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.
Bibliographical noteFunding Information:
We thank the children as well as their families and referring physicians for their important contributions to our ongoing work on cerebellar disorders. This study was funded by the National Institutes of Health under National Institute of Neurological Disorders and Stroke ( NINDS ) or National Institute of Child Health and Human Development ( NICHD ) grant numbers 5R01NS050375 to W.B.D, R01NS095733 to K.J.M., K08NS092898 to G.M.M., and R24HD000836 to I.A.G. The University of Washington Center for Mendelian Genomics provided sequencing and data analysis, supported by National Human Genome Research Institute ( NHGRI ) grant number U54HG006493 to D.A.N. and M.J.B., and the University of Washington Intellectual and Developmental Disabilities Research Center (IDDRC) Genetics Core, supported by NICHD grant number U54HG006493 , provided support to D.D. Additional funding was provided by The Dandy-Walker Alliance and The Philly Baer Foundation . L.G.B. was supported by grant number HG200328 from the Intramural Research Program of the NHGRI . Human fetal material was provided, in part, by the Joint Medical Research Council and Wellcome ( MR/R006237/1 ) Human Developmental Biology Resource. The content is solely the responsibility of the authors and does not necessarily represent the official views of the funding sources. Please note that the authors cite OMIM according to journal editorial policy but do not endorse the referenced OMIM data.
- Dandy-Walker malformation
- cerebellar hypoplasia
- intellectual disability