%0 Journal Article %J Am J Hum Genet %D 2019 %T Redefining the Etiologic Landscape of Cerebellar Malformations. %A Aldinger, Kimberly A %A Timms, Andrew E %A Thomson, Zachary %A Mirzaa, Ghayda M %A Bennett, James T %A Rosenberg, Alexander B %A Roco, Charles M %A Hirano, Matthew %A Abidi, Fatima %A Haldipur, Parthiv %A Cheng, Chi V %A Collins, Sarah %A Park, Kaylee %A Zeiger, Jordan %A Overmann, Lynne M %A Alkuraya, Fowzan S %A Biesecker, Leslie G %A Braddock, Stephen R %A Cathey, Sara %A Cho, Megan T %A Chung, Brian H Y %A Everman, David B %A Zarate, Yuri A %A Jones, Julie R %A Schwartz, Charles E %A Goldstein, Amy %A Hopkin, Robert J %A Krantz, Ian D %A Ladda, Roger L %A Leppig, Kathleen A %A McGillivray, Barbara C %A Sell, Susan %A Wusik, Katherine %A Gleeson, Joseph G %A Nickerson, Deborah A %A Bamshad, Michael J %A Gerrelli, Dianne %A Lisgo, Steven N %A Seelig, Georg %A Ishak, Gisele E %A Barkovich, A James %A Curry, Cynthia J %A Glass, Ian A %A Millen, Kathleen J %A Doherty, Dan %A Dobyns, William B %X

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.

%B Am J Hum Genet %V 105 %P 606-615 %8 2019 Sep 05 %G eng %N 3 %1 https://www.ncbi.nlm.nih.gov/pubmed/31474318?dopt=Abstract %R 10.1016/j.ajhg.2019.07.019