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<p>X-linked Intellectual Disability (XLID) is one of the heterogenous neurodevelopmental disorders caused by a gene defect on the X chromosome. Clinical symptoms of ID are comprised of the disability of adapting to social environments and cognitive dysfunction which is often defined by having an IQ of less than 70. Whole exome sequencing revealed a hemizygous variant c.2680G &gt; A (p.Asp894Asn) in <i>IQSEC2</i> in the proband, further validated by Sanger sequencing. Subsequently, the three-dimensional structures of the wild and mutated type (Asp894Asn) <i>IQSEC2</i> were deduced by structural bioinformatics approaches in order to compare the structural changes in both the structures. Molecular dynamics simulations revealed that the D894N mutation significantly destabilizes the protein structure, as reflected by increased backbone RMSD, elevated residue-level fluctuations (RMSF), and altered intramolecular interactions, collectively leading to enhanced conformational variability in the mutant protein compared with the wild type. The results obtained from this study will pave the way for early diagnosis, genetic counseling, and better therapeutic interventions.</p>

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Phenotypic expansion and structural analysis of the IQSEC2 p.Asp894Asn variant in a consanguineous Pashtun family

  • 期刊论文

  • 发表日期：

    2026年6月29日

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  • Muhammad Ayaz,
  • Ibrar Khan,
  • Sheraz Ahmed,
  • Nousheen Bibi,
  • Muhammad Adil Abid,
  • Attaur Rehman,
  • Valentina Turchetti,
  • Aizaz ur Rahman,
  • Hayat Khan,
  • Danish Nabi,
  • Valeed Khan,
  • Henry Houlden,
  • Stephanie Efthymiou,
  • Muhammad Ilyas

摘要

X-linked Intellectual Disability (XLID) is one of the heterogenous neurodevelopmental disorders caused by a gene defect on the X chromosome. Clinical symptoms of ID are comprised of the disability of adapting to social environments and cognitive dysfunction which is often defined by having an IQ of less than 70. Whole exome sequencing revealed a hemizygous variant c.2680G > A (p.Asp894Asn) in IQSEC2 in the proband, further validated by Sanger sequencing. Subsequently, the three-dimensional structures of the wild and mutated type (Asp894Asn) IQSEC2 were deduced by structural bioinformatics approaches in order to compare the structural changes in both the structures. Molecular dynamics simulations revealed that the D894N mutation significantly destabilizes the protein structure, as reflected by increased backbone RMSD, elevated residue-level fluctuations (RMSF), and altered intramolecular interactions, collectively leading to enhanced conformational variability in the mutant protein compared with the wild type. The results obtained from this study will pave the way for early diagnosis, genetic counseling, and better therapeutic interventions.