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<p>Pantothenate kinase-associated neurodegeneration (PKAN) is a common subtype of neurodegeneration with brain iron accumulation (NBIA), caused by biallelic variants in the <i>PANK2</i> gene. In this study, we investigated five unrelated patients clinically suspected of PKAN (four atypical, one classical) using next-generation sequencing followed by Sanger confirmation and segregation analysis where appropriate. We identified five distinct missense variants, including one novel association, all occurring in biallelic states. Notably, two patients carried the same homozygous variant (ENST00000610179.7:c.503G &gt; T), previously associated with atypical PKAN, which may suggest either an elevated local carrier frequency or an unrecognized founder effect. The ENST00000610179.7:c.1253C&gt;T; p.(Thr418Met) variant, identified in a patient with late-onset PKAN, has previously been reported in both classical and atypical forms of the disease, suggesting that residual enzyme activity may contribute to the observed phenotypic variability. To evaluate the impact of missense variants, we employed DynaMut2 and AlphaMissense. Two variants were predicted to be structurally destabilizing and pathogenic, while others showed neutral or conflicting predictions. Our findings highlight the complexity of interpreting missense variants in PKAN and support the utility of combining in silico predictions with detailed genotype–phenotype correlations. Although no consistent pattern was observed across all prediction tools and clinical outcomes, this study contributes to the expanding mutational spectrum of <i>PANK2</i> and emphasizes the need for further functional validation to improve diagnostic accuracy in NBIA disorders.</p>

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Missense variants in PKAN: insights from a multi-patient genetic analysis

  • 期刊论文

  • 发表日期：

    2025年11月25日

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  • Melisa Kılıç,
  • Sevcan Mercan,
  • Banu Özen Barut,
  • Duruhan Meltem Demirkıran,
  • Gül Yalçın Çakmaklı,
  • Nihan Hande Akçakaya,
  • Kanay Yararbaş,
  • Omer Faruk Duzenli,
  • Murat Gültekin,
  • Zuhal Yapıcı,
  • Sibel Aylin Uğur İşeri

摘要

Pantothenate kinase-associated neurodegeneration (PKAN) is a common subtype of neurodegeneration with brain iron accumulation (NBIA), caused by biallelic variants in the PANK2 gene. In this study, we investigated five unrelated patients clinically suspected of PKAN (four atypical, one classical) using next-generation sequencing followed by Sanger confirmation and segregation analysis where appropriate. We identified five distinct missense variants, including one novel association, all occurring in biallelic states. Notably, two patients carried the same homozygous variant (ENST00000610179.7:c.503G > T), previously associated with atypical PKAN, which may suggest either an elevated local carrier frequency or an unrecognized founder effect. The ENST00000610179.7:c.1253C>T; p.(Thr418Met) variant, identified in a patient with late-onset PKAN, has previously been reported in both classical and atypical forms of the disease, suggesting that residual enzyme activity may contribute to the observed phenotypic variability. To evaluate the impact of missense variants, we employed DynaMut2 and AlphaMissense. Two variants were predicted to be structurally destabilizing and pathogenic, while others showed neutral or conflicting predictions. Our findings highlight the complexity of interpreting missense variants in PKAN and support the utility of combining in silico predictions with detailed genotype–phenotype correlations. Although no consistent pattern was observed across all prediction tools and clinical outcomes, this study contributes to the expanding mutational spectrum of PANK2 and emphasizes the need for further functional validation to improve diagnostic accuracy in NBIA disorders.