Multiomic approaches identify a rare CCG repeat expansion in BCLAF3 in neurodevelopmental disorders.

Hypermethylated CCG repeat expansion in the 5'UTR of BCLAF3 (Xp22), constituting a previously uncharacterised fragile site (FRAXG); the surrounding chromatin shifts from open euchromatin to closed heterochromatin, with repression of BCLAF3 RNA and protein expression.

The authors describe a hypermethylated CCG repeat expansion at Xp22, in the 5'UTR of BCLAF3, in males with neurodevelopmental disorders. Using fibroblasts and neuronal models derived from one family, they show repression of BCLAF3 RNA and protein and establish that the expansion constitutes a previously uncharacterised fragile site (FRAXG) that shifts the surrounding chromatin from open euchromatin to closed heterochromatin. Screening 12,375 methylation arrays and 15,963 short-read genomes from probands with neurodevelopmental presentations identified three additional unrelated males and one related male cousin, with long-read validation (n = 2) or short-read prediction (n = 2). Long-read sequencing in three carrier mothers showed X-inactivation skewed against the expanded allele, and expansions were absent from long-read control populations. In the UK Biobank the expansion appears roughly 20-fold rarer than FMR1 expansions.

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

A convincing multiomic study: cellular models, long-read validation, large-scale screening and population data all converge on a new X-linked aetiology. The operational lesson is that this kind of locus escapes standard analysis — methylation and long-read data make the diagnosis, not variant annotation. Case numbers remain small and the phenotypic spectrum is undefined, so this is a strong candidate locus rather than an immediate routine test.

Analysis by Dr Thibaut Benquey