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Am J Hum Genet. 2019 Sep 5;105(3):606-615. doi: 10.1016/j.ajhg.2019.07.019. Epub 2019 Aug 29.

Redefining the Etiologic Landscape of Cerebellar Malformations.

Author information

1
Center for Integrative Brain Research, Seattle Children's Research Institute, Seattle, WA 98101, USA.
2
Center for Developmental Biology and Regenerative Medicine, Seattle Children's Research Institute, Seattle, WA 98101, USA.
3
Center for Integrative Brain Research, Seattle Children's Research Institute, Seattle, WA 98101, USA; Department of Pediatrics, University of Washington, Seattle, WA 98105, USA.
4
Center for Developmental Biology and Regenerative Medicine, Seattle Children's Research Institute, Seattle, WA 98101, USA; Department of Pediatrics, University of Washington, Seattle, WA 98105, USA.
5
Department of Electrical Engineering, University of Washington, Seattle, WA 98105, USA.
6
Department of Bioengineering, University of Washington, Seattle, WA 98105, USA.
7
Greenwood Genetic Center, Greenwood, SC 29646, USA.
8
Institute of Genetic Medicine, Newcastle University, International Centre for life, Central Parkway, Newcastle upon Tyne NE1 3BZ, UK.
9
Department of Genetics, King Faisal Specialist Hospital Research Center, Riyadh, 11211, Saudi Arabia.
10
Medical Genomics and Metabolic Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, 20892 USA.
11
Department of Pediatrics, Saint Louis University School of Medicine, St. Louis, MO 63104, USA.
12
GeneDx, Gaithersburg, MD 20877, USA.
13
Department of Pediatrics and Adolescent Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China.
14
Section of Genetics and Metabolism, University of Arkansas for Medical Sciences, Little Rock, AR, 72202, USA.
15
Mitochondrial Medicine Frontier Program, Division of Human Genetics, Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, PA, 19104, USA; The Department of Pediatrics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, 19104, USA.
16
Division of Human Genetics, Department of Pediatrics, Cincinnati Children's Hospital Medical Center and University of Cincinnati College of Medicine, Cincinnati, OH 45229, USA.
17
The Department of Pediatrics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, 19104, USA; Division of Human Genetics and Molecular Biology, The Children's Hospital of Philadelphia, Philadelphia, PA, 19104 USA.
18
Department of Pediatrics, Milton S Hershey Medical Center, Hershey, PA 17033, USA; Departments of Pathology, Milton S Hershey Medical Center, Hershey, PA 17033, USA.
19
Genetic Services, Kaiser Permanente Washington, Seattle, WA 98112, USA.
20
Department of Medical Genetics, Children's and Women's Health Centre of British Columbia, Vancouver, BC V6H 3N1, Canada.
21
Department of Pediatrics, Milton S Hershey Medical Center, Hershey, PA 17033, USA.
22
Division of Human Genetics, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA.
23
Department of Neurosciences, Howard Hughes Medical Institute, University of California, San Diego, La Jolla, CA 92093, USA.
24
Department of Genome Sciences, University of Washington, Seattle, WA 98195, USA; University of Washington Center for Mendelian Genomics, Seattle, WA 98195, USA.
25
Department of Pediatrics, University of Washington, Seattle, WA 98105, USA; Department of Genome Sciences, University of Washington, Seattle, WA 98195, USA; University of Washington Center for Mendelian Genomics, Seattle, WA 98195, USA.
26
University College London Institute of Child Health, London WC1N 1EH, UK.
27
Department of Electrical Engineering, University of Washington, Seattle, WA 98105, USA; Paul G. Allen School of Computer Science & Engineering, University of Washington, Seattle, WA 98195, USA.
28
Center for Integrative Brain Research, Seattle Children's Research Institute, Seattle, WA 98101, USA; Department of Radiology, University of Washington, Seattle, WA 98195, USA.
29
Departments of Radiology, Neurology, Pediatrics, and Neurosurgery, University of California, San Francisco, San Francisco, CA 94143, USA.
30
Genetic Medicine, Department of Pediatrics, University of California San Francisco, Fresno, CA, 93701, USA.
31
Center for Integrative Brain Research, Seattle Children's Research Institute, Seattle, WA 98101, USA; Department of Pediatrics, University of Washington, Seattle, WA 98105, USA; Department of Neurology, University of Washington, Seattle, WA 98105, USA. Electronic address: wbd@uw.edu.

Abstract

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.

KEYWORDS:

Dandy-Walker malformation; autism; cerebellar hypoplasia; cerebellum; epilepsy; exome; genes; heterotopia; intellectual disability; twins

PMID:
31474318
PMCID:
PMC6731369
[Available on 2020-03-05]
DOI:
10.1016/j.ajhg.2019.07.019

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