Genetic heterogeneity of heritable ectopic mineralization disorders in a large international cohort.
Genetic heterogeneity of heritable ectopic mineralization disorders in a large international cohort.
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DOI：
10.1016/j.gim.2021.08.011
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发表时间：
2022-01
期刊：
影响因子：
--
通讯作者：
Li Q
中科院分区：
文献类型：
--
作者：
Saeidian AH;Youssefian L;Huang J;Touati A;Vahidnezhad H;Kowal L;Caffet M;Wurst T;Singh J;Snook AE;Ryu E;Fortina P;Terry SF;Schoenecker JG;Uitto J;Li Q
遗传性异位矿化障碍包括一组在非骨骼结缔组织中具有广泛临床表现的病症。我们报告了由 478 名异位矿化患者组成的大型国际队列的基因发现。使用由 29 个报告与异位矿化相关的基因组成的下一代测序面板来鉴定序列变异。在体外和体内实验系统中分析了选定剪接和错义变异的致病性。 25个基因中总共公开了872个意义不明的变异以及可能的致病和致病变异。 ABCC6 是导致弹性假黄瘤（一种遗传性多系统异位矿化障碍）的基因，在 425 名患者中总共鉴定出 159 个不同的变异。依赖于生物信息学预测的变异致病性解释并未达成共识。我们对 14 个 ABCC6 变体进行的体外和体内功能评估强调了这一困境，并为其致病性提供了明确的解释。这些结果扩展了 ABCC6 变异库，为遗传性异位矿化疾病的遗传异质性提供了新的线索，并提供了证据，表明在适当的实验系统中进行功能表征对于确定遗传变异的致病性是必要的。
Heritable ectopic mineralization disorders comprise a group of conditions with a broad range of clinical manifestations in non-skeletal connective tissues. We report the genetic findings from a large international cohort of 478 patients afflicted with ectopic mineralization. Sequence variations were identified using a next-generation sequencing panel consisting of 29 genes reported in association with ectopic mineralization. The pathogenicity of select splicing and missense variants was analyzed in experimental systems in vitro and in vivo. A total of 872 variants of unknown significance as well as likely pathogenic and pathogenic variants were disclosed in 25 genes. A total of 159 distinct variants were identified in 425 patients in ABCC6, the gene responsible for pseudoxanthoma elasticum, a heritable multi-system ectopic mineralization disorder. The interpretation of variant pathogenicity relying on bioinformatic predictions did not provide a consensus. Our in vitro and in vivo functional assessment of fourteen ABCC6 variants highlighted this dilemma and provided unambiguous interpretations to their pathogenicity. The results expand the ABCC6 variant repertoire, shed new light on the genetic heterogeneity of heritable ectopic mineralization disorders, and provide evidence that functional characterization in appropriate experimental systems is necessary to determine the pathogenicity of genetic variants.
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影响因子：
6.5
作者：
Pomozi, Viola;Brampton, Christopher;Fueloep, Krisztina;Chen, Li-Hsieh;Apana, Ailea;Li, Qiaoli;Uitto, Jouni;Le Saux, Olivier;Varadi, Andras
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患有假性透明瘤弹性瘤样表型的GGCX和ABCC6基因的突变。
影响因子：
6.5
作者：
Li, Qiaoli;Grange, Dorothy K.;Armstrong, Nicole L.;Whelan, Alison J.;Hurley, Maria Y.;Rishavy, Mark A.;Hallgren, Kevin W.;Berkner, Kathleen L.;Schurgers, Leon J.;Jiang, Qiujie;Uitto, Jouni
通讯作者：
Uitto, Jouni
影响因子：
14.9
作者：
Rentzsch P;Witten D;Cooper GM;Shendure J;Kircher M
通讯作者：
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