A 20-gene panel was designed based on the genes' association with craniosynostosis, and clinically validated through retrospective testing of an Australian and New Zealand cohort of 233 individuals with craniosynostosis in whom previous testing had not identified a causative variant within FGFR1-3 hot-spot regions or the TWIST1 gene.
Subsequently, mutations in the FGFR2, FGFR3, TWIST1, and EFNB1 genes have been shown to account for approximately 25% of craniosynostosis, whilst several additional genes make minor contributions.
Future TWIST mutational analysis on patients with craniosynostosis and radial ray involvement will shed light on whether Baller-Gerold syndrome should be a distinct entity or some cases should be reclassified as a heterogeneous form of SCS.
Thirty-two unrelated patients with features of Saethre-Chotzen syndrome, a common autosomal dominant condition of craniosynostosis and limb anomalies, were screened for mutations in TWIST, FGFR2, and FGFR3.
The most common genetic mutations identified in syndromic craniosynostosis involve the fibroblast growth factor receptor (FGFR) family with other mutations occurring in genes for transcription factors TWIST, MSX2, and GLI3, and other proteins EFNB1, RAB23, RECQL4, and POR, presumed to be involved either upstream or downstream of the FGFR signaling pathway.
Given that RUNX2 is required as a master switch for osteoblast differentiation and interacts with TWIST1, mutations in which also cause craniosynostosis, we conclude that the duplication in this family is pathogenic, albeit with reduced penetrance.
We have now undertaken such a screen in 259 patients with craniosynostosis in whom mutations in other genes (e.g., FGFR1, FGFR3, and TWIST) had been excluded; part of this screen was a cohort-based study, enabling unbiased estimates of the mutation distribution to be obtained.
Saethre-Chotzen syndrome (SCS), one of the most common forms of syndromic craniosynostosis (premature fusion of the cranial sutures), results from haploinsufficiency of TWIST1, caused by deletions of the entire gene or loss-of-function variants within the coding region.
Chromosome conformation capture analyses show that TWIST1 lost genomic interactions with several enhancers due to the chromothripsis event, which likely led to deregulation of TWIST1 expression and contributed to the patient's craniosynostosis phenotype.
Therefore, we have identified dimer partner selection as an important mediator of Twist1 function and provide a mechanistic understanding of craniosynostosis due to TWIST haploinsufficiency.
Consistent with such a relationship, Twist1-Jagged1 double heterozygotes exhibit a substantial increase in the severity of craniosynostosis over individual heterozygotes.
This is a confirmatory case report providing further evidence for TWIST1 haploinsufficiency in SCS, although a possible role of PTP-oc as genetic factor underlying or at least influencing the development of craniosynostosiscould not be a priori excluded.
TSLP receptor is highly expressed in CRS compared to controls and independently from the polyps suggesting an early common inflammatory pathway in the two CRS phenotypes.
The list of genes that are involved in CS includes those coding for the different fibroblast growth factor receptors and a ligand of ephrin receptors, but also genes encoding transcription factors, such as MSX2 and TWIST.