Seven novel genetic variants in a North Indian cohort with classical homocystinuria

Area of Science:

• Genetics and Genomics
• Biochemistry
• Pediatric Medicine

Background:

• Classical homocystinuria is a metabolic disorder often caused by mutations in the cystathionine beta-synthase (CBS) gene.
• Identifying specific gene variants is crucial for accurate diagnosis and genetic counseling, particularly in diverse populations like India where variants may be population-specific.
• Previous studies have not fully elucidated the spectrum of CBS gene variants in Indian children with classical homocystinuria.

Purpose of the Study:

• To identify the spectrum of pathogenic variants in the CBS gene in Indian children diagnosed with classical homocystinuria.
• To characterize novel CBS gene variants and their potential impact on protein function.
• To investigate the association of MTHFR gene polymorphism (C677T) with classical homocystinuria in this cohort.

Main Methods:

• Sanger sequencing was performed on the coding exons and flanking intronic regions of the CBS gene in 16 children (under 18 years) with suspected classical homocystinuria.
• Restriction fragment length polymorphism (RFLP) was used to screen for the common MTHFR gene C677T variant.
• Mutation Taster software was employed to predict the deleteriousness of identified novel variants.

Main Results:

• Fifteen distinct pathogenic or likely pathogenic variants in the CBS gene were identified in 14 out of 16 children.
• Seven novel variants (three frameshift deletions, two nonsense, one missense, one splice site) were discovered and predicted to be deleterious.
• Common worldwide mutations (I278T, G307S, IVS 11-2A>C) were absent in this Indian cohort. Six children were heterozygous for the MTHFR C677T polymorphism.

Conclusions:

• This study details the genotype of classical homocystinuria in Indian children, reporting seven novel CBS gene variants.
• The findings underscore the genetic heterogeneity of classical homocystinuria and highlight the importance of population-specific genetic analysis.
• Accurate genetic diagnosis facilitates genetic counseling, prenatal diagnosis, and the development of tailored therapeutic strategies.