Periventricular heterotopia in 6q terminal deletion syndrome: role of the C6orf70 gene. V. Conti1, A. Carabalona2,3, E. Pallesi-Pocachard2,3, E. Parrini1, R. Leventer4,5,6, E. Buhler7, G. McGillivray8, F. Michel2,3, P. Striano9, D. Mei1, F. Watrin2,3, S. Lise10, A. Pagnamenta10, J. Taylor10, U. Kini11, J. Clayton-Smith12, F. Novara13, O. Zuffardi13, W. Dobyns14, I. Scheffer15,16, S. Robertson17, S. Berkovic15, A. Represa2,3, D. Keays18, C. Cardoso2,3, R. Guerrini1,19 1) Pediatric Neurology and Neurogenetics Unit and Laboratories, A. Meyer Children's Hospital - Department of Neuroscience, Pharmacology and Child Health, University of Florence, Florence, Italy; 2) INMED INSERM U901, Marseille, France; 3) Aix-Marseille University, Marseille, France; 4) Department of Neurology, Royal Childrens Hospital, Parkville Victoria, Australia; 5) Murdoch Childrens Research Institute, Parkville Victoria, Australia; 6) Department of Paediatrics, University of Melbourne, Victoria, Australia; 7) Plateforme postgenomique INMED-INSERM, Marseille, France; 8) Victorian Clinical Genetics Services, Murdoch Childrens Research Institute, Victoria, Australia; 9) Pediatric Neurology and Muscular Diseases Unit, Department of Neurosciences, Rehabilitation, Ophtalmology, Genetics, Maternal and Child Health, University of Genoa, "G. Gaslini" Institute, Genova, Italy; 10) NIHR Biomedical Research Centre, Wellcome Trust Centre for Human Genetics, Oxford, UK; 11) Department of Clinical Genetics, Oxford Radcliffe NHS Trust, Oxford, UK; 12) Genetic Medicine, St Marys Hospital, University of Manchester, UK; 13) Department of Pediatric Science and Human and Hereditary Pathology, General Biology and Medical Genetics Section, University of Pavia, Pavia, Italy; 14) Center for Integrative Brain Research Seattle Children's Research Institute Seattle WA; 15) Epilepsy Research Centre, Department of Medicine, University of Melbourne, Austin Health, Victoria, Australia; 16) Florey Institute for Neuroscience and Mental Health, and Department of Paediatrics, University of Melbourne, Royal Childrens Hospital, Parkville Victoria, Australia; 17) Department of Paediatrics and Child Health, Dunedin School of Medicine University of Otago, Dunedin, New Zealand; 18) Research Institute of Molecular Pathology, Vienna, Austria; 19) IRCCS Stella Maris Foundation, Pisa, Italy.

   Periventricular nodular heterotopia (PNH) is caused by defective neuronal migration that results in heterotopic neuronal nodules lining the lateral ventricles. Mutations in Filamin-A (FLNA) or ADP-ribosylation factor guanine nucleotide-exchange factor-2 (ARFGEF2) cause PNH, but most patients with this malformation do not have an assigned aetiology. Using comparative genomic hybridization (array-CGH), we identified 12 patients with developmental brain abnormalities, variably combining PNH, corpus callosum dysgenesis, colpocephaly, cerebellar hypoplasia and polymicrogyria, harboring a common 1.2 Mb minimal critical deletion in 6q27. These anatomic features were mainly associated with epilepsy, ataxia and cognitive impairment. Using whole exome sequencing in 14 patients with isolated PNH but no copy number variants, we identified one patient with PNH, developmental delay and epilepsy and a de novo missense mutation in the chromosome 6 open reading frame 70 (C6orf70), mapping in the minimal critical deleted region. Using immunohistochemistry and western blot, we demonstrated that in human cell lines, C6orf70 shows primarily a cytoplasmic vesicular puncta-like distribution and that the mutation affects its stability and subcellular distribution. We also performed in utero silencing of C6orf70 and of Phf10 and Dll1, the two additional genes mapping in the 6q27 minimal critical deleted region that are expressed in human and rodent brain. Silencing of C6orf70 in the developing rat neocortex produced a PNH phenotype that was rescued by concomitant expression of wild-type human C6orf70 protein. Silencing of the contiguous Phf10 or Dll1 genes only produced slightly delayed migration but not PNH. The complex brain phenotype observed in the 6q terminal deletion syndrome likely results from the combined haploinsufficiency of contiguous genes mapping to a small 1.2 Mb region. Our data suggest that, of the genes within this minimal critical region, C6orf70 plays a major role in the control of neuronal migration and its haploinsufficiency or mutation causes PNH.

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