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Redefining the Etiologic Landscape of Cerebellar Malformations.

Aldinger, Kimberly A; Timms, Andrew E; Thomson, Zachary; Mirzaa, Ghayda M; Bennett, James T; Rosenberg, Alexander B; Roco, Charles M; Hirano, Matthew; Abidi, Fatima; Haldipur, Parthiv; Cheng, Chi V; Collins, Sarah; Park, Kaylee; Zeiger, Jordan; Overmann, Lynne M; Alkuraya, Fowzan S; Biesecker, Leslie G; Braddock, Stephen R; Cathey, Sara; Cho, Megan T; Chung, Brian H Y; Everman, David B; Zarate, Yuri A; Jones, Julie R; Schwartz, Charles E; Goldstein, Amy; Hopkin, Robert J; Krantz, Ian D; Ladda, Roger L; Leppig, Kathleen A; McGillivray, Barbara C; Sell, Susan; Wusik, Katherine; Gleeson, Joseph G; Nickerson, Deborah A; Bamshad, Michael J; Gerrelli, Dianne; Lisgo, Steven N; Seelig, Georg; Ishak, Gisele E; Barkovich, A James; Curry, Cynthia J; Glass, Ian A; Millen, Kathleen J; Doherty, Dan; Dobyns, William B.
Am J Hum Genet; 105(3): 606-615, 2019 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-31474318
Cerebellar malformations are diverse congenital anomalies frequently associated with developmental disability. Although genetic and prenatal non-genetic causes have been described, no systematic analysis has been performed. Here, we present a large-exome sequencing study of Dandy-Walker malformation (DWM) and cerebellar hypoplasia (CBLH). We performed exome sequencing in 282 individuals from 100 families with DWM or CBLH, and we established a molecular diagnosis in 36 of 100 families, with a significantly higher yield for CBLH (51%) than for DWM (16%). The 41 variants impact 27 neurodevelopmental-disorder-associated genes, thus demonstrating that CBLH and DWM are often features of monogenic neurodevelopmental disorders. Though only seven monogenic causes (19%) were identified in more than one individual, neuroimaging review of 131 additional individuals confirmed cerebellar abnormalities in 23 of 27 genetic disorders (85%). Prenatal risk factors were frequently found among individuals without a genetic diagnosis (30 of 64 individuals [47%]). Single-cell RNA sequencing of prenatal human cerebellar tissue revealed gene enrichment in neuronal and vascular cell types; this suggests that defective vasculogenesis may disrupt cerebellar development. Further, de novo gain-of-function variants in PDGFRB, a tyrosine kinase receptor essential for vascular progenitor signaling, were associated with CBLH, and this discovery links genetic and non-genetic etiologies. Our results suggest that genetic defects impact specific cerebellar cell types and implicate abnormal vascular development as a mechanism for cerebellar malformations. We also confirmed a major contribution for non-genetic prenatal factors in individuals with cerebellar abnormalities, substantially influencing diagnostic evaluation and counseling regarding recurrence risk and prognosis.
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