Heterozygous pathogenic variants involving cause a new skeletal disorder resembling cleidocranial dysplasia.

Background: Cleidocranial dysplasia (CCD) is a rare skeletal dysplasia with significant clinical variability. Patients with CCD typically present with delayed closure of fontanels and cranial sutures, dental anomalies, clavicular hypoplasia or aplasia and short stature. Runt-related transcription factor 2 ( is currently the only known disease-causing gene for CCD, but several studies have suggested locus heterogeneity.

Methods: The cohort consists of eight subjects from five unrelated families partially identified through GeneMatcher. Exome or genome sequencing was applied and in two subjects the effect of the variant was investigated at RNA level.

Results: In each subject a heterozygous pathogenic variant in was detected, whereas no genomic alteration involving was found. Three variants (one splice site alteration, one nonsense variant, one 2 bp duplication) were shown to result in a premature stop codon. A large intragenic deletion was found to delete exon 4, without affecting expression. The effect of a second splice site variant could not be determined but most likely results in a shortened or absent protein. Affected individuals showed similarities with -related CCD, including dental and clavicular abnormalities. Normal stature and neurocognitive problems were however distinguishing features. encodes the core-binding factor β subunit, which can interact with all RUNX proteins (RUNX1, RUNX2, RUNX3) to form heterodimeric transcription factors. This may explain the phenotypic differences between -related and -related CCD.

Conclusion: We confirm the previously suggested locus heterogeneity for CCD by identifying five pathogenic variants in in a cohort of eight individuals with clinical and radiographic features reminiscent of CCD.