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Differental DNA methylation in Nicolaides-Baraitser syndrome

ABSTRACT: Nicolaides-Baraitser syndrome (NCBRS) is a neurodevelopmental disorder caused by pathogenic sequence variants in SMARCA2 which encodes the catalytic component of the chromatin remodeling BAF (SWI/SNF) complex. We identified an NCBRS-SMARCA2 DNA methylation (DNAm) signature of 429 differentially methylated CpG sites in blood cells of individuals with NCBRS (n=8) compared to neurotypical controls (n=23) using the Illumina MethylationEPIC array. The genes to which these CpGs mapped were enriched for roles in cell differentiation, calcium signaling, and neuronal function consistent with NCBRS pathophysiology. The DNAm signature, demonstrating 100% sensitivity and specificity, was used to generated a model enabling classification of variants of unknown significance (VUS) in SMARCA2 as pathogenic (like NCBRS cases) or benign (like controls). Model assignments were concordant with the clinical phenotype and predicted protein effects for most cases; variants within the SMARCA2 ATPase/helicase domain classified as pathogenic and those outside as benign. A patient with a mild NCBRS phenotype and a SMARCA2 VUS distal to the ATPase/helicase domain demonstrated an intermediate DNAm signature profile, suggesting the signature output reflects the phenotype of individual cases. At most of the signature sites, the methylation values for this patient resembled those of either NCBRS cases or controls; the ontology of the genes overlapping these NCBRS- or control-like CpG sites were consistent with the patient?s unique clinical presentation. The NCBRS-SMARCA2 DNAm signature provides alternate means of functional molecular classification of SMARCA2 VUS as benign or pathogenic, as well as providing insight into downstream BAF complex targets.

ORGANISM(S): Homo sapiens

PROVIDER: GSE125367 | GEO | 2019/06/27

REPOSITORIES: GEO

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Project description:Germline BRCA2 loss-of function (LOF) variants identified by clinical genetic testing predispose to breast, ovarian, prostate and pancreatic cancer. However, variants of uncertain significance (VUS) (n>5000) limit the clinical use of testing results. Thus, there is an urgent need for functional characterization and clinical classification of all BRCA2 variants. Here we report on comprehensive saturation genome editing-based functional characterization of 99% of all possible single nucleotide variants (SNVs) in the BRCA2 DNA Binding Domain hotspot for pathogenic missense variants that is encoded by exons 15 to 26. The assay was based on deep sequence analysis of HAP1 haploid cells endogenously targeted using a CRISPR/cas9 knockin approach. A total of 6959 SNVs were characterized for effects on cell survival. The assay was validated relative to nonsense and synonymous variants, ClinVar pathogenic/likely pathogenic and benign/likely benign variants and homology directed repair cell based DNA repair assay results, all of which showed >94% sensitivity and specificity. Variants were assigned posterior probabilities of pathogenicity using a VarCall two component Bayesian mixture model and were further grouped according to ACMG strength of evidence under the PS3/BS3 rule resulting in Benign Strong (n=5430), Benign Moderate (n=190), Benign Supporting (n=61), VUS (122), Pathogenic Strong (n=1021), Pathogenic Moderate (n=88), and Pathogenic Supporting (n=47). Breast cancer case-control association studies showed that pooled SNVs encoding functionally pathogenic missense variants were associated with increased risks of breast (odds ratio (OR)3.81, 95%CI: 2.88-5.07) and ovarian cancer (OR 5.93, 95%CI: 4.12-8.52). The functional data were also combined with other sources of information in the ClinGen BRCA1/2 VCEP ACMG/AMP-classification model. A total of 785 SNVs, including 261 missense SNVs, were classified as pathogenic or likely pathogenic, while 5566 SNVs, including 3786 missense SNVs, were classified as benign or likely benign. These classified variants can now be used for risk assessment and clinical care of variant carriers.

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Differental DNA methylation in Nicolaides-Baraitser syndrome

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