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Redefining the Etiologic Landscape of Cerebellar Malformations.

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.

SUBMITTER: Aldinger KA

PROVIDER: S-EPMC6731369 | biostudies-literature | 2019 Sep

REPOSITORIES: biostudies-literature

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Redefining the Etiologic Landscape of Cerebellar Malformations.

Aldinger Kimberly A KA Timms Andrew E AE Thomson Zachary Z Mirzaa Ghayda M GM Bennett James T JT Rosenberg Alexander B AB Roco Charles M CM Hirano Matthew M Abidi Fatima F Haldipur Parthiv P Cheng Chi V CV Collins Sarah S Park Kaylee K Zeiger Jordan J Overmann Lynne M LM Alkuraya Fowzan S FS Biesecker Leslie G LG Braddock Stephen R SR Cathey Sara S Cho Megan T MT Chung Brian H Y BHY Everman David B DB Zarate Yuri A YA Jones Julie R JR Schwartz Charles E CE Goldstein Amy A Hopkin Robert J RJ Krantz Ian D ID Ladda Roger L RL Leppig Kathleen A KA McGillivray Barbara C BC Sell Susan S Wusik Katherine K Gleeson Joseph G JG Nickerson Deborah A DA Bamshad Michael J MJ Gerrelli Dianne D Lisgo Steven N SN Seelig Georg G Ishak Gisele E GE Barkovich A James AJ Curry Cynthia J CJ Glass Ian A IA Millen Kathleen J KJ Doherty Dan D Dobyns William B WB

American journal of human genetics 20190829 3

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 sig ...[more]

PMID: 31474318

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Project description:ObjectiveThe objective of this study was to evaluate the existing Spetzler-Martin (SM), Spetzler-Ponce (SP), and Lawton-Young (LY) grading systems for cerebellar arteriovenous malformations (AVMs) and to propose a new grading system to estimate the risks associated with these lesions.MethodsData for patients with cerebellar AVMs treated microsurgically in two tertiary medical centers were retrospectively reviewed. Data from patients at institution 1 were collected from September 1999 to February 2013, and at institution 2 from October 2008 to October 2015. Patient outcomes were classified as favorable (modified Rankin Scale [mRS] score 0-2) or poor (mRS score 3-6) at the time of discharge. Using chi-square and logistic regression analysis, variables associated with poor outcomes were assigned risk points to design the proposed grading system. The proposed system included neurological status prior to treatment (poor, +2 points), emergency surgery (+1 point), age > 60 years (+1 point), and deep venous drainage (deep, +1 point). Risk point totals of 0-1 comprised grade 1, 2-3 grade 2, and 4-5 grade 3.ResultsA total of 125 cerebellar AVMs of 1328 brain AVMs were reviewed in 125 patients, 120 of which were treated microsurgically and included in the study. With our proposed grading system, we found poor outcomes differed significantly between each grade (p < 0.001), while with the SM, SP, and LY grading systems they did not (p = 0.22, p = 0.25, and p = 1, respectively). Logistic regression revealed grade 2 had 3.3 times the risk of experiencing a poor outcome (p = 0.008), while grade 3 had 9.9 times the risk (p < 0.001). The proposed grading system demonstrated a superior level of predictive accuracy (area under the receiver operating characteristic curve [AUROC] of 0.72) compared with the SM, SP, and LY grading systems (AUROC of 0.61, 0.57, and 0.51, respectively).ConclusionsThe authors propose a novel grading system for cerebellar AVMs based on emergency surgery, venous drainage, preoperative neurological status, and age that provides a superior prognostication power than the formerly proposed SM, SP, and LY grading systems. This grading system is clinically predictive of patient outcomes and can be used to better guide vascular neurosurgeons in clinical decision-making.

Dataset Information

Redefining the Etiologic Landscape of Cerebellar Malformations.

Publications

Redefining the Etiologic Landscape of Cerebellar Malformations.

Similar Datasets

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