BioProject

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. More...

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. Overall design: NCBRS blood samples (SMARCA2_1, SMARCA2_2, SMARCA2_5, SMARCA2_6, SMARCA2_7, SMARCA2_8, SMARCA2_9, SMARCA2_11), SMARCA2 test variants (SMARCA2_4, SMARCA2_10, SMARCA2_12, SMARCA2_14, SMARCA2_15, SMARCA2_16, SMARCA2_17, SMARCA2_18, SMARCA2_19) control blood samples (n=23) have DNA methylation measured on the Infinium MethylationEPIC Bead Chip array (GPL21145). Test cases with vairants of unknown significane Pyrosequencing in cases and matched controls was done as described in the associated publication. There are no replications in this submission. Less...