TCF12 – TCF12-related Craniosynostosis

The TCF12 gene is associated with TCF12-related craniosynostosis under an autosomal dominant inheritance model. Affected individuals present with premature fusion of cranial sutures, predominantly the coronal sutures. Heterozygous loss-of-function variants in TCF12 lead to haploinsufficiency of a basic helix–loop–helix transcription factor critical for suture patency.

Exome sequencing of 347 unrelated individuals with craniosynostosis identified 38 distinct heterozygous TCF12 variants, predominantly frameshift, nonsense, and splice-site changes that truncate the protein. These mutations accounted for 32% of bilateral and 10% of unilateral coronal synostosis cases and were absent from population databases (PMID:23354436).

Structural variant analysis in 18 index cases with coronal synostosis and 43 family members uncovered four large intragenic rearrangements—three exon deletions (84.9 kb, 8.6 kb, 5.4 kb) and one 11.3 kb tandem duplication—in four families. These events were confirmed by deletion-specific PCR and cDNA analysis, underscoring the importance of CNV screening in TCF12 (PMID:27158814).

LoF variants co-segregate with craniosynostosis in at least four multiplex families, supporting autosomal dominant transmission. Segregation data include three families with exon deletions and one with tandem duplication, each demonstrating concordant transmission in affected relatives.

Functional assays demonstrate that TCF12 and TWIST1 synergistically activate osteogenic target promoters in vitro, and mice heterozygous for Tcf12 and Twist1 loss-of-function alleles develop severe coronal synostosis mirroring the human phenotype. These results highlight dosage sensitivity of TCF12–TWIST1 heterodimers in cranial suture development (PMID:23354436).

The pathogenic mechanism is haploinsufficiency: reduced TCF12 disrupts bHLH heterodimer formation and downstream transcriptional regulation of cranial osteoblast differentiation. Lack of evidence for dominant-negative effects further supports simple loss-of-function as the disease mechanism.

In summary, robust genetic and experimental data establish a definitive autosomal dominant association between TCF12 haploinsufficiency and coronal craniosynostosis. Clinical testing for sequence and copy-number variants in TCF12 is recommended for individuals with coronal suture pathology. Key Take-home: TCF12 haploinsufficiency is a definitive cause of TCF12-related craniosynostosis with clear diagnostic and mechanistic implications.

References

• Nature genetics • 2013 • Mutations in TCF12, encoding a basic helix-loop-helix partner of TWIST1, are a frequent cause of coronal craniosynostosis. PMID:23354436
• Human mutation • 2016 • Identification of Intragenic Exon Deletions and Duplication of TCF12 by Whole Genome or Targeted Sequencing as a Cause of TCF12-Related Craniosynostosis. PMID:27158814

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