Expanding Clinical and Variant Spectrum of CBX1-Related Syndrome: Report of Three Novel Cases.

CBX1

Heterozygous de novo CBX1 missense variants in the HP1β chromodomain, the region mediating interaction with trimethylated H3K9

CBX1-related syndrome combines developmental delay, hypotonia, autistic features and mild dysmorphism; it had been described in only three individuals carrying heterozygous missense variants in the HP1β chromodomain, the region mediating interaction with trimethylated H3K9. The authors report three new patients with heterozygous de novo CBX1 variants, all located in the chromodomain. Patients with p.(Leu40Pro) and p.(Cys60Arg) had global developmental delay, whereas the patient with p.(Cys60Gly) mainly had speech delay without motor delay. In in vitro cellular assays, p.(Cys60Gly) showed an intermediate phenotype between wild type and the two other variants, suggesting a genotype-phenotype correlation.

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

Doubling the published series, from three to six patients, is valuable for an ultra-rare syndrome: it reinforces the chromodomain as a critical region for interpreting CBX1 missense variants in exome/genome data. The correlation with the cellular assay is suggestive but rests on a single 'intermediate' variant; more patients are needed before it can serve as a prognostic tool.

Analysis by Dr Thibaut Benquey