PDF(Pubmed)
Abstract：
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.
METHODS: 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.
UNASSIGNED: 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.
CONCLUSIONS: Our data expand the spectrum of variants and phenotypic spectrum associated with homozygous variants of SMAD6 to include craniosynostosis.
METHODS: 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.
UNASSIGNED: 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.
CONCLUSIONS: Our data expand the spectrum of variants and phenotypic spectrum associated with homozygous variants of SMAD6 to include craniosynostosis.
摘要：
背景：SMAD6编码骨形态发生蛋白（BMP）信号通路的细胞内抑制剂。直到现在,SMAD6中罕见的杂合功能丧失变异被证明会增加包括心血管疾病在内的不同临床疾病的风险,颅骨滑膜形成和尺桡骨滑膜形成。仅描述了两名具有双等位基因SMAD6变体的无关患者，这些变体表现出复杂的心血管表型和面部畸形。
方法：这里，我们介绍了前两名具有纯合SMAD6变异体的颅骨融合症患者.男性先证者,都出生在健康的近亲，被诊断为异位性滑膜和双侧或单侧桡尺骨滑膜。此外,一个先证者有全球发育迟缓。超声心动图评估未发现心脏或流出道异常。
■小说的错觉（c。[584T>G]；[584T>G]，p.[（Val195Gly）];[（Val195Gly）]）和错义/剪接位点变体（c.[817G>A]；[817G>A]，r.[(817g>a，817delins[a;817+2_817+228])];[(817g>a,817删除[a；817+2_817+228])]，p.[(Glu273Lys,Glu273Serfs*72)];[(Glu273Lys,Glu273Serfs*72）]）都位于蛋白质的功能性MH1结构域中，并且在gnomAD数据库中尚未报道。变体的功能分析显示BMP信号传导或异常剪接的抑制减少，分别,与亚形态的作用机制一致。
结论：我们的数据扩大了与SMAD6纯合变体相关的变体谱和表型谱，包括颅骨融合。
方法：这里，我们介绍了前两名具有纯合SMAD6变异体的颅骨融合症患者.男性先证者,都出生在健康的近亲，被诊断为异位性滑膜和双侧或单侧桡尺骨滑膜。此外,一个先证者有全球发育迟缓。超声心动图评估未发现心脏或流出道异常。
■小说的错觉（c。[584T>G]；[584T>G]，p.[（Val195Gly）];[（Val195Gly）]）和错义/剪接位点变体（c.[817G>A]；[817G>A]，r.[(817g>a，817delins[a;817+2_817+228])];[(817g>a,817删除[a；817+2_817+228])]，p.[(Glu273Lys,Glu273Serfs*72)];[(Glu273Lys,Glu273Serfs*72）]）都位于蛋白质的功能性MH1结构域中，并且在gnomAD数据库中尚未报道。变体的功能分析显示BMP信号传导或异常剪接的抑制减少，分别,与亚形态的作用机制一致。
结论：我们的数据扩大了与SMAD6纯合变体相关的变体谱和表型谱，包括颅骨融合。
