A Cryptic CBFB Deletion–Inversion Expands the Mutational Spectrum of Variants Associated With Cleidocranial Dysplasia

ABSTRACTCBFB 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.