Duplication 2p16 is associated with perisylvian polymicrogyria

Abstract

Polymicrogyria (PMG) is a heterogeneous brain malformation that may result from prenatal vascular disruption or infection, or from numerous genetic causes that still remain difficult to identify. We identified three unrelated patients with polymicrogyria and duplications of chromosome 2p, defined the smallest region of overlap, and performed gene pathway analysis using Cytoscape. The smallest region of overlap in all three children involved 2p16.1-p16.3. All three children have bilateral perisylvian polymicrogyria (BPP), intrauterine and postnatal growth deficiency, similar dysmorphic features, and poor feeding. Two of the three children had documented intellectual disability. Gene pathway analysis suggested a number of developmentally relevant genes and gene clusters that were over-represented in the critical region.We narrowed a rare locus for polymicrogyria to a region of 2p16.1-p16.3 that contains 33-34 genes, 23 of which are expressed in cerebral cortex during human fetal development. Using pathway analysis, we showed that several of the duplicated genes contribute to neurodevelopmental pathways including morphogen, cytokine, hormonal and growth factor signaling, regulation of cell cycle progression, cell morphogenesis, axonal guidance, and neuronal migration. These findings strengthen the † Died June 16, 2019.Christopher A Walsh and William B Dobyns contributed equally to the manuscript.We wish to thank the families of these children for sharing their medical information with us. We are grateful to Dr. Anne De Leener, Laboratory of Cytogenetics at Hôpital Erasme, Université Libre de Bruxelles, for the karyotype and FISH analysis in the family of Patient PS-10203. We are grateful to Dr.