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Article: Redefining the Etiologic Landscape of Cerebellar Malformations

TitleRedefining the Etiologic Landscape of Cerebellar Malformations
Authors
Keywordsautism
cerebellar hypoplasia
cerebellum
Dandy-Walker malformation
epilepsy
Issue Date2019
PublisherCell Press. The Journal's web site is located at http://www.cell.com/AJHG/
Citation
American Journal of Human Genetics, 2019, v. 105 n. 3, p. 606-615 How to Cite?
AbstractCerebellar 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
Persistent Identifierhttp://hdl.handle.net/10722/278245
ISSN
2019 Impact Factor: 10.502
2015 SCImago Journal Rankings: 8.769
PubMed Central ID

 

DC FieldValueLanguage
dc.contributor.authorAldinger, KA-
dc.contributor.authorTimms, AE-
dc.contributor.authorThomson, Z-
dc.contributor.authorMirzaa, GM-
dc.contributor.authorBennett, JT-
dc.contributor.authorRosenberg, AB-
dc.contributor.authorRoco, CM-
dc.contributor.authorHirano, M-
dc.contributor.authorAbidi, F-
dc.contributor.authorHaldipur, P-
dc.contributor.authorCheng, CV-
dc.contributor.authorCollins, S-
dc.contributor.authorPark, K-
dc.contributor.authorZeiger, J-
dc.contributor.authorOvermann, LM-
dc.contributor.authorAlkuraya, FS-
dc.contributor.authorBiesecker, LG-
dc.contributor.authorBraddock, SR-
dc.contributor.authorCathey, S-
dc.contributor.authorCho, MT-
dc.contributor.authorChung, BHY-
dc.contributor.authorEverman, DB-
dc.contributor.authorZarate, YA-
dc.contributor.authorJones, JR-
dc.contributor.authorSchwartz, CE-
dc.contributor.authorGoldstein, A-
dc.contributor.authorHopkin, RJ-
dc.contributor.authorKrantz, ID-
dc.contributor.authorLadda, RL-
dc.contributor.authorLeppig, KA-
dc.contributor.authorMcGillivray, BC-
dc.contributor.authorSell, S-
dc.contributor.authorWusik, K-
dc.contributor.authorGleeson, JG-
dc.contributor.authorNickerson, DA-
dc.contributor.authorBamshad, MJ-
dc.contributor.authorGerrelli, D-
dc.contributor.authorLisgo, SN-
dc.contributor.authorSeelig, G-
dc.contributor.authorIshak, GE-
dc.contributor.authorBarkovich, AJ-
dc.contributor.authorCurry, CJ-
dc.contributor.authorGlass, IA-
dc.contributor.authorMillen, KJ-
dc.contributor.authorDoherty, D-
dc.contributor.authorDobyns, WB-
dc.date.accessioned2019-10-04T08:10:17Z-
dc.date.available2019-10-04T08:10:17Z-
dc.date.issued2019-
dc.identifier.citationAmerican Journal of Human Genetics, 2019, v. 105 n. 3, p. 606-615-
dc.identifier.issn0002-9297-
dc.identifier.urihttp://hdl.handle.net/10722/278245-
dc.description.abstractCerebellar 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-
dc.languageeng-
dc.publisherCell Press. The Journal's web site is located at http://www.cell.com/AJHG/-
dc.relation.ispartofAmerican Journal of Human Genetics-
dc.subjectautism-
dc.subjectcerebellar hypoplasia-
dc.subjectcerebellum-
dc.subjectDandy-Walker malformation-
dc.subjectepilepsy-
dc.titleRedefining the Etiologic Landscape of Cerebellar Malformations-
dc.typeArticle-
dc.identifier.emailChung, BHY: bhychung@hku.hk-
dc.identifier.authorityChung, BHY=rp00473-
dc.identifier.doi10.1016/j.ajhg.2019.07.019-
dc.identifier.pmid31474318-
dc.identifier.pmcidPMC6731369-
dc.identifier.scopuseid_2-s2.0-85071427405-
dc.identifier.hkuros306987-
dc.identifier.volume105-
dc.identifier.issue3-
dc.identifier.spage606-
dc.identifier.epage615-
dc.publisher.placeUnited States-

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