A cryptic CBFB deletion–inversion expands the mutational spectrum of variants associated with cleidocranial dysplasia

CBFB encodes the core-binding factor β subunit, a small protein which heterodimerises with RUNX1-3 and activates transcription of genes important in bone development. Recently, five families with cleidocranial dysplasia (CCD) were identified harbouring presumed loss of function variants in CBFB. Prompted by a multidisciplinary team review of an affected mother and daughter from the 100 000 Genomes Project with genetically unsolved CCD, we inspected read alignments and identified a deletion–inversion–deletion that removes the first two exons of CBFB. This cryptic variant comprised interlinked deletions of 1310 bp and 1935 bp and had remained undetected by both array-CGH and the Canvas algorithm. The rearrangement was likely mediated by a palindromic AluSx repeat < 1 kb from the transcriptional start site. Due to high GC content and repeats, reduced read depth is observed at one of the breakpoints. Although the clinical presentation of CBFB-related CCD appears to be very similar to RUNX2-related CCD, our patients were of normal stature. The mild developmental delay observed in previously reported cases of CBFB-related CCD was not observed. In conclusion, our data strengthens the evidence linking aberrations of the core-binding factor complex to CCD and extends the mutational spectrum of pathogenic variants.