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

Abstract

Classical homocystinuria is the most common cause of isolated homocystinuria. The variants of the CBS gene remain unidentified in Indian children with this disorder. Based on the hallmark clinical features, family history, and/or biochemical clues for classical homocystinuria, 16 children below the age of 18 years were evaluated by Sanger sequencing of the coding exons of CBS gene with flanking intronic regions. The common C677T variant of the MTHFR gene was also screened by restriction fragment length polymorphism. Fifteen children were clinically suspected of having classical homocystinuria and one asymptomatic child with positive family history. Only seven children had biochemical features of classical homocystinuria. Sanger sequencing of the CBS gene confirmed 15 different pathogenic or likely pathogenic variants in 14 cases. Of these, seven variants were novel (three frameshift deletions, two nonsense, one missense, one splice site variant) and were predicted to be deleterious by Mutation Taster software. Seven cases were homozygous, another six were compound heterozygous, and one case was single heterozygous in the study. None of the three most frequent mutations reported worldwide viz., I278T, G307S, and IVS 11-2A>C were found in our cohort. No variants were detected in the exons 2, 8, 12, and 14 as compared to reported literature. Eleven out of 15 variants were associated with the conserved catalytic domain of the CBS polypeptide. The MTHFR polymorphism C677T was observed in heterozygous state in six cases. Our study reports the detailed genotype and seven novel variants in the CBS gene, causing classical homocystinuria in Indian children. The genetic analysis will help to offer accurate genetic counseling, prenatal diagnosis, and development of mutation-based novel therapeutic strategies.

Early Diagnosis of Classic Homocystinuria in Kuwait through Newborn Screening: A 6-Year Experience

“…In Kuwait, the biochemical confirmation of HCU is typically followed by a confirmatory molecular testing for the CBS gene. Molecular testing of affected newborns as well as late diagnosed individuals with HCU has revealed the same founder missense variant reported in Qatar, c.1006C>T, p.(Arg336Cys) [6], as well as two other previously reported pathogenic variants, one reported in Saudi population, c.969G>A, p.(Yrp323Ter) [48], while the other variant c.982G>A, p.(Asp328Asn), was previously reported in two affected individuals of Filipino and Indian ethnicities [49,50] (Table 3).…”

Association of selected genetic variants in CBS and MTHFR genes in a cohort of children with homocystinuria in Sri Lanka

“…However, those are the only reported mutations in the CBS gene in the Chinese population [ 20 ] and were also the first time that c.833T>C was reported in the Asian population. Kaur R. et al conducted a study on 16 northern Indian children in 2020 who did not identify with the c.833T>C mutation [ 21 ]. In 2021, Wasim M. et al conducted a mutation analysis on 429 patients with an intellectual disability from northern areas of Punjab, Pakistan.…”

“…According to the ExAC browser, c.19del was previously reported in a heterozygous state in two South Asian alleles, which was not found to be related to homocystinuria. In a study done by Kaur R. et al, in 2020, out of sixteen children, four patients were confirmed to have c.19del in North Indian children with homocystinuria [ 21 ]. However, these frequencies will not reflect the actual frequency distributions of these variants in Sri Lanka, as the number of samples studied in this preliminary research is insufficient to conclude a result.…”

Congenital cataract: An ocular manifestation of classical homocystinuria

“…This variant in the CBS gene was first reported in the Danish population (Kraus et al, 1999 ) but no studies were done on the structure–function relationship of this variant. The two most frequently reported mutations in homocystinuria patients around the world are p.G307S (31%) and p.I278T (24%) (Kaur et al, 2020 ) associated with myopia and ectopia lentis and both of these are present in the catalytic domain affecting the catalytic activity of the protein.…”