Unexpected role of SIX1 variants in craniosynostosis: expanding the phenotype of SIX1-related disorders.
Unexpected role of SIX1 variants in craniosynostosis: expanding the phenotype of SIX1-related disorders.
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DOI：
10.1136/jmedgenet-2020-107459
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发表时间：
2022-03
影响因子：
4
通讯作者：
Wilkie AOM
中科院分区：
文献类型：
--
作者：
Calpena E;Wurmser M;McGowan SJ;Atique R;Bertola DR;Cunningham ML;Gustafson JA;Johnson D;Morton JEV;Passos-Bueno MR;Timberlake AT;Lifton RP;Wall SA;Twigg SRF;Maire P;Wilkie AOM
致病性杂合SIX 1变异（主要是错义）发生在鳃耳综合征（BOS），但与颅缝早闭的相关性尚未报道。我们使用全外显子组/基因组（n=628）或RNA（n=386）测序研究了原因不明的颅缝早闭先证者，并对另外615例患者进行了SIX 1的靶向重测序。在Six 1 nLacZ/+报告小鼠中检测胚胎颅缝中SIX 1蛋白的表达。从1629例无关的颅缝早闭病例中，我们发现了7种不同的SIX 1变异体（3种错义突变，包括2种新生突变，4种无义突变，其中一种也存在于受影响的双胞胎中）。与群体数据相比，SIX 1功能丧失变体的富集是高度显著的（p=0.00003）。所有颅缝早闭患者均矢状缝融合，另外4例为双侧椎弓根早闭。相关的BOS特征常常减弱;一些携带者亲属出现非渗透性。SIX 1在颅骨基底层（可能对应于硬脑膜）和中矢状间充质中表达。颅缝早闭与杂合子SIX 1变异相关，与经典BOS相比，可能存在功能缺失变异的富集。我们建议在颅缝早闭中筛查SIX 1，特别是当矢状面±寰枢椎早闭和/或存在任何BOS表型时。这些发现突出了SIX 1在颅缝内稳态中的作用。
Pathogenic heterozygous SIX1 variants (predominantly missense) occur in branchio-otic syndrome (BOS), but an association with craniosynostosis has not been reported. We investigated probands with craniosynostosis of unknown cause using whole exome/genome (n=628) or RNA (n=386) sequencing, and performed targeted resequencing of SIX1 in 615 additional patients. Expression of SIX1 protein in embryonic cranial sutures was examined in the Six1 nLacZ/+ reporter mouse. From 1629 unrelated cases with craniosynostosis we identified seven different SIX1 variants (three missense, including two de novo mutations, and four nonsense, one of which was also present in an affected twin). Compared with population data, enrichment of SIX1 loss-of-function variants was highly significant (p=0.00003). All individuals with craniosynostosis had sagittal suture fusion; additionally four had bilambdoid synostosis. Associated BOS features were often attenuated; some carrier relatives appeared non-penetrant. SIX1 is expressed in a layer basal to the calvaria, likely corresponding to the dura mater, and in the mid-sagittal mesenchyme. Craniosynostosis is associated with heterozygous SIX1 variants, with possible enrichment of loss-of-function variants compared with classical BOS. We recommend screening of SIX1 in craniosynostosis, particularly when sagittal±lambdoid synostosis and/or any BOS phenotypes are present. These findings highlight the role of SIX1 in cranial suture homeostasis.
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影响因子：
4.1
作者：
Fernandez-Marmiesse A;Gouveia S;Couce ML
通讯作者：
Couce ML
影响因子：
3.7
作者：
Mutai H;Suzuki N;Shimizu A;Torii C;Namba K;Morimoto N;Kudoh J;Kaga K;Kosaki K;Matsunaga T
通讯作者：
Matsunaga T
影响因子：
64.8
作者：
Karczewski, Konrad J;Francioli, Laurent C;MacArthur, Daniel G
通讯作者：
MacArthur, Daniel G
影响因子：
4.6
作者：
Laclef, C;Hamard, G;Maire, P
通讯作者：
Maire, P
影响因子：
11.8
作者：
DeSisto J;O'Rourke R;Jones HE;Pawlikowski B;Malek AD;Bonney S;Guimiot F;Jones KL;Siegenthaler JA
通讯作者：
Siegenthaler JA