nexpected role of SIX1 variants in craniosynostosis: expanding the phenotype of SIX1-related disorder

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Calpena, Eduardo ^[1] ; Wurmser, Maud ^[2] ; McGowan, Simon J. ^[3] ; Atique, Rodrigo ^[4] ; Bertola, Debora R. ^{[5, 6]} ; Cunningham, Michael L. ^{[7, 8, 9]} ; Gustafson, Jonas A. ; Johnson, David ^{[7, 8, 10, 11]} ; Morton, V, Jenny E. ; Passos-Bueno, Maria Rita ^[4] ; Timberlake, Andrew T. ^[12] ; Lifton, Richard P. ; Wall, Steven A. ; Twigg, Stephen R. F. ^[1] ; Maire, Pascal ^[2] ; Wilkie, Andrew O. M. ^[1]

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^[1] Univ Oxford, MRC Weatherall Inst Mol Med, Clin Genet Grp, Oxford - England

^[2] Univ Paris, CNRS, INSERM, Inst Cochin, Paris - France

^[3] Univ Oxford, Ctr Computat Biol, MRC Weatherall Inst Mol Med, Oxford - England

^[4] Univ Sao Paulo, Ctr Estudos Genoma Humano, Sao Paulo - Brazil

^[5] Univ Sao Paulo, Hosp Clin, Fac Med, Inst Crianca, Unidade Genet Clin, Sao Paulo - Brazil

^[6] Seattle Childrens Res Inst, Ctr Dev Biol & Regenerat Med, Seattle, WA - USA

^[7] Univ Washington, Seattle Childrens Hosp, Seattle Childrens Craniofacial Ctr, Seattle, WA 98195 - USA

^[8] Univ Washington, Dept Pediat, Div Craniofacial Med, Seattle, WA 98195 - USA

^[9] Oxford Univ Hosp NHS Fdn Trust, Craniofacial Unit, Oxford - England

^[10] Birmingham Womens & Childrens Hosp NHS Fdn Trust, West Midlands Reg Clin Genet Serv, Birmingham, W Midlands - England

^[11] Birmingham Womens & Childrens Hosp NHS Fdn Trust, Birmingham Hlth Partners, Birmingham, W Midlands - England

^[12] Rockefeller Univ, 1230 York Ave, New York, NY 10021 - USA

• Tipo de documento: Artigo Científico
• Fonte: JOURNAL OF MEDICAL GENETICS; v. 59, n. 2 JAN 2021.
• Citações Web of Science: 1

Resumo

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 Six1 ( nLacZ/+ ) 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. (AU)

• Processo FAPESP: 13/08028-1 - CEGH-CEL - Centro de Estudos do Genoma Humano e de Células-Tronco
• Beneficiário: Mayana Zatz
• Modalidade de apoio: Auxílio à Pesquisa - Centros de Pesquisa, Inovação e Difusão - CEPIDs