SMAD6 variants in craniosynostosis: genotype and phenotype evaluation.,Genetics in Medicine

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SMAD6 variants in craniosynostosis: genotype and phenotype evaluation.
Genetics in Medicine ( IF 6.6 ) Pub Date : 2020-06-05 , DOI: 10.1038/s41436-020-0817-2
Eduardo Calpena ₁ , Araceli Cuellar ₂ , Krithi Bala ₂ , Sigrid M A Swagemakers ₃ , Nils Koelling ₁ , Simon J McGowan ₁ , Julie M Phipps ₁ , Meena Balasubramanian ₄ , Michael L Cunningham ₅ , Sofia Douzgou _{6,

7} , Wanda Lattanzi _{8,

9} , Jenny E V Morton ₁₀ , Deborah Shears _{11,

12} , Astrid Weber ₁₃ , Louise C Wilson ₁₄ , Helen Lord ₁₅ , Tracy Lester ₁₅ , David Johnson ₁₂ , Steven A Wall ₁₂ , Stephen R F Twigg ₁ , Irene M J Mathijssen ₁₆ , Freya Boardman-Pretty _{17,

18} , , Simeon A Boyadjiev ₂ , Andrew O M Wilkie _{1,

11,

12}

Affiliation

MRC Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford, UK.
Department of Pediatrics, University of California-Davis, Sacramento, CA, USA.
Departments of Pathology and Bioinformatics, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands.
Sheffield Clinical Genetics Service, Sheffield Children's NHS Foundation Trust, Sheffield, UK.
Division of Craniofacial Medicine, Department of Pediatrics, University of Washington, Seattle, WA, USA.
Manchester Centre for Genomic Medicine, Central Manchester University Hospitals NHS Foundation Trust, Saint Mary's Hospital, Manchester, UK.
Division of Evolution and Genomic Sciences, School of Biological Sciences, Faculty of Biology, Medicines and Health, University of Manchester, Manchester, UK.
Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy.
Department of Life Science and Public Health, Università Cattolica del Sacro Cuore, Rome, Italy.
West Midlands Regional Clinical Genetics Service and Birmingham Health Partners, Birmingham Women's and Children's Hospitals NHS Foundation Trust, Birmingham, UK.
Oxford Centre for Genomic Medicine, Oxford University Hospitals NHS Foundation Trust, Oxford, UK.
Craniofacial Unit, Oxford University Hospitals NHS Trust, John Radcliffe Hospital, Oxford, UK.
Department of Clinical Genetics, Liverpool Women's NHS Foundation Trust, Liverpool, UK.
Clinical Genetics Service, Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK.
Oxford Genetics Laboratories, Oxford University Hospitals NHS Foundation Trust, The Churchill Hospital, Oxford, UK.
Department of Plastic and Reconstructive Surgery and Hand Surgery, Erasmus MC, University Medical Center Rotterdam, Rotterdam, the Netherlands.
Genomics England, London, UK.
William Harvey Research Institute, Queen Mary University of London, London, UK.

Purpose

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.

Methods

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.

Results

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 < 10⁻⁷). Combined with eight additional variants, ≥20/26 were transmitted from an unaffected parent but rs1884302 genotype did not predict phenotype.

Conclusion

Pathogenic SMAD6 variants substantially increase the risk of both nonsyndromic and syndromic presentations of craniosynostosis, especially metopic synostosis. Functional analysis is important to evaluate missense variants. Genotyping of rs1884302 is not clinically useful. Mechanisms to explain the remarkable diversity of phenotypes associated with SMAD6 variants remain obscure.

中文翻译：

颅缝早闭中的 SMAD6 变异：基因型和表型评估。

目的

先前报道在非综合征矢状和异位骨联结中杂合错义和截短SMAD6变体的富集，并且SMAD6变体与BMP2 (rs1884302) 附近常见多态性的相互作用被认为导致外显率不一致。我们确定了所有类型颅缝早闭中SMAD6变异的发生情况，评估了不同错义变异对 SMAD6 功能的影响，并独立测试了 rs1884302 基因型是否显着改变表型。

方法

我们对 795 名未解决的任何类型颅缝早闭患者进行了SMAD6重新测序，并对SMAD6阳性个体和亲属进行了 rs1884302 基因分型。我们检查了 SMAD6 错义变体的抑制活性和稳定性。

结果

我们发现了 18 种（2.3%）不同的罕见破坏性SMAD6变异，与 gnomAD 数据相比，同位骨性连接的发生率最高（5.8%），功能丧失变异丰富了 18.3 倍（ P < 10 ^-7 ）。与八个其他变异相结合，≥20/26 是从未受影响的亲本传播的，但 rs1884302 基因型不能预测表型。