Reassessing the association: Evaluation of a polyalanine deletion variant of RUNX2 in non-syndromic sagittal and metopic craniosynostosis.

Autor: Walton IS; MRC Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, University of Oxford, Oxford, UK., McCann E; Department of Clinical Genetics, Liverpool Women's NHS Foundation Trust, Liverpool, England, UK., Weber A; Department of Clinical Genetics, Liverpool Women's NHS Foundation Trust, Liverpool, England, UK., Morton JEV; West Midlands Regional Clinical Genetics Service and Birmingham Health Partners, Birmingham Women's and Children's Hospitals NHS Foundation Trust, Birmingham, UK.; Birmingham Craniofacial Unit, Birmingham Women's and Children's Hospitals NHS Foundation Trust, Birmingham, UK., Noons P; Birmingham Craniofacial Unit, Birmingham Women's and Children's Hospitals NHS Foundation Trust, Birmingham, UK., Wilson LC; Clinical Genetics Service, Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK., Ching RC; Oxford Craniofacial Unit, Oxford University Hospitals NHS Foundation Trust, Oxford, UK., Cilliers D; Oxford Centre for Genomic Medicine, Oxford University Hospitals NHS Foundation Trust, Oxford, UK., Johnson D; Oxford Craniofacial Unit, Oxford University Hospitals NHS Foundation Trust, Oxford, UK., Phipps JM; Oxford Centre for Genomic Medicine, Oxford University Hospitals NHS Foundation Trust, Oxford, UK., Shears DJ; Oxford Craniofacial Unit, Oxford University Hospitals NHS Foundation Trust, Oxford, UK.; Oxford Centre for Genomic Medicine, Oxford University Hospitals NHS Foundation Trust, Oxford, UK., Thomas GPL; Oxford Craniofacial Unit, Oxford University Hospitals NHS Foundation Trust, Oxford, UK., Wall SA; Oxford Craniofacial Unit, Oxford University Hospitals NHS Foundation Trust, Oxford, UK., Twigg SRF; MRC Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, University of Oxford, Oxford, UK., Wilkie AOM; MRC Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, University of Oxford, Oxford, UK.; Oxford Craniofacial Unit, Oxford University Hospitals NHS Foundation Trust, Oxford, UK.; Oxford Centre for Genomic Medicine, Oxford University Hospitals NHS Foundation Trust, Oxford, UK.
Jazyk: angličtina
Zdroj: Journal of anatomy [J Anat] 2024 Dec; Vol. 245 (6), pp. 874-878. Date of Electronic Publication: 2024 May 17.
DOI: 10.1111/joa.14052
Abstrakt: The RUNT-related transcription factor RUNX2 plays a critical role in osteoblast differentiation, and alterations to gene dosage cause distinct craniofacial anomalies. Uniquely amongst the RUNT-related family, vertebrate RUNX2 encodes a polyglutamine/polyalanine repeat (Gln 23 -Glu-Ala 17 in humans), with the length of the polyalanine component completely conserved in great apes. Surprisingly, a frequent 6-amino acid deletion polymorphism, p.(Ala84_Ala89)del, occurs in humans (termed 11A allele), and a previous association study (Cuellar et al. Bone 137:115395;2020) reported that the 11A variant was significantly more frequent in non-syndromic sagittal craniosynostosis (nsSag; allele frequency [AF] = 0.156; 95% confidence interval [CI] 0.126-0.189) compared to non-syndromic metopic craniosynostosis (nsMet; AF = 0.068; 95% CI 0.045-0.098). However, the gnomAD v.2.1.1 control population used by Cuellar et al. did not display Hardy-Weinberg equilibrium, hampering interpretation. To re-examine this association, we genotyped the RUNX2 11A polymorphism in 225 individuals with sporadic nsSag as parent-child trios and 164 singletons with sporadic nsMet, restricting our analysis to individuals of European ancestry. We compared observed allele frequencies to the non-transmitted alleles in the parent-child trios, and to the genome sequencing data from gnomAD v.4, which display Hardy-Weinberg equilibrium. Observed AFs (and 95% CI) were 0.076 (0.053-0.104) in nsSag and 0.082 (0.055-0.118) in nsMet, compared with 0.062 (0.042-0.089) in non-transmitted parental alleles and 0.065 (0.063-0.067) in gnomAD v.4.0.0 non-Finnish European control genomes. In summary, we observed a non-significant excess, compared to gnomAD data, of 11A alleles in both nsSag (relative risk 1.18, 95% CI 0.83-1.67) and nsMet (relative risk 1.29, 95% CI 0.87-1.92), but we did not replicate the much higher excess of RUNX2 11A alleles in nsSag previously reported (p = 0.0001).
(© 2024 The Authors. Journal of Anatomy published by John Wiley & Sons Ltd on behalf of Anatomical Society.)
Databáze: MEDLINE
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