Journal article
Homozygous SMAD6 variants in two unrelated patients with craniosynostosis and radioulnar synostosis
- Abstract:
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Background
SMAD6 encodes an intracellular inhibitor of the bone morphogenetic protein (BMP) signalling pathway. Until now, rare heterozygous loss-of-function variants in SMAD6 were demonstrated to increase the risk of disparate clinical disorders including cardiovascular disease, craniosynostosis and radioulnar synostosis. Only two unrelated patients harbouring biallelic SMAD6 variants presenting a complex cardiovascular phenotype and facial dysmorphism have been described.Cases
Here, we present the first two patients with craniosynostosis harbouring homozygous SMAD6 variants. The male probands, both born to healthy consanguineous parents, were diagnosed with metopic synostosis and bilateral or unilateral radioulnar synostosis. Additionally, one proband had global developmental delay. Echocardiographic evaluation did not reveal cardiac or outflow tract abnormalities.Molecular analyses
The novel missense (c.[584T>G];[584T>G], p.[(Val195Gly)];[(Val195Gly)]) and missense/splice-site variant (c.[817G>A];[817G>A], r.[(817g>a,817delins[a;817+2_817+228])];[(817g>a,817delins[a;817+2_817+228])], p.[(Glu273Lys,Glu273Serfs*72)];[(Glu273Lys,Glu273Serfs*72)]) both locate in the functional MH1 domain of the protein and have not been reported in gnomAD database. Functional analyses of the variants showed reduced inhibition of BMP signalling or abnormal splicing, respectively, consistent with a hypomorphic mechanism of action.Conclusion
Our data expand the spectrum of variants and phenotypic spectrum associated with homozygous variants of SMAD6 to include craniosynostosis.
- Publication status:
- Published
- Peer review status:
- Peer reviewed
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(Preview, Version of record, pdf, 5.8MB, Terms of use)
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- Publisher copy:
- 10.1136/jmg-2023-109151
Authors
- Publisher:
- BMJ Publishing Group
- Journal:
- Journal of Medical Genetics More from this journal
- Volume:
- 61
- Issue:
- 4
- Pages:
- 363-368
- Place of publication:
- England
- Publication date:
- 2024-01-30
- Acceptance date:
- 2023-11-29
- DOI:
- EISSN:
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1468-6244
- ISSN:
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0022-2593
- Pmid:
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38290823
- Language:
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English
- Pubs id:
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1614758
- Local pid:
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pubs:1614758
- Deposit date:
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2024-05-22
Terms of use
- Copyright holder:
- Luyckx et al
- Copyright date:
- 2024
- Rights statement:
- © Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY. Published by BMJ. https://creativecommons.org/licenses/by/4.0/ This is an open access article distributed in accordance with the Creative Commons Attribution 4.0 Unported (CC BY 4.0) license, which permits others to copy, redistribute, remix, transform and build upon this work for any purpose, provided the original work is properly cited, a link to the licence is given, and indication of whether changes were made.
- Licence:
- CC Attribution (CC BY)
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