Townes-Brocks syndrome with craniosynostosis in two siblings

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.