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Genotype-phenotype correlations
Short report
ARF1 haploinsufficiency causes periventricular nodular heterotopia with variable clinical expressivity
  1. Simone Gana1,
  2. Antonella Casella1,2,
  3. Sara Cociglio3,4,
  4. Elena Tartara5,
  5. Elisa Rognone6,
  6. Elisa Giorgio1,2,
  7. Anna Pichiecchio7,
  8. Simona Orcesi3,
  9. Enza Maria Valente1,2
  1. 1 Medical Genetics Unit, Foundation National Neurological Institute C Mondino Institute for Hospitalization and Care Scientific, Pavia, Italy
  2. 2 Department of Molecular Medicine, University of Pavia, Pavia, Italy
  3. 3 Department of Child Neurology and Psychiatry, Foundation National Neurological Institute C Mondino Institute for Hospitalization and Care Scientific, Pavia, Italy
  4. 4 Department of Brain and Behavioural Sciences, University of Pavia, Pavia, Italy
  5. 5 Epilepsy Center, Foundation National Neurological Institute C Mondino Institute for Hospitalization and Care Scientific, Pavia, Italy
  6. 6 Department of Neuroradiology, Foundation National Neurological Institute C Mondino Institute for Hospitalization and Care Scientific, Pavia, Italy
  7. 7 Neuroradiology Department, University of Pavia, Pavia, Italy
  1. Correspondence to Professor Enza Maria Valente, Department of Molecular Medicine, University of Pavia, 27100 Pavia, Lombardia, Italy; enzamaria.valente{at}unipv.it

Abstract

The primary anatomical defect leading to periventricular nodular heterotopia occurs within the neural progenitors along the neuroepithelial lining of the lateral ventricles and results from a defect in the initiation of neuronal migration, following disruption of the neuroependyma and impaired neuronal motility. Growing evidence indicates that the FLNA-dependent actin dynamics and regulation of vesicle formation and trafficking by activation of ADP-ribosylation factors (ARFs) can play an important role in this cortical malformation. We report the first inherited variant of ARF1 in a girl with intellectual disability and periventricular nodular heterotopia who inherited the variant from the father with previously undiagnosed single nodular heterotopia and mild clinical expression. Additionally, both patients presented some features suggestive of hypohidrotic ectodermal dysplasia. These clinical features showed similarities to those of three previously reported cases with ARF1 missense variants, confirming that haploinsufficiency of this gene causes a recognisable neurological disorder with abnormal neuronal migration and variable clinical expressivity.

  • high-throughput nucleotide sequencing
  • codon
  • nonsense

https://doi.org/10.1136/jmedgenet-2021-107783

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    Footnotes

    • SG and AC contributed equally.

    • Contributors SG and EMV conceived the study and wrote the manuscript. AC and EG performed the genetic analysis and contributed to the writing of the manuscript. SC, ET, ER, AP and SO performed the clinical, neuropsychiatric and neuroradiological evaluation and contributed to manuscript editing.

    • Funding This study was funded by the Italian Ministry of Health and the Pierfranco and Luisa Mariani Foundation (PADAPORT project).

    • Competing interests None declared.

    • Provenance and peer review Not commissioned; externally peer reviewed.

    • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.