. Although over 191 CBS mutations have been reported worldwide, Chinese cases remain rare and lack common hotspot mutations. This study aimed to characterize novel CBS variants in a Chinese family to expand the known mutational spectrum and inform genetic counseling practices.

A Chinese Yi family affected by HCU was analyzed. Clinical features, whole-exome sequencing (WES), and metabolic data were collected. Ancestry composition was evaluated using principal component analysis (PCA) and ADMIXTURE analysis. The pathogenicity of CBS variants was assessed through three-dimensional protein modeling, Western blotting, and enzyme activity assays.

The proband, a 9-year-old girl with lens dislocation and seizures, carried compound heterozygous CBS mutations: c.1006C>T (p.Arg336Cys) and c.1061_1069del (p.Val354_Val356del), both located within the catalytic domain of the CBS protein. Structural and functional analyses demonstrated that the latter variant disrupts CBS expression and enzymatic activity. Her asymptomatic brother also carried the same compound heterozygous variants and exhibited mild hyperhomocysteinemia. Ancestry analysis revealed predominant East Asian ancestry with 5.2% Central African Pygmy admixture.

This study identifies the first CBS c.1061_1069del variant and confirms c.1006C>T pathogenicity in China. The findings expand the CBS mutation spectrum, underscore the importance of ethnicity-specific variants, and provide valuable insights for prenatal diagnosis and genetic counseling in Chinese populations.