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Background <p>The <i>ATP9A</i> gene encodes a P4-type ATPase involved in phospholipid translocation, essential for vesicular trafficking and neuronal development. Pathogenic <i>ATP9A</i> variants cause autosomal recessive neurodevelopmental disorders characterized by intellectual disability and microcephaly, yet the impact of missense variants remains poorly understood.</p> Methods <p>A 7-year-old female patient with cognitive impairment, microcephaly, and developmental delay was admitted to Başakşehir Çam and Sakura City Hospital. Whole exome sequencing (WES) using Illumina technology identified a novel homozygous <i>ATP9A</i> variant, confirmed by Sanger sequencing and segregation analysis. In silico tools (RosettaFold, DynaMut, mCSM, SDM, DUET, AggreScan3D) assessed its structural impact. Quantitative real-time polymerase chain reaction (RT-qPCR) was conducted to evaluate the relative expression levels of <i>ATP9A</i>.</p> Results <p>WES revealed a homozygous missense variant, ATP9A: NM_006045.3:c.1091G &gt; C:p.(Arg364Thr), classified as variant of uncertain significance based on ACMG guidelines (PP2, PM2, PM3). Protein modeling demonstrated reduced stability (ΔΔG = − 1.51 to − 0.26&#xa0;kcal/mol), increased flexibility, and a 2.4-fold decrease in solvent accessibility. The variant disrupted polar and hydrophobic interactions within the P-type ATPase IV domain, thereby increasing aggregation propensity. Expression analysis revealed elevated <i>ATP9A</i> mRNA levels, suggesting a compensatory cellular response.</p> Conclusion <p>This novel <i>ATP9A</i> variant broadens the mutational spectrum of <i>ATP9A</i>-related neurodevelopmental disorders. Structural destabilization of the p.(Arg364Thr) protein may contribute to the patient’s cognitive impairment and microcephaly, warranting further functional studies.</p>

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The role of ATP9A (c.1091G > C; p.(Arg364Thr)) variant in cognitive impairment: diagnostic insight from whole exome sequencing

  • 期刊论文

  • 发表日期：

    2026年1月28日

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  • Cuneyd Yavas,
  • Asmaa Abuaisha,
  • Emir Nekay,
  • Alper Gezdirici,
  • Halil Ibrahim Yilmaz,
  • Ekrem Akbulut,
  • Pinar Arican

摘要

Background

The ATP9A gene encodes a P4-type ATPase involved in phospholipid translocation, essential for vesicular trafficking and neuronal development. Pathogenic ATP9A variants cause autosomal recessive neurodevelopmental disorders characterized by intellectual disability and microcephaly, yet the impact of missense variants remains poorly understood.

Methods

A 7-year-old female patient with cognitive impairment, microcephaly, and developmental delay was admitted to Başakşehir Çam and Sakura City Hospital. Whole exome sequencing (WES) using Illumina technology identified a novel homozygous ATP9A variant, confirmed by Sanger sequencing and segregation analysis. In silico tools (RosettaFold, DynaMut, mCSM, SDM, DUET, AggreScan3D) assessed its structural impact. Quantitative real-time polymerase chain reaction (RT-qPCR) was conducted to evaluate the relative expression levels of ATP9A.

Results

WES revealed a homozygous missense variant, ATP9A: NM_006045.3:c.1091G > C:p.(Arg364Thr), classified as variant of uncertain significance based on ACMG guidelines (PP2, PM2, PM3). Protein modeling demonstrated reduced stability (ΔΔG = − 1.51 to − 0.26 kcal/mol), increased flexibility, and a 2.4-fold decrease in solvent accessibility. The variant disrupted polar and hydrophobic interactions within the P-type ATPase IV domain, thereby increasing aggregation propensity. Expression analysis revealed elevated ATP9A mRNA levels, suggesting a compensatory cellular response.

Conclusion

This novel ATP9A variant broadens the mutational spectrum of ATP9A-related neurodevelopmental disorders. Structural destabilization of the p.(Arg364Thr) protein may contribute to the patient’s cognitive impairment and microcephaly, warranting further functional studies.