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Background <p>The Helsmoortel-Van der Aa syndrome is an autosomal-dominant neurodevelopment disorder caused by heterozygous de novo variants in the <i>Activity-Dependent Neuroprotective Protein (ADNP)</i> gene, characterized by autism, intellectual disability, dysmorphic facial features, and deficits in multiple organ systems. ADNP is a zinc finger DNA-binding protein that primarily interacts with chromatin remodelers regulating embryonic development, while also associating with components of the cytoskeleton, thereby regulating autophagy and microtubule dynamics during development. In this study, we investigated these nucleocytoskeletal alterations explaining neurodevelopmental delay in a child with Helsmoortel-Van der Aa syndrome who had an unaffected dizygotic twin brother.</p> Results <p>We performed a genome-wide methylation array on PBMCs from dizygotic twins, showing a predominant CpG hypomethylation episignature. Enrichment analysis of methylated genes revealed significant pathway changes in actin filament organization, Wnt signaling, embryonic development, heart development, and the immune system. In addition, transcriptome sequencing substantiated the affected pathways regulating nuclear and cytoskeletal filamentous alterations associated with autism and neurodevelopmental delay. Brain magnetic resonance imaging showed a mild generalized prominence of the subarachnoid space overlying both hemispheres, revealing intricate patterns of neurodevelopmental delay.</p> Conclusions <p>We report the first molecular study performed on dizygotic twins of which one was diagnosed with Helsmoortel-Van der Aa syndrome, revealing Wnt signaling and filamentous cytoskeletal alterations as a potential drug targets for therapy.</p> Limitations <p>Indications for neurodegeneration, following these cytoskeletal perturbations, have been observed in cellular and murine models for the Helsmoortel-Van der Aa syndrome. However, clinical evidence remains unclear due to the young age of patients, limiting long-term studies on the aging brain. Further longitudinal imaging studies combined with histopathological autopsy sections are required to study the impact of an <i>ADNP</i> variant in the brain as patients come to age.</p>

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A frameshift variant in activity-dependent neuroprotective protein (ADNP) causes nucleocytoskeletal alterations in a dizygotic male twin: a case study

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年11月10日

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  • Claudio Peter D’Incal,
  • Anke Van Dijck,
  • Dale John Annear,
  • Lusine Harutyunyan,
  • Ellen Elinck,
  • Alexander J. M. Dingemans,
  • Bert B. A. de Vries,
  • Ligia Mateiu,
  • Marije Meuwissen,
  • Anna C. Jansen,
  • R. Frank Kooy

摘要

Background

The Helsmoortel-Van der Aa syndrome is an autosomal-dominant neurodevelopment disorder caused by heterozygous de novo variants in the Activity-Dependent Neuroprotective Protein (ADNP) gene, characterized by autism, intellectual disability, dysmorphic facial features, and deficits in multiple organ systems. ADNP is a zinc finger DNA-binding protein that primarily interacts with chromatin remodelers regulating embryonic development, while also associating with components of the cytoskeleton, thereby regulating autophagy and microtubule dynamics during development. In this study, we investigated these nucleocytoskeletal alterations explaining neurodevelopmental delay in a child with Helsmoortel-Van der Aa syndrome who had an unaffected dizygotic twin brother.

Results

We performed a genome-wide methylation array on PBMCs from dizygotic twins, showing a predominant CpG hypomethylation episignature. Enrichment analysis of methylated genes revealed significant pathway changes in actin filament organization, Wnt signaling, embryonic development, heart development, and the immune system. In addition, transcriptome sequencing substantiated the affected pathways regulating nuclear and cytoskeletal filamentous alterations associated with autism and neurodevelopmental delay. Brain magnetic resonance imaging showed a mild generalized prominence of the subarachnoid space overlying both hemispheres, revealing intricate patterns of neurodevelopmental delay.

Conclusions

We report the first molecular study performed on dizygotic twins of which one was diagnosed with Helsmoortel-Van der Aa syndrome, revealing Wnt signaling and filamentous cytoskeletal alterations as a potential drug targets for therapy.

Limitations

Indications for neurodegeneration, following these cytoskeletal perturbations, have been observed in cellular and murine models for the Helsmoortel-Van der Aa syndrome. However, clinical evidence remains unclear due to the young age of patients, limiting long-term studies on the aging brain. Further longitudinal imaging studies combined with histopathological autopsy sections are required to study the impact of an ADNP variant in the brain as patients come to age.