Redefining the Etiologic Landscape of Cerebellar Malformations

Kimberly A Aldinger; Andrew E Timms; Zachary Thomson; Ghayda M Mirzaa; James T Bennett; Alexander B Rosenberg; Charles M Roco; Matthew Hirano; Fatima Abidi; Parthiv Haldipur; Chi V Cheng; Sarah Collins; Kaylee Park; Jordan Zeiger; Lynne M Overmann; Fowzan S Alkuraya; Leslie G Biesecker; Stephen R Braddock; Sara Cathey; Megan T Cho; Brian H Y Chung; David B Everman; Yuri A Zarate; Julie R Jones; Charles E Schwartz; Amy Goldstein; Robert J Hopkin; Ian D Krantz; Roger L Ladda; Kathleen A Leppig; Barbara C McGillivray; Susan Sell; Katherine Wusik; Joseph G Gleeson; Deborah A Nickerson; Michael J Bamshad; Dianne Gerrelli; Steven N Lisgo; Georg Seelig; Gisele E Ishak; A James Barkovich; Cynthia J Curry; Ian A Glass; Kathleen J Millen; Dan Doherty; William B Dobyns

doi:10.1016/j.ajhg.2019.07.019

Redefining the Etiologic Landscape of Cerebellar Malformations

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

Authors

Kimberly A Aldinger¹, Andrew E Timms², Zachary Thomson¹, Ghayda M Mirzaa³, James T Bennett⁴, Alexander B Rosenberg⁵, Charles M Roco⁶, Matthew Hirano⁵, Fatima Abidi⁷, Parthiv Haldipur¹, Chi V Cheng¹, Sarah Collins¹, Kaylee Park¹, Jordan Zeiger¹, Lynne M Overmann⁸, Fowzan S Alkuraya⁹, Leslie G Biesecker¹⁰, Stephen R Braddock¹¹, Sara Cathey⁷, Megan T Cho¹², Brian H Y Chung¹³, David B Everman⁷, Yuri A Zarate¹⁴, Julie R Jones⁷, Charles E Schwartz⁷, Amy Goldstein¹⁵, Robert J Hopkin¹⁶, Ian D Krantz¹⁷, Roger L Ladda¹⁸, Kathleen A Leppig¹⁹, Barbara C McGillivray²⁰, Susan Sell²¹, Katherine Wusik²², Joseph G Gleeson²³, Deborah A Nickerson²⁴, Michael J Bamshad²⁵, Dianne Gerrelli²⁶, Steven N Lisgo⁸, Georg Seelig²⁷, Gisele E Ishak²⁸, A James Barkovich²⁹, Cynthia J Curry³⁰, Ian A Glass³, Kathleen J Millen³, Dan Doherty³, William B Dobyns³¹

Affiliations

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, N.I.H., Intramural
Research Support, Non-U.S. Gov't

MeSH terms

Cerebellum / abnormalities*
Cerebellum / diagnostic imaging
Cohort Studies
Female
Humans
Male
Pregnancy

Abstract

Publication types

MeSH terms

Grants and funding