Unexpected role of SIX1 variants in craniosynostosis: expanding the phenotype of SIX1-related disorders.

Abstract

BACKGROUND:

Pathogenic heterozygous SIX1 variants (predominantly missense) occur in branchio-otic syndrome (BOS), but an association with craniosynostosis has not been reported.

METHODS:

We investigated probands with craniosynostosis of unknown cause using whole exome/genome (n=628) or RNA (n=386) sequencing, and performed targeted resequencing of SIX1 in 615 additional patients. Expression of SIX1 protein in embryonic cranial sutures was examined in the Six1nLacZ/+ reporter mouse.

RESULTS:

From 1629 unrelated cases with craniosynostosis we identified seven different SIX1 variants (three missense, including two de novo mutations, and four nonsense, one of which was also present in an affected twin). Compared with population data, enrichment of SIX1 loss-of-function variants was highly significant (p=0.00003). All individuals with craniosynostosis had sagittal suture fusion; additionally four had bilambdoid synostosis. Associated BOS features were often attenuated; some carrier relatives appeared non-penetrant. SIX1 is expressed in a layer basal to the calvaria, likely corresponding to the dura mater, and in the mid-sagittal mesenchyme.

CONCLUSION:

Craniosynostosis is associated with heterozygous SIX1 variants, with possible enrichment of loss-of-function variants compared with classical BOS. We recommend screening of SIX1 in craniosynostosis, particularly when sagittal±lambdoid synostosis and/or any BOS phenotypes are present. These findings highlight the role of SIX1 in cranial suture homeostasis.

• Authors: Eduardo Calpena, Maud Wurmser, Simon J McGowan, Rodrigo Atique, Débora R Bertola, Michael L Cunningham, Jonas A Gustafson, David Johnson, Jenny E V Morton, Maria Rita Passos-Bueno, Andrew T Timberlake, Richard P Lifton, Steven A Wall, Stephen R F Twigg, Pascal Maire, Andrew O M Wilkie
• Journal: Journal of medical genetics (J Med Genet) Vol. 59 Issue 2 Pg. 165-169 (02 2022) ISSN: 1468-6244 [Electronic] England
• PMID: 33436522 (Publication Type: Case Reports, Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: © Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY. Published by BMJ.

Chemical References

• Homeodomain Proteins
• SIX1 protein, human

Topics

• Animals
• Child, Preschool
• Cohort Studies
• Cranial Sutures (embryology, pathology)
• Craniosynostoses (complications, embryology, genetics)
• DNA Mutational Analysis
• Genetic Association Studies
• Homeodomain Proteins (genetics, physiology)
• Humans
• Infant
• Mice
• Pedigree
• Phenotype
• RNA-Seq
• Whole Genome Sequencing