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<p>Functional neuronal networks are essential for brain growth and development, with myelin or “white matter” playing a key role not just in neuronal transmission but also in axonal support, maintenance, and repair. Disruption of these networks through genetic variation contributes to a range of neurodevelopmental disorders, including both primary inherited white matter disorders and an ever increasing list of secondary leukodystrophies or leucoencephalopathies. Traditionally identified using neuroimaging techniques such as magnetic resonance imaging (MRI), clinico-radiological heterogeneity means MRI alone is rarely sufficient in providing a diagnosis requiring integration with genomic techniques and expert medical review. In this study, we describe an exome-first approach in a cohort of 78 consanguineous families with undiagnosed neurodevelopmental disorders in a healthcare resource-poor setting. The aim is to demonstrate that, even in the absence of MRI imaging, we have the potential to improve diagnostic accuracy and yield. We report positive findings in six families, including known variants in <i>MLC1, AIMP1, ASPA, and DEGS1</i>, and novel variants in <i>XPA</i> and <i>POLR3B</i>. This study highlights the effectiveness of whole-exome sequencing as a diagnostic tool for heterogeneous neurological disorders and provides additional evidence supporting gene-disease associations in conditions linked to white matter pathology.</p>

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Whole-exome sequencing reveals novel and previously reported variants in genes linked to white matter pathology in neurodevelopmental disorders

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年7月9日

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  • Naeem Ahmad,
  • Tooba Aleem,
  • Chunyu Liu,
  • Maliha Rashid,
  • Javeria Tehreem,
  • Mary Ann Minal Junaid,
  • Muhammad Farrukh Asif,
  • Shakir Ullah,
  • Sami Ullah,
  • Tehseen Ullah Khan Afridi,
  • Usman Raza Baig,
  • Muhammad Tariq,
  • Tahir Naeem Khan,
  • Lydia Green,
  • James A. Poulter,
  • Naveed Altaf Malik

摘要

Functional neuronal networks are essential for brain growth and development, with myelin or “white matter” playing a key role not just in neuronal transmission but also in axonal support, maintenance, and repair. Disruption of these networks through genetic variation contributes to a range of neurodevelopmental disorders, including both primary inherited white matter disorders and an ever increasing list of secondary leukodystrophies or leucoencephalopathies. Traditionally identified using neuroimaging techniques such as magnetic resonance imaging (MRI), clinico-radiological heterogeneity means MRI alone is rarely sufficient in providing a diagnosis requiring integration with genomic techniques and expert medical review. In this study, we describe an exome-first approach in a cohort of 78 consanguineous families with undiagnosed neurodevelopmental disorders in a healthcare resource-poor setting. The aim is to demonstrate that, even in the absence of MRI imaging, we have the potential to improve diagnostic accuracy and yield. We report positive findings in six families, including known variants in MLC1, AIMP1, ASPA, and DEGS1, and novel variants in XPA and POLR3B. This study highlights the effectiveness of whole-exome sequencing as a diagnostic tool for heterogeneous neurological disorders and provides additional evidence supporting gene-disease associations in conditions linked to white matter pathology.