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.

Genetic tests aid in counseling of fetuses with cerebellar vermis defects

“…Several genes have been associated both with CVH and DWM, including FOXP1 , SETD2 , TUBA1A reported before 12 and CEP290 in our study. These genetic findings may support the common disruption to rhombic lip development in the two malformations 7 .…”

“…These genetic findings may support the common disruption to rhombic lip development in the two malformations 7 . Although the numbers in this study were too small to draw definitive conclusions, we noticed that the diagnostic yield among fetuses of DWM (6/11 [54.5%]) was more than twice that of CVH, which was substantially higher than the 16% reported in a postnatal study with the largest cohort of DWM and cerebellar hypoplasia up to date 12 . The inconsistency between the two studies is probably due to the exclusion of AR diseases in their study, such as ciliopathies, which account for 50% of the monogenetic etiology in our study.…”

“…With the increased application of whole exome sequencing (WES), case reports of CVD patients often show an association with monogenetic diseases. Recently, in a large cohort of postnatal patients with cerebellar malformations, the monogenetic diagnostic rate was 36%, 12 indicating that WES may also contribute for fetuses with prenatal diagnoses of CVD. The purpose of this study was to assess the genetic diagnostic capacity of microarray and WES in fetal CVD and provide information for prenatal counseling.…”

Missense variants in the Arg206 residue of HNRNPH2: Further evidence of causality and expansion of the phenotype

“…For instance, three patients-including oursshowed abnormalities of the cerebellar vermis. This confirms that cerebellar hypoplasia often occurs as a co-morbidity of several different neurodevelopmental disorders and, if additional individuals with Bain type XLID and cerebellar abnormalities were identified, HNRNPH2 could be included in the list of genes that cause this brain phenotype (Aldinger et al, 2019;Peron, Bradbury, Viskochil, & Dias, 2019 Note: Recurrent pathogenic variants in multiple patients are color-coded in the online version: p.Arg206Trp in red (most commonly found variant); p.Arg206Gln in blue; all other variants in black (reported in one patient each). Numbers in the last column refer to the patients with abnormal findings over the total.…”

“…For instance, three patients—including ours—showed abnormalities of the cerebellar vermis. This confirms that cerebellar hypoplasia often occurs as a co‐morbidity of several different neurodevelopmental disorders and, if additional individuals with Bain type XLID and cerebellar abnormalities were identified, HNRNPH2 could be included in the list of genes that cause this brain phenotype (Aldinger et al, ; Peron, Bradbury, Viskochil, & Dias, ).…”