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

• Published in: Journal of medical genetics Vol. 60; no. 5; pp. 498 - 504
• Main Authors: Beyltjens, Tessi, Boudin, Eveline, Revencu, Nicole, Boeckx, Nele, Bertrand, Miriam, Schütz, Leon, Haack, Tobias B, Weber, Axel, Biliouri, Eleni, Vinkšel, Mateja, Zagožen, Anja, Peterlin, Borut, Pai, Shashidhar, Telegrafi, Aida, Henderson, Lindsay B, Ells, Courtney, Turner, Lesley, Wuyts, Wim, Van Hul, Wim, Hendrickx, Gretl, Mortier, Geert R
• Format: Journal Article
• Language: English
• Published: England BMJ Publishing Group Ltd 01.05.2023; BMJ Publishing Group LTD; BMJ Publishing Group
• Series: Original research
• Subjects: Aplasia; Base Sequence; Bone dysplasia; Cbfa-1 protein; Cleidocranial Dysplasia - genetics; Cleidocranial Dysplasia - pathology; Codon, Nonsense; Cognition; Core Binding Factor Alpha 1 Subunit - genetics; Core Binding Factor beta Subunit - genetics; Cranial sutures; Craniofacial syndromes; Dysplasia; Exons; Gene expression; genetic variation; Genomes; human genetics; Humans; Hypoplasia; musculoskeletal diseases; Nonsense mutation; Novel Disease Loci; phenotype; Proteins; Runx1 protein; Runx3 protein; Skeleton; Stop codon; Sutures; Transcription factors; Values; Whole genome sequencing; phenotype; human genetics; genetic variation; musculoskeletal diseases
• ISSN: 0022-2593; 1468-6244; 1468-6244
• DOI: 10.1136/jmg-2022-108739

BackgroundCleidocranial 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 (RUNX2) is currently the only known disease-causing gene for CCD, but several studies have suggested locus heterogeneity.MethodsThe 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.ResultsIn each subject a heterozygous pathogenic variant in CBFB was detected, whereas no genomic alteration involving RUNX2 was found. Three CBFB 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 CBFB 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 RUNX2-related CCD, including dental and clavicular abnormalities. Normal stature and neurocognitive problems were however distinguishing features. CBFB 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 CBFB-related and RUNX2-related CCD.ConclusionWe confirm the previously suggested locus heterogeneity for CCD by identifying five pathogenic variants in CBFB in a cohort of eight individuals with clinical and radiographic features reminiscent of CCD.