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

Isaac S Walton; Emma McCann; Astrid Weber; Jenny E V Morton; Peter Noons; Louise C Wilson; Rosanna C Ching; Deirdre Cilliers; David Johnson; Julie M Phipps; Deborah J Shears; Gregory P L Thomas; Steven A Wall; Stephen R F Twigg; Andrew O M Wilkie

doi:10.1111/joa.14052

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

J Anat. 2024 May 17. doi: 10.1111/joa.14052. Online ahead of print.

Authors

Isaac S Walton¹, Emma McCann², Astrid Weber², Jenny E V Morton^{3

4}, Peter Noons⁴, Louise C Wilson⁵, Rosanna C Ching⁶, Deirdre Cilliers⁷, David Johnson⁶, Julie M Phipps⁷, Deborah J Shears^{6

7}, Gregory P L Thomas⁶, Steven A Wall⁶, Stephen R F Twigg¹, Andrew O M Wilkie^{1

6

7}

Affiliations

¹ MRC Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, University of Oxford, Oxford, UK.
² Department of Clinical Genetics, Liverpool Women's NHS Foundation Trust, Liverpool, England, UK.
³ West Midlands Regional Clinical Genetics Service and Birmingham Health Partners, Birmingham Women's and Children's Hospitals NHS Foundation Trust, Birmingham, UK.
⁴ Birmingham Craniofacial Unit, Birmingham Women's and Children's Hospitals NHS Foundation Trust, Birmingham, UK.
⁵ Clinical Genetics Service, Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK.
⁶ Oxford Craniofacial Unit, Oxford University Hospitals NHS Foundation Trust, Oxford, UK.
⁷ Oxford Centre for Genomic Medicine, Oxford University Hospitals NHS Foundation Trust, Oxford, UK.

PMID: 38760592
DOI: 10.1111/joa.14052

Abstract

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 (Gln₂₃-Glu-Ala₁₇ 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).

Keywords: RUNX2; craniosynostosis; genetic association; metopic synostosis; polyalanine; sagittal synostosis.

Abstract

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