SMAD6 variants in craniosynostosis: genotype and phenotype evaluation
| Autor: | Irene M.J. Mathijssen, Helen Lord, Wanda Lattanzi, Stephen R.F. Twigg, Andrew O.M. Wilkie, Nils Koelling, David W. Johnson, Eduardo Calpena, Astrid Weber, Araceli Cuellar, Sigrid M. A. Swagemakers, Jenny Morton, Deborah J. Shears, Julie M. Phipps, Tracy Lester, Simeon A. Boyadjiev, Simon J. McGowan, Sofia Douzgou, Louise C. Wilson, Michael L. Cunningham, Steven A. Wall, Meena Balasubramanian, Krithi Bala |
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| Přispěvatelé: | Pathology, Plastic and Reconstructive Surgery and Hand Surgery |
| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
Genotype
Smad6 Protein Mutation Missense SMAD6 BMP2 metopic synostosis digenic inheritance two-locus protein instability Penetrance Biology Article Craniosynostosis 03 medical and health sciences Craniosynostoses 0302 clinical medicine Genotype-phenotype distinction medicine Missense mutation Metopic synostosis Humans Settore BIO/13 - BIOLOGIA APPLICATA Genotyping Genetics (clinical) 030304 developmental biology Genetics 0303 health sciences Correction medicine.disease Phenotype 030217 neurology & neurosurgery |
| Zdroj: | Genetics in Medicine Genetics in Medicine, 22(9), 1498-1506. Lippincott Williams & Wilkins |
| ISSN: | 1098-3600 |
| Popis: | Enrichment of heterozygous missense and truncating SMAD6 variants was previously reported in nonsyndromic sagittal and metopic synostosis, and interaction of SMAD6 variants with a common polymorphism near BMP2 (rs1884302) was proposed to contribute to inconsistent penetrance. We determined the occurrence of SMAD6 variants in all types of craniosynostosis, evaluated the impact of different missense variants on SMAD6 function, and tested independently whether rs1884302 genotype significantly modifies the phenotype. We performed resequencing of SMAD6 in 795 unsolved patients with any type of craniosynostosis and genotyped rs1884302 in SMAD6-positive individuals and relatives. We examined the inhibitory activity and stability of SMAD6 missense variants. We found 18 (2.3%) different rare damaging SMAD6 variants, with the highest prevalence in metopic synostosis (5.8%) and an 18.3-fold enrichment of loss-of-function variants comparedwith gnomAD data (P |
| Databáze: | OpenAIRE |
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