Genotype and clinical care correlations in craniosynostosis: Findings from a cohort of 630 Australian and New Zealand patients

Abstract

Craniosynostosis is one of the most common craniofacial disorders encountered in clinical genetics practice, with an overall incidence of 1 in 2,500. Between 30% and 70% of syndromic craniosynostoses are caused by mutations in hotspots in the fibroblast growth factor receptor (FGFR) genes or in the TWIST1 gene with the difference in detection rates likely to be related to different study populations within craniofacial centers. Here we present results from molecular testing of an Australia and New Zealand cohort of 630 individuals with a diagnosis of craniosynostosis. Data were obtained by Sanger sequencing of FGFR1, FGFR2, and FGFR3 hotspot exons and the TWIST1 gene, as well as copy number detection of TWIST1. Of the 630 probands, there were 231 who had one of 80 distinct mutations (36%). Among the 80 mutations, 17 novel sequence variants were detected in three of the four genes screened. In addition to the proband cohort there were 96 individuals who underwent predictive or prenatal testing as part of family studies. Dysmorphic features consistent with the known FGFR1-3/TWIST1-associated syndromes were predictive for mutation detection. We also show a statistically significant association between splice site mutations in FGFR2 and a clinical diagnosis of Pfeiffer syndrome, more severe clinical phenotypes associated with FGFR2 exon 10 versus exon 8 mutations, and more frequent surgical procedures in the presence of a pathogenic mutation. Targeting gene hot spot areas for mutation analysis is a useful strategy to maximize the success of molecular diagnosis for individuals with craniosynostosis.

Expanding the mutation spectrum in 182 Spanish probands with craniosynostosis: identification and characterization of novel TCF12 variants

“…Although the mutated gene frequency order was the same, the frequency of FGFR2 mutations was significantly different to the UK study (32%), but similar to that detected in a cohort of 630 Australian craniosynostosis patients (62%). 13 This is principally due to the high incidence of Apert and Pfeiffer cases in these cohorts compared to the UK cohort.…”

“…This is in accordance with the data observed in previous studies. 13,27 Therefore, these two regions, along with FGFR3 exons 7 and 9 (otherwise known as exon 7(IIIc) and exon 10 (TM 16 )) should be included in the first level of genetic analysis. A total of eight deletions were detected, seven TWIST1 deletions and one EFNB1 deletion, in level 2.…”

“…Evidence also suggests that molecular diagnosis can help to define the treatment or surgery necessary in the short to medium term and predict the clinical evolution. 12,13 Patients with an identified TWIST1 mutation have a high rate of reoperation due to intracranial hypertension, 12 whereas mutations in TCF12 do not. 9 Thus, the knowledge of the genetic mutation permits greater monitoring of the intracranial hypertension in these patients.…”

Mutation c.943G>T (p.Ala315Ser) in FGFR2 Causing a Mild Phenotype of Crouzon Craniofacial Dysostosis in a Three-Generation Family

“…The verified mutation in our family has been described previously at least 4 times in the literature [Johnson et al, 2000;Wilkie et al, 2002;Roscioli et al, 2013]. Wilkie et al [2002] described a family in which this variant was present accompanied by a second mutation in cis .…”

“…To our knowledge, the single c.943G>T (p.Ala315Ser) mutation has been rarely reported in the literature so far, i.e., in one familial case of a 3-generation family [Johnson et al, 2000;Kan et al, 2002] and in 2 other unrelated individuals [Roscioli et al, 2013]. The 2 cases of Roscioli et al [2013] were diagnosed with Crouzon syndrome and craniosynostosis, suggesting that they may have been more severely affected.…”