Mutations in TCF12, encoding a basic helix-loop-helix partner of TWIST1, are a frequent cause of coronal craniosynostosis

Abstract

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 cases3, 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 synostosis4-6. 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.

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

“…Five variants were identified in TCF12 (Table 2), four were novel whereas one, p.(Ser281*), was previously described in two families. 9 The clinical characteristics of these five probands and family members are shown in Table 3. Cosegregation analysis was possible in four of the families (Supplementary Figure 2).…”

“…In the previously studied cohort, 14/38 mutations were identified in patients referred for SCS in whom no TWIST1 mutation had been identified. 9 Four of our five patients were initially referred for SCS, whereas the fifth was referred for the Muenke syndrome. In the 19 SCS individuals in whom a TWIST1 or TCF12 variant has been detected, 15 patients (79%) carried a TWIST1 variant, whereas four (21%) had a TCF12 variant.…”

“…8 Recently, mutations in another gene, TCF12 (MIM 600480), have been identified in patients with coronal synostosis, many of which were initially referred with SCS, and in whom no TWIST1 mutation had been identified. 9 TCF12 encodes transcription factor 12 (TCF12), a member of the basic helix-loop-helix (bHLH) E-protein family. It is expressed in many tissues, among them bone, skeletal muscle, thymus, B-and T cells, and may participate in regulating lineage-specific gene expression through the formation of heterodimers with other bHLH E-proteins, such as TWIST1.…”

“…In a study of 347 patients with craniosynostosis, 36 TCF12 mutations were detected, the majority of which resulted in exon splicing or altered the reading frame. 9 More recently, a patient with coronal craniosynostosis and intellectual disability was found to have a complex balanced maternal chromosomal rearrangement combining the reciprocal translocation of the region and an insertion which resulted in the deletion of TCF12. 10 Another gene recently implicated in craniosynostosis, ERF (MIM 611888), encodes for the transcription factor ERF (Ets2 repressor factor).…”

“…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. Likewise, other studies have confirmed that the frequency of transcranial surgery performed to reduce intracranial pressure is much higher in patients with Muenke syndrome.…”