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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  

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。

 结论


致病性SMAD6变异大大增加了颅缝早闭的非综合征性和综合征性表现的风险,尤其是异位性颅缝早闭。功能分析对于评估错义变异很重要。 rs1884302 的基因分型在临床上没有用处。解释与SMAD6变异相关的表型显着多样性的机制仍然不清楚。

更新日期:2020-06-05
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