Submission Details

TWIST1 has been repeatedly been described in association with autosomal dominant Saethre-Chotzen syndrome (SCS), an unusual form of acrocephalosyndactyly characterized by bicoronal synostosis causing brachycephaly or acrocephaly, high forehead with low anterior hairline, ptosis, hypertelorism, lacrimal duct stenosis, high palate, small ears with prominent crus, facial asymmetry, partial cutaneous syndactyly of hands and feet, and hallux valgus (7120317, 10649491). This syndrome was first described independently by Saethre and Chotzen in 1931 and 1932, respectively. The mechanism of disease is haploinsufficiency caused by either protein degradation or subcellular mislocalization based upon the variant’s location in TWIST1 (10749989). Numerous variants (nonsense, frameshift etc.) have been identified in patients with SCS. This gene-disease association is supported by genetic, segregation, and experimental evidence. After completing a lumping and splitting evaluation, the ClinGen Craniofacial Malformations expert panel decided to lump Saethre-Chotzen syndrome and Robinow-Sorauf syndrome; these conditions are not distinct entities and lack differences in phenotype, molecular mechanism, and inheritance pattern. This is consistent with the published literature (12791045). Notably, TWIST1 has also been described in association with non-syndromic Craniosynostosis and Sweeney-Cox syndrome. These conditions will be assessed separately. In summary, TWIST is definitively associated with autosomal dominant Saethre-Chotzen syndrome. This has been repeatedly demonstrated in both the research and clinical diagnostic settings and has been upheld over time. This classification was approved by the ClinGen Craniofacial Malformations Gene Curation Expert panel on 1/28/21 (SOP version 8).