Ten Iranian patients expand the genetic spectrum of classical homocystinuria

Researchers have catalogued the genetic and clinical features of classical homocystinuria in ten Iranian patients, identifying two CBS gene variants never described before and uncovering evidence for a possible founder effect in southeastern Iran. The study, published in Molecular Genetics and Genomics, combined clinical and molecular analysis of ten affected individuals from ten Iranian consanguineous families with a comprehensive review of the global literature, pooling data from 2,654 previously published cases for a total of 2,664 patients with the disorder.

Classical homocystinuria is an autosomal recessive disorder caused by pathogenic variants in the cystathionine beta-synthase gene, known as CBS. Data on the clinical and molecular spectrum of CBS deficiency in Iranian patients had remained limited, and the study set out to evaluate the phenotypic and genotypic features of affected individuals in Iran alongside the wider published record.

Molecular analysis of the ten patients identified ten distinct missense variants. Eight of these had been reported before: p.Gly153Arg, p.Gly116Arg, p.Gly259Ser, p.Thr191Met, p.Gly307Ser, p.Thr353Met, p.Asp444Tyr and p.Asn228Ser. The remaining two, p.Ala452Val and p.Ile311Asn, are novel additions to the known variant catalogue.

The accompanying literature review identified a total of 228 variants in the CBS gene worldwide. A striking pattern emerged from this compilation: the central pyridoxal 5′-phosphate-binding catalytic domain of the enzyme harbours more than 70 percent of all pathogenic variants, showing how concentrated the disease-causing variants are within this functional region of the protein.

The review also documented pronounced population-specific founder effects, including p.Arg336Cys in Qatar, p.Trp323* in Saudi Arabia, p.Gly307Ser in Celtic populations and p.Thr191Met in Spanish and Latin American populations. Against this backdrop, the recurrent occurrence of p.Gly116Arg among the Iranian patients from southeastern Iran suggests a possible regional founder effect of its own.

Clinically, the pooled data showed that the most frequent manifestations of the disease are ectopia lentis in 55.5 percent of cases, intellectual disability in 42 percent, and marfanoid habitus in 24 percent.

Yet the study also observed marked inter- and intra-familial phenotypic discordance: siblings and even individuals carrying identical genotypes did not necessarily share the same symptoms. The authors attribute this variability to modifier genes, differences in treatment approach and environmental factors.

By adding two new variants and a possible Iranian founder mutation to the record, the work expands the mutational and clinical spectrum of CBS deficiency in Iranian patients, and the literature review highlights the marked genetic and phenotypic heterogeneity of the disease.

Subject of Research: Genetic and clinical analysis of ten Iranian patients with classical homocystinuria combined with a global review of CBS gene variants

Article Title: Expanding the mutational and clinical spectrum of classical homocystinuria: analysis of ten iranian patients and a literature review of global CBS variants

Article References: Kojur, K. N., Eshraghi, P., Abbaszadegan, M. R., Gholoobi, A., & Hamzehloei, T. (2026). Expanding the mutational and clinical spectrum of classical homocystinuria: analysis of ten iranian patients and a literature review of global CBS variants. Molecular Genetics and Genomics, 301(1), Article 206. https://doi.org/10.1007/s00438-026-02533-w

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DOI: 10.1007/s00438-026-02533-w

Keywords: classical homocystinuria, CBS gene, founder effect, Iranian patients, missense variants, ectopia lentis, intellectual disability, marfanoid habitus, genetic heterogeneity, autosomal recessive, Expanding, mutational