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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.
American journal of human genetics, 09/2019, Letnik: 105, Številka: 3Journal Article
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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JCR | SNIP | JCR | SNIP | JCR | SNIP | JCR | SNIP |
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in: SICRIS
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