Impact of Selected Genetic Variants of CBS and MTHFR Genes in a Cohort of Children with Homocystinuria in Sri Lanka

Homocystinuria is a rare inborn error of metabolism with the characteristic accumulation of homocysteine and its metabolites in the urine and blood. Homocystinuria is inherited in an autosomal recessive pattern where potential genetic impact for this condition is caused by genes associated with transsulfuration or methylation pathways, such as cystathionine- -synthase (CBS) and methylenetetrahydrofolate reductase (MTHFR), 5-methyltetrahydrofolate-homocysteine methyltransferase (MTR), 5-methyltetrahydrofolate-homocysteine methyltransferase reductase (MTRR). In addition, deficiencies of cofactors (vitamins B2, B6, B12, and B9/folate) of the key enzymes in the main pathways are also causative factors of the disease. Clinical manifestations of the condition are dislocation of the eye lens, nearsightedness, skeletal abnormalities, and intellectual disabilities. The global prevalence of homocystinuria is approximately 1 in 200,000-335,000 worldwide, where more than 190 homocystinuria-associated CBS mutations, as well as 19 MTHFR gene mutations, have been documented worldwide, yet there are only a few researches have been done on Asian populations, and none in Sri Lanka. The current study focused on selected genetic variants in the CBS and MTHFR genes in a cohort of Sri Lankan children with homocystinuria, confirmed clinically and biochemically and followed up by a consultant chemical pathologist at Lady Ridgeway Hospital for Children, Colombo, Sri Lanka. Eight clinically confirmed patients were selected for the preliminary project within six months and screened for selected genetic variants in CBS and MTHFR genes. c.833 T>C and c.19del in CBS and c.665 C>T and c.1286 A>C in the MTHFR gene were selected and analyzed using SNaPshot mini-sequencing and direct sequencing. As per the analysis, no c.833T>C was reported, but four patients were in the homozygous state for the c.19del variant in the CBS gene. While seven were heterozygous for c.1286A>C, while one patient was heterozygous for c.665C>T in the MTHFR gene. In the study's conclusion, it was identified that c.19del is with a high prevalence in the studied cohort of Sri Lankan children, while c.833T>C is absent, whereas c.1286A>C was more frequent than c.665C>T. The current study was the first study to our knowledge discussing the genetic impact of homocystinuria in the Sri Lanka context; since it was a preliminary approach to establishing genetics variance of candidate genes in homocystinuria, further comprehensive studies would be suggested with a larger sample size with larger time frame as this is a rare disease though critical of seeking early detection for disease management.