Townes-Brocks syndrome with craniosynostosis in two siblings
Open accessAbstract
This report describes a novel truncating c.709C > T p.(Gln237*) SALL1 variant in two siblings exhibiting sagittal craniosynostosis as a unique feature of Townes-Brocks syndrome (TBS, OMIM #107480). TBS is a rare autosomal dominant syndrome with variable phenotypes, including anorectal, renal, limb, and ear abnormalities, which results from heterozygous variants in the SALL1 gene, predominantly located in the 802 bp "hot spot region" within exon 2. Recent studies have suggested that aberrations in primary cilia and sonic hedgehog signalling contribute to the TBS phenotypes. The presence of the novel c.709C > T p.(Gln237*) SALL1 variant was confirmed in both the siblings and their father, whereas no mutations currently associated with craniosynostosis were detected. We hypothesise that the truncating c.709C > T p.(Gln237*) SALL1 variant, which occurs outside the "hot spot region" and inside the glutamine-rich domain coding region, could interfere with ciliary signalling and mechanotransduction, contributing to premature fusion of calvarial sutures. This report broadens the genetic and phenotypic spectrum of TBS and provides the first clinical evidence of craniosynostosis as a novel feature of the syndrome.
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Genetics versus environment in the pathophysiology of sagittal synostosis
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“…variants in genes such as FGFR2 , TCF12 , ERF , KAT6B , ACTB , SH3PXD2B , SALL1 , IFT140 , SON , CASK , FOXP2 , EXTL3 , and SOX6 have often been identified in patients with additional dysmorphic, skeletal, neurodevel-opmental, or systemic disorders [41, 47–49, 78, 84, 86, 90, 100, 101, 108–110].”
- Authors
- Lugli, L., Rossi, C., Ceccarelli, P. L., Calabrese, O., Bedetti, L., Miselli, F., Bianchini, M. A., Iughetti, L., & Berardi, A.
- Affiliations
- University of Modena and Reggio Emilia (IT)
- Corresponding author
- Lugli, Licia
- ORCID
- Venue
- European Journal of Medical Genetics
- Publisher
- Elsevier BV
- Published
- 2022-12
- Volume
- 65
- Issue
- 12
- Pages
- 104642
- ISSN
- 1769-7212 (ISSN-L)
- OpenAlex
- W4306319034
- Cited by
- 5
- References
- 16
- Citations by year
- 2026: 1 · 2025: 1 · 2024: 2
- FWCI
- 0.45
- Type
- journal article
- Language
- en
- Open access
- green
- hdl.handle.net
- Licence
- Locations
- European Journal of Medical Genetics (publishedVersion)
- PubMed (publishedVersion)
- IRIS UNIMORE (University of Modena and Reggio Emilia) (submittedVersion, cc-by)
- 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
- Townes-Brocks syndrome, craniosynostosis, truncating mutations, siblings, autosomal dominant syndrome, primary cilia, Sonic hedgehog signaling, mechanotransduction, phenotypic spectrum, glutamine-rich domain
- MeSH terms
- Abnormalities, Multiple, Anus, Imperforate, Craniosynostoses, Hearing Loss, Sensorineural, Humans, Syndrome, Thumb, Transcription Factors, Siblings, Mechanotransduction, Cellular, Hedgehog Proteins
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