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<p>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 <i>MMACHC</i> , <i>ABCD4</i> (associated with Cobalamin J type), <i>HCFC1</i> (associated with Cobalamin X type), <i>CBS</i>, <i>TCN2</i> and <i>MTHFS</i> 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. </p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年7月21日

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  • Davoud Amirkashani,
  • Ghazal Tavakoli,
  • Amirreza Peyrovinasab,
  • Erfan Tavakoli,
  • Peyman Eshraghi,
  • Hossein Moravej,
  • Mahdi Vafadar,
  • Faezeh Rezaei,
  • Behnoosh Tasharrofi

摘要

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.