3 research outputs found
Reassessing the association: Evaluation of a polyalanine deletion variant of RUNX2 in nonâsyndromic sagittal and metopic craniosynostosis
The RUNTârelated transcription factor RUNX2 plays a critical role in osteoblast differentiation, and alterations to gene dosage cause distinct craniofacial anomalies. Uniquely amongst the RUNTârelated family, vertebrate RUNX2 encodes a polyglutamine/polyalanine repeat (Gln23âGluâAla17 in humans), with the length of the polyalanine component completely conserved in great apes. Surprisingly, a frequent 6âamino 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 nonâsyndromic sagittal craniosynostosis (nsSag; allele frequency [AF] = 0.156; 95% confidence interval [CI] 0.126â0.189) compared to nonâsyndromic metopic craniosynostosis (nsMet; AF = 0.068; 95% CI 0.045â0.098). However, the gnomAD v.2.1.1 control population used by Cuellar et al. did not display HardyâWeinberg equilibrium, hampering interpretation. To reâexamine this association, we genotyped the RUNX2 11A polymorphism in 225 individuals with sporadic nsSag as parentâchild trios and 164 singletons with sporadic nsMet, restricting our analysis to individuals of European ancestry. We compared observed allele frequencies to the nonâtransmitted alleles in the parentâchild trios, and to the genome sequencing data from gnomAD v.4, which display HardyâWeinberg equilibrium. Observed AFs (and 95% CI) were 0.076 (0.053â0.104) in nsSag and 0.082 (0.055â0.118) in nsMet, compared with 0.062 (0.042â0.089) in nonâtransmitted parental alleles and 0.065 (0.063â0.067) in gnomAD v.4.0.0 nonâFinnish European control genomes. In summary, we observed a nonâsignificant excess, compared to gnomAD data, of 11A alleles in both nsSag (relative risk 1.18, 95% CI 0.83â1.67) and nsMet (relative risk 1.29, 95% CI 0.87â1.92), but we did not replicate the much higher excess of RUNX2 11A alleles in nsSag previously reported (p = 0.0001)
Diagnostic value of exome and whole genome sequencing in craniosynostosis
Background. Craniosynostosis, the premature fusion of one or more cranial sutures, occurs in ~1 in 2250 births, either in isolation or as part of a syndrome. Mutations in at least 57 genes have been associated with craniosynostosis, but only a minority of these are included in routine laboratory genetic testing.
Methods. We utilised exome or whole genome sequencing to seek a genetic cause in a cohort of 40 subjects with craniosynostosis, selected by clinical or molecular geneticists as being high priority cases, and in whom prior clinically-driven genetic testing had been negative.
Results. We identified likely associated mutations in 15 patients (37.5%), involving 14 different genes. All genes were mutated in single families, except for IL11RA (2 families). We classified the other positive diagnoses as follows: commonly mutated craniosynostosis genes with atypical presentation (EFNB1, TWIST1); other core craniosynostosis genes (CDC45, MSX2, ZIC1); genes for which mutations are only rarely associated with craniosynostosis (FBN1, HUWE1, KRAS, STAT3); and known disease genes for which a causal relationship with craniosynostosis is currently unknown (AHDC1, NTRK2). In two further families, likely novel disease genes are currently undergoing functional validation. In 5 of the 15 positive cases, the (previously unanticipated) molecular diagnosis had immediate, actionable consequences for either genetic or medical management (mutations in EFNB1, FBN1, KRAS, NTRK2, STAT3).
Conclusions. This substantial genetic heterogeneity, and the multiple actionable mutations identified, emphasises the benefits of exome/whole genome sequencing to identify causal mutations in craniosynostosis cases for which routine clinical testing has yielded negative results
Diagnostic value of exome and whole genome sequencing in craniosynostosis
Background Craniosynostosis, the premature fusion of one or more cranial sutures, occurs in ~1 in 2250 births, either in isolation or as part of a syndrome. Mutations in at least 57 genes have been associated with craniosynostosis, but only a minority of these are included in routine laboratory genetic testing. Methods We used exome or whole genome sequencing to seek a genetic cause in a cohort of 40 subjects with craniosynostosis, selected by clinical or molecular geneticists as being high-priority cases, and in whom prior clinically driven genetic testing had been negative. Results We identified likely associated mutations in 15 patients (37.5%), involving 14 different genes. All genes were mutated in single families, except for IL11RA (two families). We classified the other positive diagnoses as follows: commonly mutated craniosynostosis genes with atypical presentation (EFNB1, TWIST1); other core craniosynostosis genes (CDC45, MSX2, ZIC1); genes for which mutations are only rarely associated with craniosynostosis (FBN1, HUWE1, KRAS, STAT3); and known disease genes for which a causal relationship with craniosynostosis is currently unknown (AHDC1, NTRK2). In two further families, likely novel disease genes are currently undergoing functional validation. In 5 of the 15 positive cases, the (previously unanticipated) molecular diagnosis had immediate, actionable consequences for either genetic or medical management (mutations in EFNB1, FBN1, KRAS, NTRK2, STAT3). Conclusions This substantial genetic heterogeneity, and the multiple actionable mutations identified, emphasises the benefits of exome/whole genome sequencing to identify causal mutations in craniosynostosis cases for which routine clinical testing has yielded negative results