Craniosynostosis, the premature fusion of the cranial sutures, is a heterogeneous disorder with a prevalence of ~1 in 2, 200 (refs. 1,2). A specific genetic etiology can be identified in ~21% of cases 3 , including mutations of TWIST1, which encodes a class II basic helix-loop-helix (bHLH) transcription factor, and causes Saethre-Chotzen syndrome, typically associated with coronal URLs. ANNOVAR, http://www.openbioinformatics.org/annovar; GBrowse2, http://gmod.org/wiki/GBrowse; MRC-Holland, www.mrc-holland.com/pages/indexpag.html; PolyPhen-2, http://genetics.bwh.harvard.edu/pph2; SAMtools, http:// samtools.sourceforge.net. Accession codes.All cDNA numbering of TCF12 follows NCBI reference NM_207037.1, starting with A of the ATG initiation codon (=1). We used NM_207040.1 to design primers to the alternatively spliced first exon (9A). The genomic reference sequence is available from NC_000015.9. Europe PMC Funders GroupAuthor Manuscript Nat Genet. Author manuscript; available in PMC 2013 September 01. [4][5][6] . Starting with an exome sequencing screen, we identified 38 heterozygous TCF12 mutations in 347 samples from unrelated individuals with craniosynostosis. The mutations predominantly occurred in patients with coronal synostosis and accounted for 32% and 10% of subjects with bilateral and unilateral pathology, respectively. TCF12 encodes one of three class I E-proteins that heterodimerize with class II bHLH proteins such as TWIST1. We show that TCF12 and TWIST1 act synergistically in a transactivation assay, and that mice doubly heterozygous for loss-of-function mutations in Tcf12 and Twist1 exhibit severe coronal synostosis. Hence, the dosage of TCF12/TWIST1 heterodimers is critical for coronal suture development.Our exome sequencing approach focused on bilateral coronal craniosynostosis (Fig. 1a) because of previous evidence that this pathological group is loaded with cases of monogenic etiology 3 . We examined the variant lists from whole exome data 7 of seven unrelated patients with bilateral coronal synostosis, negative for previously described mutations 8 , for genes showing non-synonymous changes in two or more samples. Two samples had different heterozygous frameshift mutations in TCF12 (transcription factor 12; also known as HEB, HTF4 and ALF1) 9-11 ; one (Family #19) had a single nucleotide deletion and the other (#30) a 4-nucleotide deletion (details in Supplementary Table 1). The mutations were confirmed by dideoxy-sequencing of the original DNA samples (primary sequence results for all families are shown in Supplementary Fig. 1). In addition a text search of the exome sequence data revealed a novel T>A variant in TCF12 in a third sample (#22), located 20 nucleotides upstream of the start of exon 17. This variant was predicted to generate a cryptic splice acceptor site that was confirmed experimentally ( Supplementary Fig. 2a). Thus, we had identified different heterozygous disruptive mutations of TCF12 in 3 of 7 samples from patients with bilateral coronal synostosis. We interrogated oth...

The GP130 cytokine receptor subunit encoded by IL6ST is the shared receptor for ten cytokines of the IL-6 family. We describe a homozygous non-synonymous variant in IL6ST (p.R281Q) in a patient with craniosynostosis and retained deciduous teeth. We characterize the impact of the variant on cytokine signaling in vitro using transfected cell lines as well as primary patient-derived cells and support these findings using a mouse model with the corresponding genome-edited variant Il6st p.R279Q. We show that human GP130 p.R281Q is associated with selective loss of IL-11 signaling without affecting IL-6, IL-27, OSM, LIF, CT1, CLC, and CNTF signaling. In mice Il6st p.R279Q lowers litter size and causes facial synostosis and teeth abnormalities. The effect on IL-11 signaling caused by the GP130 variant shows incomplete penetrance but phenocopies aspects of IL11RA deficiency in humans and mice. Our data show that a genetic variant in a pleiotropic cytokine receptor can have remarkably selective defects.

The version of the Article previously published did not acknowledge Freya Boardman-Pretty 17,18 and the Genomics England Research Consortium in the author list. This has now been corrected in both the PDF and HTML versions of the Article.