TWIST1 – Saethre-Chotzen syndrome

TWIST1 is a basic helix-loop-helix transcription factor encoded by TWIST1 whose heterozygous loss-of-function variants cause autosomal dominant Saethre-Chotzen syndrome. This craniosynostosis disorder is characterized by premature fusion of the coronal sutures, ptosis, facial asymmetry and limb anomalies.

Large case series and family studies have established definitive clinical validity. In a cohort of 32 unrelated patients screened for TWIST1, FGFR2 and FGFR3 mutations, 12 families harbored TWIST1 variants in 68% of Saethre-Chotzen cases (PMID:9585583). In a five-generation pedigree, a 7p21 microdeletion encompassing TWIST1 segregated with the phenotype in 16 relatives (PMID:15099347). A large Indian family carrying a nonsense Q28Ter mutation demonstrated variable expressivity among 17 carriers (PMID:11977182).

TWIST1 variant spectrum exceeds 80 distinct alleles, including missense substitutions in the basic-DNA-binding domain, nonsense mutations (e.g., c.352C>A (p.Arg118Ser)), frameshift indels, and multi-megabase deletions. These variants are identified in de novo and familial settings, with recurrent founder alleles and large gene deletions detected by FISH and array-CGH (PMID:15547403).

Genetic evidence supports a haploinsufficiency mechanism: loss of one functional TWIST1 copy leads to craniofacial suture synostosis. Segregation in multiple pedigrees (n=16), de novo occurrences, and absence of pathogenic variants in unaffected controls reinforce definitive association.

Functional studies demonstrate that TWIST1 deficiency perturbs osteoblast differentiation and cranial suture development. Knock-in and knock-down models show reduced FGF receptor-2, Runx2, osteocalcin and bone sialoprotein expression, with rescue by TWIST1 or FGFR2 re-expression restoring osteoblast markers and delaying suture fusion (PMID:15829502). In vitro assays reveal mutant protein degradation, loss of heterodimerization with E12/E47, and impaired nuclear localization, confirming loss-of-function (PMID:10749989).

These data establish TWIST1 as definitively implicated in Saethre-Chotzen syndrome. Routine genetic testing for point mutations and copy-number analysis of TWIST1 is recommended in patients with coronal synostosis, blepharoptosis, limb anomalies or palpebral deformities. Key Take-home: TWIST1 sequencing and deletion analysis underpin diagnostic confirmation and genetic counseling.

References

• Clinical genetics • 2004 • Deletion of the TWIST gene in a large five-generation family. PMID:15099347
• American journal of human genetics • 1998 • Genetic heterogeneity of Saethre-Chotzen syndrome, due to TWIST and FGFR mutations. PMID:9585583
• The Journal of craniofacial surgery • 2004 • Postnatal onset of craniosynostosis in a case of Saethre-Chotzen syndrome. PMID:15547403
• American journal of medical genetics • 2002 • Saethre-Chotzen syndrome: notable intrafamilial phenotypic variability in a large family with Q28X TWIST mutation. PMID:11977182
• Human molecular genetics • 2005 • A role for fibroblast growth factor receptor-2 in the altered osteoblast phenotype induced by Twist haploinsufficiency in the Saethre-Chotzen syndrome. PMID:15829502
• Human molecular genetics • 2000 • Saethre-Chotzen mutations cause TWIST protein degradation or impaired nuclear location. PMID:10749989

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