Scholarlink

<p>Microcephaly primary hereditary (MCPH) is a rare neurodevelopmental disorder characterized by a reduced head circumference and variable severity of intellectual disability, typically inherited in an autosomal recessive pattern. Mutations in over 32 genes have been associated with the etiology of MCPH to date, among which <i>ASPM</i> gene is the most frequently mutated, accounting for approximately 68.8% globally. In Pakistan, particularly within the Pashtun population of Khyber Pakhtunkhwa (KP), <i>ASPM</i> mutations are highly prevalent. In this study, we analysed clinical and genetic features of nine consanguineous MCPH families. Among these, six families revealed recurrent nonsense mutation p.Trp1326*(c.3978G &gt; A), increasing the evidence of it being a founder mutation. In addition to this, genetic analysis of other Pashtun origin families found previously reported nonsense mutation in the same <i>ASPM</i> gene, which include p.Arg3244*(c.9730&#xa0;C &gt; T), p.Tyr3164*(c.9492T &gt; G), and p.Ser1176*(c.3527&#xa0;C &gt; G). Clinical assessments of patients revealed microcephaly with mild to severe intellectual disability, impaired interpersonal skills, delayed speech, with no evidence of skeletal, muscular, and major organ abnormalities. Protein modeling and conformation analysis suggested less similarity between wild-type and mutated ASPM proteins, which ranged from 0.24% to 0.68%. Further to the current study, a total of 58 families are known to carry the <i>ASPM</i> p.Trp1326* mutation in the Pashtun Population. These findings emphasize the critical role of <i>ASPM</i> in MCPH pathogenesis, strengthening the evidence of recurrent p.Trp1326* mutation as a founder variant in the Pashtun population. The present study signifies the importance of genetic screening and counselling for effective diagnosis of MCPH in high-risk Pashtun origin Pakistani population.</p>

错误：搜索内容不能为空，请输入英文关键词
错误：关键词超出字数限制，请精简
高级检索

Mutation screening of the ASPM gene in multiple Pashtun origin MCPH families revealed the recurrent nonsense mutation p.Trp1326*: A step towards the development of a genetic diagnostic test

  • 期刊论文

  • 发表日期：

    2025年12月26日

查看全文
  • Hamna Batool Hashmi,
  • Muhammad Muzammal,
  • Aiman Saleem,
  • Muhammad Zubair,
  • Ansaar Hussain,
  • Muhammad Zeeshan Ali,
  • Muhammad Saad Salman,
  • Amjad Ullah Khan,
  • Nazia Farid Burki,
  • Safdar Abbas,
  • Muzammil Ahmad Khan,
  • Christian Windpassinger

摘要

Microcephaly primary hereditary (MCPH) is a rare neurodevelopmental disorder characterized by a reduced head circumference and variable severity of intellectual disability, typically inherited in an autosomal recessive pattern. Mutations in over 32 genes have been associated with the etiology of MCPH to date, among which ASPM gene is the most frequently mutated, accounting for approximately 68.8% globally. In Pakistan, particularly within the Pashtun population of Khyber Pakhtunkhwa (KP), ASPM mutations are highly prevalent. In this study, we analysed clinical and genetic features of nine consanguineous MCPH families. Among these, six families revealed recurrent nonsense mutation p.Trp1326*(c.3978G > A), increasing the evidence of it being a founder mutation. In addition to this, genetic analysis of other Pashtun origin families found previously reported nonsense mutation in the same ASPM gene, which include p.Arg3244*(c.9730 C > T), p.Tyr3164*(c.9492T > G), and p.Ser1176*(c.3527 C > G). Clinical assessments of patients revealed microcephaly with mild to severe intellectual disability, impaired interpersonal skills, delayed speech, with no evidence of skeletal, muscular, and major organ abnormalities. Protein modeling and conformation analysis suggested less similarity between wild-type and mutated ASPM proteins, which ranged from 0.24% to 0.68%. Further to the current study, a total of 58 families are known to carry the ASPM p.Trp1326* mutation in the Pashtun Population. These findings emphasize the critical role of ASPM in MCPH pathogenesis, strengthening the evidence of recurrent p.Trp1326* mutation as a founder variant in the Pashtun population. The present study signifies the importance of genetic screening and counselling for effective diagnosis of MCPH in high-risk Pashtun origin Pakistani population.