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
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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.
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