Redefining the Etiologic Landscape of Cerebellar Malformations.

TitleRedefining the Etiologic Landscape of Cerebellar Malformations.
Publication TypeJournal Article
Year of Publication2019
AuthorsAldinger, KA, Timms, AE, Thomson, Z, Mirzaa, GM, Bennett, JT, Rosenberg, AB, Roco, CM, Hirano, M, Abidi, F, Haldipur, P, Cheng, CV, Collins, S, Park, K, Zeiger, J, Overmann, LM, Alkuraya, FS, Biesecker, LG, Braddock, SR, Cathey, S, Cho, MT, H Y Chung, B, Everman, DB, Zarate, YA, Jones, JR, Schwartz, CE, Goldstein, A, Hopkin, RJ, Krantz, ID, Ladda, RL, Leppig, KA, McGillivray, BC, Sell, S, Wusik, K, Gleeson, JG, Nickerson, DA, Bamshad, MJ, Gerrelli, D, Lisgo, SN, Seelig, G, Ishak, GE, A Barkovich, J, Curry, CJ, Glass, IA, Millen, KJ, Doherty, D, Dobyns, WB
JournalAm J Hum Genet
Date Published2019 Sep 05

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.

Alternate JournalAm. J. Hum. Genet.
PubMed ID31474318
PubMed Central IDPMC6731369
Grant List / / Wellcome Trust / United Kingdom
K08 NS092898 / NS / NINDS NIH HHS / United States
U54 HG006493 / HG / NHGRI NIH HHS / United States
R01 NS095733 / NS / NINDS NIH HHS / United States
R01 NS050375 / NS / NINDS NIH HHS / United States
R24 HD000836 / HD / NICHD NIH HHS / United States
Z01 HG200328 / HG / NHGRI NIH HHS / United States
UM1 HG006493 / HG / NHGRI NIH HHS / United States