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Background <p>Leber congenital amaurosis (LCA) is a severe inherited retinal disorder that appears in early childhood and represents one of the primary causes of pediatric blindness. More than 25 genes, including <i>NMNAT1</i>, have been linked to this condition.</p> Methods <p>A 5-year-old boy presenting clinical signs of LCA underwent whole-exome sequencing (WES). Comprehensive ophthalmic assessments, including optical coherence tomography (OCT) and electroretinography (ERG), were performed to evaluate retinal structure and function. In silico prediction tools, conservation analysis, molecular docking, and root mean square fluctuation (RMSF) simulations were used to investigate the structural and functional consequences of the detected variants. Segregation analysis was also performed in available family members.</p> Results <p>OCT imaging revealed marked atrophy of the outer retinal layers with disruption of photoreceptor and ellipsoid zones. ERG recordings demonstrated severely reduced scotopic and photopic responses, indicating generalized retinal dysfunction. Two novel compound heterozygous variants in <i>NMNAT1</i> (NM_022787.4): c.731T &gt; A (p.Val244Asp) and <i>NMNAT1</i> (NM_022787.4): c.28G &gt; T (p.Val10Phe) were identified. Segregation analysis confirmed a trans configuration. Based on combined evidence, both variants were reclassified according to ACMG guidelines. Structural analysis showed significant alterations in the variant proteins and increased overall stability relative to the wild type. Docking studies demonstrated global and local changes.</p> Conclusion <p>These findings introduce two novel <i>NMNAT1</i> variants linked to LCA9 and underscore the importance of combining clinical data, genetic evaluation, and computational analysis when interpreting rare variants. Further laboratory studies are still needed to clarify their pathogenic roles.</p>

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Novel compound heterozygous variants in NMNAT1 associated with leber congenital amaurosis: clinical and mutational profiles

  • 期刊论文

  • 发表日期：

    2026年3月27日

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  • Moein Kohkalani,
  • Seyyed Amin Seyyed Rezaei,
  • Elaheh Hasani,
  • Maryam Naghinejad,
  • Mahmoud Shekari Khaniani,
  • Akbar Amirfiroozy,
  • Mohammad Taheri

摘要

Background

Leber congenital amaurosis (LCA) is a severe inherited retinal disorder that appears in early childhood and represents one of the primary causes of pediatric blindness. More than 25 genes, including NMNAT1, have been linked to this condition.

Methods

A 5-year-old boy presenting clinical signs of LCA underwent whole-exome sequencing (WES). Comprehensive ophthalmic assessments, including optical coherence tomography (OCT) and electroretinography (ERG), were performed to evaluate retinal structure and function. In silico prediction tools, conservation analysis, molecular docking, and root mean square fluctuation (RMSF) simulations were used to investigate the structural and functional consequences of the detected variants. Segregation analysis was also performed in available family members.

Results

OCT imaging revealed marked atrophy of the outer retinal layers with disruption of photoreceptor and ellipsoid zones. ERG recordings demonstrated severely reduced scotopic and photopic responses, indicating generalized retinal dysfunction. Two novel compound heterozygous variants in NMNAT1 (NM_022787.4): c.731T > A (p.Val244Asp) and NMNAT1 (NM_022787.4): c.28G > T (p.Val10Phe) were identified. Segregation analysis confirmed a trans configuration. Based on combined evidence, both variants were reclassified according to ACMG guidelines. Structural analysis showed significant alterations in the variant proteins and increased overall stability relative to the wild type. Docking studies demonstrated global and local changes.

Conclusion

These findings introduce two novel NMNAT1 variants linked to LCA9 and underscore the importance of combining clinical data, genetic evaluation, and computational analysis when interpreting rare variants. Further laboratory studies are still needed to clarify their pathogenic roles.