Saethre–Chotzen syndrome caused by TWIST 1 gene mutations: functional differentiation from Muenke coronal synostosis syndrome
Abstract
The Saethre-Chotzen syndrome (SCS) is an autosomal dominant craniosynostosis syndrome with uni- or bilateral coronal synostosis and mild limb deformities. It is caused by loss-of-function mutations of the TWIST 1 gene. In an attempt to delineate functional features separating SCS from Muenke's syndrome, we screened patients presenting with coronal suture synostosis for mutations in the TWIST 1 gene, and for the Pro250Arg mutation in FGFR3. Within a total of 124 independent pedigrees, 39 (71 patients) were identified to carry 25 different mutations of TWIST 1 including 14 novel mutations, to which six whole gene deletions were added. The 71 patients were compared with 42 subjects from 24 pedigrees carrying the Pro250Arg mutation in FGFR3 and 65 subjects from 61 pedigrees without a detectable mutation. Classical SCS associated with a TWIST 1 mutation could be separated phenotypically from the Muenke phenotype on the basis of the following features: low-set frontal hairline, gross ptosis of eyelids, subnormal ear length, dilated parietal foramina, interdigital webbing, and hallux valgus or broad great toe with bifid distal phalanx. Functional differences were even more important: intracranial hypertension as a consequence of early progressive multisutural fusion was a significant problem in SCS only, while mental delay and sensorineural hearing loss were associated with the Muenke's syndrome. Contrary to previous reports, SCS patients with complete loss of one TWIST allele showed normal mental development.
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Saethre-Chotzen syndrome results from haploinsufficiency of TWIST1, which may be caused by whole gene deletions, intragenic nonsense and frameshifting mutations, and missense substitutions; missense substitutions are largely confined to the BHLH motif.
“Saethre-Chotzen syndrome results from haploinsufficiency of TWIST1, which may be the consequence of many different mutations, including whole gene deletions, intragenic nonsense and frameshifting mutations, and missense substitutions; note that the last category is largely confined to the highly conserved BHLH motif required for DNA binding and dimerisation (Figure 2c) (ref.26).”
From Craniosynostosis (2011) · cites this paper as [26]
No genotype-phenotype correlation is described for Saethre-Chotzen syndrome, except that large deletions are associated with learning disability and occasional C-terminal Twist box missense mutations may confer increased risk of a more non-specific synostosis phenotype with unknown penetrance.
“No genotype-phenotype correlation is described, except that large deletions are associated with learning disability (not generally a feature of Saethre-Chotzen syndrome), 26,27 and occasional missense mutations in the C-terminal Twist box apparently confer increased risk of a more non-specific synostosis phenotype (with unknown penetrance).28”
From Craniosynostosis (2011) · cites this paper as [26]
Large TWIST1 deletions are linked to a higher risk of learning disability.
“large TWIST1 deletions are associated with a higher risk of learning disability.26,27”
From Craniosynostosis (2011) · cites this paper as [26]
The clearest causal link between chromosome abnormalities and craniosynostosis is with deletions of 7p21.1, which includes the TWIST1 gene.
“The clearest causal link is with deletions of 7p21.1, which includes the TWIST1 gene.26,27”
From Craniosynostosis (2011) · cites this paper as [26]
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References 36 · Cited by 151
- Authors
- Kress, W., Schropp, C., Lieb, G., Petersen, B., Büsse-Ratzka, M., Kunz, J., Reinhart, E., Schäfer, W.-D., Sold, J., Hoppe, F., Pahnke, J., Trusen, A., Sörensen, N., Krauss, J., & Collmann, H.
- Affiliations
- University of Würzburg (DE)
- Philipps University of Marburg (DE)
- Corresponding author
- Kress, Wolfram
- Venue
- European Journal of Human Genetics
- Published
- 2005-10-26
- Volume
- 14
- Issue
- 1
- Pages
- 39-48
- ISSN
- 1018-4813 (ISSN-L)
- 1476-5438
- OpenAlex
- W2031251221
- Cited by
- 151
- References
- 36
- Citations by year
- 2026: 6 · 2025: 2 · 2024: 7 · 2023: 6 · 2022: 4 · 2021: 8 · 2020: 10 · 2019: 9 · 2018: 7 · 2017: 7 · 2016: 6 · 2015: 7 · 2014: 9 · 2013: 8 · 2012: 6
- FWCI
- 3.06
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- European Journal of Human Genetics (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Craniofacial Disorders and Treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomics and Rare Diseases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › dental development and anomalies
- Keywords
- Saethre-Chotzen syndrome, Muenke syndrome, coronal synostosis, craniosynostosis, loss-of-function mutations, novel mutations, intracranial hypertension, sensorineural hearing loss, eyelid ptosis, autosomal dominant inheritance, genotype-phenotype correlation
- MeSH terms
- Acrocephalosyndactylia, Adolescent, Arginine, Child, Preschool, Ear, Hearing Loss, Sensorineural, Humans, Intracranial Pressure, Intellectual Disability, Mutation, Nuclear Proteins, Pedigree, Proline, Repetitive Sequences, Nucleic Acid, Syndrome, Synostosis, Amino Acid Substitution, Receptor, Fibroblast Growth Factor, Type 3, Twist-Related Protein 1
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