Rare and de novo coding variants in chromodomain genes in Chiari I malformation

Abstract

Three variants were misnamed in the text and mislabeled in Figure 2. The relevant sentence has been changed to read, ''The three de novo CHD8 mutations observed in CM1 include two stop-gain mutations (GenBank: NM_001170629.2; c.4414C>T [p.Arg1472*] and c.4514G>A [p.Trp1505*]) and a splice donor site mutation (c.2907þ1G>T [p.?]).

Childhood‐onset progressive dystonia associated with pathogenic truncating variants in CHD8

“…The adoption of unbiased genomic sequencing as a routine biomedical tool has enabled the characterization of many phenotype‐gene relationships not previously described. CHD8 pathogenic variants have originally been linked to a specific subtype of autism, 1 but the ascertainment of additional patients has revealed a more complex clinical constellation encompassing neurological, neuropsychiatric, and systemic abnormalities 2–4 …”

“…CHD8 pathogenic variants have originally been linked to a specific subtype of autism, 1 but the ascertainment of additional patients has revealed a more complex clinical constellation encompassing neurological, neuropsychiatric, and systemic abnormalities. [2][3][4] In the present case study, we further expand the neurological phenotype associated with CHD8 variants to include childhood-onset progressive dystonia. Although our independent index patients harboring CHD8 heterozygous lossof-function variants displayed previously reported clinical features of CHD8-associated disease (e.g., mild intellectual impairment and autistic traits), their chief complaints were neck/limb-onset dystonic symptoms with evolution towards generalized dystonia.…”

“…CHD8 encodes a member of the Chromodomain‐Helicase‐DNA binding family of chromatin remodelers, a class of proteins involved in various biological processes including development, cognition, and motor functioning 1 . Over the past few years, a few dozens of pathogenic CHD8 variants have been reported, mostly comprising nonsense and frameshifting alleles 1–4 . Although still referred to as „susceptibility to autism‐18“ in the OMIM database (MIM:615032), the phenotype associated with truncating variants in CHD8 is known to extend beyond autistic traits 2–4 .…”

“… 1 Over the past few years, a few dozens of pathogenic CHD8 variants have been reported, mostly comprising nonsense and frameshifting alleles. 1 , 2 , 3 , 4 Although still referred to as „susceptibility to autism‐18“ in the OMIM database (MIM:615032), the phenotype associated with truncating variants in CHD8 is known to extend beyond autistic traits. 2 , 3 , 4 CHD8 variants have been found in cohorts of patients with developmental delay, overgrowth and intellectual disability, behavioral disorders, and cerebellar malformations.…”

Functional and morphological changes in hypoplasic posterior fossa

“…Although the causality of these genes has to be proved yet, this study suggests that CIM could arise from the action of different genes, the combination of which would explain the differences in the PCF morpho-volumetric analysis and the absence of a significant PCF hypoplasia in several CIM subjects compared to controls. Furthermore, a very recent multicenter study, based on the whole exome sequencing of 232 CIM families (668 patients), showed that chromodomain genes (namely, CHD3 and CHD8 genes) can contribute to CIM genesis [43]. These genes are implicated in macrocephaly (as it happens in zebrafishes), and macrocephaly (large head circumference without associated brain or CSF anomalies) was largely present in the families enrolled for this study.…”