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Background <p>Charcot–Marie–Tooth disease (CMT) is a heterogeneous group of one of the most common inherited neurological disorders with an estimated prevalence of 1 in 2,500 people. CMT Type 2S (CMT2S) is characterized by childhood-onset axonal motor and sensory neuropathy without respiratory failure. It is caused by pathogenic variants in the <i>IGHMBP2</i> gene. This study aimed to identify the genetic defect responsible for sensory motor polyneuropathy in a large consanguineous Pakistani family with at least six affected individuals.</p> Methods <p>Genomic DNA from the affected and normal individuals of the recruited family was isolated. Whole exome sequencing of the proband’s DNA was performed, and a standard bioinformatics data analysis pipeline was used to analyze the reads. The genotypes of the shortlisted candidate variants in the proband and his family members were tested for segregation by Sanger sequencing and the functional effects of the candidate variants were predicted by in silico prediction tools, including I-TASSER, VarSome, and Franklin by Genoox.</p> Results <p>A homozygous missense variant NM_002180.3:c.1591C &gt; A, p.(Pro531Thr) in <i>IGHMBP2</i> was identified segregating in the family with the disease phenotype. In silico tools predicted deleterious functional effects of the variant on the protein and was classified as likely pathogenic (PM2, PP3, PP1) according to ACMG guidelines. This variant was first reported in compound heterozygous condition with another variant in a sporadic CMT2S patient of Pakistani origin.</p> Conclusions <p>Our study confirms the implication of recurring variant c.1591C &gt; A in the etiopathogenesis of CMT2S and highlights the clinical significance of whole exome sequencing in the diagnosis of clinically and genetically heterogeneous inherited neuropathies. These data should be helpful in carrier identification of the extended family to improve genetic counseling and prenatal diagnosis.</p>

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A Homozygous IGHMBP2 Missense Variant Segregating in a Large Consanguineous Pakistani Family Affected with Autosomal Recessive Charcot–Marie–Tooth Disease Type 2S

  • 期刊论文

  • 发表日期：

    2025年11月27日

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  • Aman Ullah,
  • Ranjha Khan,
  • Muhammad Naeem

摘要

Background

Charcot–Marie–Tooth disease (CMT) is a heterogeneous group of one of the most common inherited neurological disorders with an estimated prevalence of 1 in 2,500 people. CMT Type 2S (CMT2S) is characterized by childhood-onset axonal motor and sensory neuropathy without respiratory failure. It is caused by pathogenic variants in the IGHMBP2 gene. This study aimed to identify the genetic defect responsible for sensory motor polyneuropathy in a large consanguineous Pakistani family with at least six affected individuals.

Methods

Genomic DNA from the affected and normal individuals of the recruited family was isolated. Whole exome sequencing of the proband’s DNA was performed, and a standard bioinformatics data analysis pipeline was used to analyze the reads. The genotypes of the shortlisted candidate variants in the proband and his family members were tested for segregation by Sanger sequencing and the functional effects of the candidate variants were predicted by in silico prediction tools, including I-TASSER, VarSome, and Franklin by Genoox.

Results

A homozygous missense variant NM_002180.3:c.1591C > A, p.(Pro531Thr) in IGHMBP2 was identified segregating in the family with the disease phenotype. In silico tools predicted deleterious functional effects of the variant on the protein and was classified as likely pathogenic (PM2, PP3, PP1) according to ACMG guidelines. This variant was first reported in compound heterozygous condition with another variant in a sporadic CMT2S patient of Pakistani origin.

Conclusions

Our study confirms the implication of recurring variant c.1591C > A in the etiopathogenesis of CMT2S and highlights the clinical significance of whole exome sequencing in the diagnosis of clinically and genetically heterogeneous inherited neuropathies. These data should be helpful in carrier identification of the extended family to improve genetic counseling and prenatal diagnosis.