TWIST1 – Sweeney-Cox syndrome

Sweeney-Cox syndrome is a recently delineated craniofacial disorder characterized by facial ablepharon, hypertelorism and underdeveloped eyelids, with the defining feature of coronal craniosynostosis. Patients present with de novo heterozygous missense changes in the basic domain of the TWIST1 transcription factor, distinct from the haploinsufficiency variants seen in Saethre-Chotzen syndrome. Genetic diagnosis relies on targeted sequencing of the TWIST1 bHLH region.

Three unrelated individuals have been reported with de novo substitutions at the Glu117 residue of TWIST1: c.351G>T (p.Glu117Asp) in a male infant presenting with ablepharon, hypertelorism and bicoronal synostosis (PMID:30450715), and p.Glu117Val plus p.Glu117Gly in two subjects with frontonasal dysplasia and overlapping malformations (PMID:28369379). No segregating family cases have been described.

Variant spectrum is confined to missense substitutions at Glu117, with functional prediction concordant across in silico tools. Phenotypic overlap with Barber-Say and ablepharon-macrostomia syndromes is marked by facial features, but the presence of craniosynostosis distinguishes Sweeney-Cox syndrome from these TWIST2-related allelic disorders.

A systematic allelic series engineered into the C. elegans hlh-8 locus demonstrated graded severity of phenotypes corresponding to human SCOS variants, supporting a dominant-negative mechanism for Glu117 substitutions (PMID:28369379). This in vivo model recapitulates craniofacial dysmorphology and confirms antimorphic activity of the basic domain mutations.

Mechanistic studies suggest that localized basic domain substitutions at Glu117 exert antimorphic effects akin to mild haploinsufficiency, impairing DNA binding and dimerization without complete loss of function. The combination of recurrent de novo variants and concordant functional modeling establishes a robust gene–disease relationship.

Key Take-home: Heterozygous missense variants at Glu117 in TWIST1 are diagnostic for Sweeney-Cox syndrome; sequencing of the basic helix-loop-helix domain should be prioritized in patients with ablepharon, hypertelorism and coronal synostosis.

References

• American journal of medical genetics. Part A | 2018 | Ablepharon and craniosynostosis in a patient with a localized TWIST1 basic domain substitution. PMID:30450715
• Human molecular genetics | 2017 | Localized TWIST1 and TWIST2 basic domain substitutions cause four distinct human diseases that can be modeled in Caenorhabditis elegans. PMID:28369379

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