Whole exome sequencing and genotype-phenotype correlation in homocystinuria in an Iranian population: a multicenter study

Abstract

Abstract Homocystinuria is an uncommon metabolic disorder characterized by increased homocysteine concentrations. The condition may arise from mutations in the cystathionine beta-synthase (CBS) gene (classic) or in other genes associated with the cobalamin and folate metabolic pathways (non-classic). This study investigated the genetic diversity and clinical outcomes of homocystinuria in an Iranian pediatric population, exploring genotype-phenotype correlations. A multicenter cross-sectional study carried out from January 2024 to August 2025 at three principal referral centers in Iran. A total of 48 pediatric patients diagnosed with homocystinuria and possessing whole-exome sequencing (WES) results were included. Clinical data, including neurological, ocular, and vascular manifestations, were extracted. The majority (52.1%) of patients in the cohort had B12-related homocystinuria, 25% had CBS-related, and 22.9% had B9-related problems. In most patients (93.7%) at least one neurological symptom was identified, with seizures and developmental delay being the most common. Nine patients (18.7%) had ocular symptoms, 7 patients (14.5%) had skeletal symptoms and skin/hair manifestations were seen in 5 patients (10.4%). Classical homocystinuria was associated with significantly elevated plasma homocysteine levels in comparison to non-classical subtypes (p = 0.011). Novel variants were identified in 10 patients (20.8%), affecting MMACHC , ABCD4 (associated with Cobalamin J type), HCFC1 (associated with Cobalamin X type), CBS , TCN2 and MTHFS genes. This study illustrates the genetic diversity and clinical variability of homocystinuria in Iran. The results highlight the clinical importance of regional genetic databases and whole-exome sequencing in the diagnosis and management of this rare metabolic disorder.