@article {685,
	title = {Redefining the Etiologic Landscape of Cerebellar Malformations.},
	journal = {Am J Hum Genet},
	volume = {105},
	year = {2019},
	month = {2019 Sep 05},
	pages = {606-615},
	abstract = {<p>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.</p>},
	issn = {1537-6605},
	doi = {10.1016/j.ajhg.2019.07.019},
	author = {Aldinger, Kimberly A and Timms, Andrew E and Thomson, Zachary and Mirzaa, Ghayda M and Bennett, James T and Rosenberg, Alexander B and Roco, Charles M and Hirano, Matthew and Abidi, Fatima and Haldipur, Parthiv and Cheng, Chi V and Collins, Sarah and Park, Kaylee and Zeiger, Jordan and Overmann, Lynne M and Alkuraya, Fowzan S and Biesecker, Leslie G and Braddock, Stephen R and Cathey, Sara and Cho, Megan T and Chung, Brian H Y and Everman, David B and Zarate, Yuri A and Jones, Julie R and Schwartz, Charles E and Goldstein, Amy and Hopkin, Robert J and Krantz, Ian D and Ladda, Roger L and Leppig, Kathleen A and McGillivray, Barbara C and Sell, Susan and Wusik, Katherine and Gleeson, Joseph G and Nickerson, Deborah A and Bamshad, Michael J and Gerrelli, Dianne and Lisgo, Steven N and Seelig, Georg and Ishak, Gisele E and Barkovich, A James and Curry, Cynthia J and Glass, Ian A and Millen, Kathleen J and Doherty, Dan and Dobyns, William B}
}
@article {555,
	title = {Rhombencephalosynapsis: Fused cerebellum, confused geneticists.},
	journal = {Am J Med Genet C Semin Med Genet},
	volume = {178},
	year = {2018},
	month = {2018 Dec},
	pages = {432-439},
	abstract = {<p>Rhombencephalosynapsis (RES) is a unique cerebellar malformation characterized by fusion of the cerebellar hemispheres with partial or complete absence of a recognizable cerebellar vermis. Subsets of patients also have other brain malformations such as midbrain fusion with aqueductal stenosis, characteristic craniofacial features (prominent forehead, flat midface, hypertelorism, ear abnormalities), and somatic malformations (heart, kidney, spine, and limb defects). Similar to known genetic brain malformations, the RES cerebellar malformation is highly stereotyped, yet no genetic causes have been identified. Here, we outline our current understanding of the genetic basis for RES, discuss limitations, and outline future approaches to identifying the causes of this fascinating brain malformation.</p>},
	issn = {1552-4876},
	doi = {10.1002/ajmg.c.31666},
	author = {Aldinger, Kimberly A and Dempsey, Jennifer C and Tully, Hannah M and Grout, Megan E and Mehaffey, Michele G and Dobyns, William B and Doherty, Dan}
}
