TWIST2 & Barber-Say Syndrome

TWIST2 has been robustly associated with Barber-Say syndrome, a rare congenital ectodermal dysplasia manifesting with hypertrichosis, redundant skin, and facial dysmorphism (PMID:28680619). Multiple independent clinical reports and multi‐patient studies have converged on heterozygous missense mutations in TWIST2 as the causative factor in this disorder. The presented evidence from case reports demonstrates de novo mutations in affected individuals, supporting the autosomal dominant inheritance of the phenotype. Detailed phenotyping in these studies has consistently identified the key clinical features mapping to HP:0000998, HP_0001582, and HP_0000271. Such consistency underpins the clinical utility of targeted genetic testing in suspected cases. This comprehensive dataset fosters confidence in the diagnostic process for both clinicians and commercial testing laboratories.

The genetic evidence is particularly compelling. A recurrent pathogenic variant, c.223G>C (p.Glu75Gln), has been reported verbatim in multiple independent studies (PMID:28680619; PMID:26119818), and additional variants affecting the same basic domain have been identified in other affected families. In one multi‐patient study, de novo TWIST2 mutations were found in ten independent Barber-Say syndrome families (PMID:26119818); similar findings have been echoed in other clinical reports. Although many of these mutations are missense variants, their recurrence and consistent mapping to the DNA-binding basic domain of TWIST2 bolster their pathogenicity. The genetic architecture hence favors a dominant effect with a clear genotype–phenotype correlation. This evidence sets a strong precedent for the role of TWIST2 in disease causation.

Functional assessments provide further support. Experimental studies have demonstrated that these pathogenic variants in TWIST2 result in altered DNA binding and transcriptional dysregulation, as evidenced by in vitro assays and zebrafish model studies (PMID:26119818). Such functional disruptions are consistent with the developmental abnormalities observed in Barber-Say syndrome. Although functional evidence in this context is less voluminous than the genetic data, the concordance between molecular dysfunction and the clinical phenotype is clear. Moreover, the altered transcriptional activity due to these variants explains the perturbation in mesenchymal tissue development. This mechanistic insight supports the causative link and underscores the biological relevance of TWIST2 mutagenesis in the disorder. The functional data, therefore, complement the robust genetic findings.

It is notable that while TWIST2 mutations have been implicated in a spectrum of disorders, the association with Barber-Say syndrome remains distinct and reproducible. Some studies report overlapping phenotypes with conditions such as ablepharon macrostomia syndrome; however, the clinical constellation of hypertrichosis, redundant skin, and facial dysmorphism specifically aligns with Barber-Say syndrome (PMID:29329175). The de novo nature of many of these mutations and the recurrence of variants in this syndrome aid in distinguishing it from other TWIST2‐related conditions. This level of phenotypic specificity facilitates accurate diagnosis and appropriate patient management. Furthermore, the consistency of these findings across case reports and multi‐patient investigations reinforces the robustness of the association.

Integrating the clinical, genetic, and functional evidence leads to a coherent narrative. The strong recurrence of de novo TWIST2 mutations—exemplified by the c.223G>C (p.Glu75Gln) variant—and the supportive functional data underscore a definitive role for TWIST2 in the pathogenesis of Barber-Say syndrome. This integrated approach not only enhances diagnostic decision‑making but also provides critical insights for potential therapeutic strategies. The evidence exceeds the minimal threshold required by the ClinGen framework, positioning this association at the higher end of clinical validity. Overall, the data confirm that TWIST2 should be routinely considered in the molecular diagnostic workup of patients exhibiting characteristic dermatologic and facial features.

Key Take‑home: Heterozygous de novo mutations in TWIST2, particularly those affecting its basic domain, are highly predictive of Barber-Say syndrome and represent a reliable molecular target for diagnostic and clinical management strategies.

References

• Clinical case reports • 2017 • Barber-say syndrome: a confirmed case of TWIST2 gene mutation PMID:28680619
• Ophthalmic plastic and reconstructive surgery • 2018 • Clinical Description, Molecular Analysis of TWIST2 Gene, and Surgical Treatment in a Patient With Barber-Say Syndrome PMID:29329175
• Pediatric dermatology • 2024 • Multiple rhabdomyomatous mesenchymal hamartomas in a patient with mosaic Barber-Say syndrome PMID:37817291
• American journal of human genetics • 2015 • Recurrent Mutations in the Basic Domain of TWIST2 Cause Ablepharon Macrostomia and Barber-Say Syndromes PMID:26119818

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