Characterizing ARID1B-related disorders and variants of uncertain significance using DNA methylation.

Loss-of-function variants in ARID1B, a subunit of the BAF chromatin remodelling complex, produce a whole-blood DNA methylation signature that can be used for variant classification.

Variants in ARID1B, a subunit of the BAF complex, are difficult to classify because of the breadth of the ARID1B-related disorder phenotype. The authors profiled whole-blood DNA methylation with the Infinium EPIC array in 22 individuals carrying ARID1B variants and 240 typically developing individuals. A specific signature of 160 CpG sites (FDR < 0.05; Δβ > 5%) was identified in six affected individuals, validated in two more, then used to classify 14 additional individuals, including rarely reported missense and in-frame variants as well as truncating variants in exons 1 and 3 previously described in unaffected individuals. The signature separated ARID1B-related profiles from those linked to SMARCA2, ARID1A and ATRX, but not from those linked to SMARCB1.

Synthesis written by Geno'X. For the full original abstract, please refer to the source publication.

The episignature addresses a daily problem, that of ARID1B missense variants in one of the genes most often implicated in neurodevelopmental disorders and already covered by WES and WGS: the bottleneck is interpretation, not detection. Two caveats: the signature was derived from only six patients, and its inability to separate ARID1B from SMARCB1 means sequence analysis must remain the reference. In practice this is a second-line test to request for an inconclusive missense or 5' truncating variant.

Analysis by Dr Thibaut Benquey