Clinical and molecular genetic characteristics of classical homocystinuria

Abstract

Classical homocystinuria is caused by a genetic mutation in the CBS gene, which leads to low levels or absence of an enzyme called cystathionine beta-synthase.The purpose of the study was to analyze the clinical features and molecular and genetic data of patients with classical homocystinuria in Belarus.The study group included patients with classical homocystinuria and their healthy siblings (3 probands and 2 siblings) from three unrelated families. Diagnosis of homocystinuria was made on a quantitative determination of the total homocysteine level in plasma. The next-generation sequencing was performed for the molecular genetic analysis of the CBS gene. The presence of the identified variants in probands and their siblings was confirmed by the Sanger sequencing.All probands had specific clinical signs of classic homocystinuria: ectopia lentis, skeletal pathology, intellectual, psychiatric, behavioural problems and seizures (in 2 of 3 probands).Homozygous missense-mutations c.430G>C (p.Glu144Gln, rs121964966), c.473C>T p.(Ala158Val, rs1376851289) and 1064C>T p.(Ala355Val, rs772384826) were identified in proband 1, 2 and 3 respectively. Healthy siblings of probands 1 and 3 were the heterozygous carriers of the corresponding mutations.Classical homocystinuria is a very rare disease in the Republic of Belarus. All cases of the disease in Belarus are caused by very rare mutations not registered in the neighboring countries and are the result of marriages between the relatives or the natives of the same area. We have described for the first time the phenotypic manifestations of the p.Glu144Gln and p.Ala355Val mutations, expanded the description of the spectrum of clinical manifestations of the Ala158Val substitution, and assessed the clinical significance of the identified variants in accordance with the modern criteria.