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Introduction <p>Mucopolysaccharidosis type I (MPS1) is a rare multisystemic autosomal recessive disorder caused by the deficiency of alpha-L-iduronidase encoded by <i>IDUA</i>. Variants in <i>IDUA</i> lead to the production of malfunctioned enzyme, accumulation of glycosaminoglycans in different tissues, and abnormal clinical manifestations. This study was aimed at investigating <i>IDUA</i> variants underlying MPS1 to determine the spectrum of mutations in Pakistani patients.</p> Methods <p>Ten patients from unrelated families were evaluated through clinical, biochemical, and molecular investigations for MPS1. All exons and exon-intron boundaries of <i>IDUA</i> were PCR amplified from genomic DNA of patients (and their parents, where available) and subjected to Sanger sequencing. The identified variants were evaluated through in silico prediction tools for structural and functional impact.</p> Results <p>Clinical and biochemical investigations in our patients were consistent with MPS1. Consanguinity was prevalent among parents of enrolled patients (80%). Pathogenic <i>IDUA</i> variant alleles were identified in 9/10 patients (17/20 alleles; 85%) including two novel variants. The missense variant c.1469T &gt; C was most frequent, identified in homozygous state in five patients (10/17 alleles; 58.8%). Two patients were homozygous for either of the two variants: c.784delC and c.1240delA. One patient was compound heterozygous for the two missense variants, c.757G &gt; T and a novel variant c.1565G &gt; T. In one patient, splice site variant c.1525-1G &gt; A was found as a single allele. In silico analyses supported the pathogenicity of the identified variants.</p> Conclusions <p>Our study highlights the spectrum of <i>IDUA</i> variants in the local population. Considering the findings of the current study and previous reports, we recommend c.1469T &gt; C as a diagnostic marker for the initial screening of MPS1 patients in Pakistan. We further suggest including this variant in the neonatal screening programs in Pakistan.</p>

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Molecular Genetic Investigation of Mucopolysaccharidosis 1 Disease in 10 Patients from Unrelated Pakistani Families

  • 期刊论文

  • 发表日期：

    2026年4月27日

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  • Hajira Batool,
  • Bibi Zubaida,
  • Tahira Batool,
  • Nadia Waheed,
  • Huma Arshad Cheema,
  • Muhammad Naeem

摘要

Introduction

Mucopolysaccharidosis type I (MPS1) is a rare multisystemic autosomal recessive disorder caused by the deficiency of alpha-L-iduronidase encoded by IDUA. Variants in IDUA lead to the production of malfunctioned enzyme, accumulation of glycosaminoglycans in different tissues, and abnormal clinical manifestations. This study was aimed at investigating IDUA variants underlying MPS1 to determine the spectrum of mutations in Pakistani patients.

Methods

Ten patients from unrelated families were evaluated through clinical, biochemical, and molecular investigations for MPS1. All exons and exon-intron boundaries of IDUA were PCR amplified from genomic DNA of patients (and their parents, where available) and subjected to Sanger sequencing. The identified variants were evaluated through in silico prediction tools for structural and functional impact.

Results

Clinical and biochemical investigations in our patients were consistent with MPS1. Consanguinity was prevalent among parents of enrolled patients (80%). Pathogenic IDUA variant alleles were identified in 9/10 patients (17/20 alleles; 85%) including two novel variants. The missense variant c.1469T > C was most frequent, identified in homozygous state in five patients (10/17 alleles; 58.8%). Two patients were homozygous for either of the two variants: c.784delC and c.1240delA. One patient was compound heterozygous for the two missense variants, c.757G > T and a novel variant c.1565G > T. In one patient, splice site variant c.1525-1G > A was found as a single allele. In silico analyses supported the pathogenicity of the identified variants.

Conclusions

Our study highlights the spectrum of IDUA variants in the local population. Considering the findings of the current study and previous reports, we recommend c.1469T > C as a diagnostic marker for the initial screening of MPS1 patients in Pakistan. We further suggest including this variant in the neonatal screening programs in Pakistan.