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Supravalvular Aortic Stenosis Caused by a Familial Chromosome 7 Inversion Disrupting the ELN Gene Uncovered by Whole-Genome Sequencing.
Molecular Syndromology ( IF 1.1 ) Pub Date : 2019-05-21 , DOI: 10.1159/000500215
Linda Pons 1, 2 , Patrice Bouvagnet 3, 4 , Mohamed Bakloul 5 , Sylvie Di Filippo 4, 5 , Adrien Buisson 1 , Nicolas Chatron 1, 2, 4 , Audrey Labalme 1 , Olivier Metton 5 , Julia Mitchell 5 , Flavie Diguet 1, 2 , Pierre-Antoine Rollat-Farnier 1 , Damien Sanlaville 1, 2, 4 , Caroline Schluth-Bolard 1, 2, 4
Affiliation  

Apparently, balanced chromosomal rearrangements usually have no phenotypic consequences for the carrier. However, in some cases, they may be associated with an abnormal phenotype. We report herein the case of a 4-year-old boy presenting with clinically isolated supravalvular aortic stenosis (SVAS). No chromosomal imbalance was detected by array CGH. The karyotype showed a balanced paracentric chromosome 7 inversion. Breakpoint characterization using paired-end whole-genome sequencing (WGS) revealed an ELN gene disruption in intron 1, accounting for the phenotype. Family study showed that the inversion was inherited, with incomplete penetrance. To our knowledge, this is the first case of a disruption of the ELN gene characterized by WGS. It contributes to refine the genotype-phenotype correlation in ELN disruption. Although this disruption is a rare etiology of SVAS, it cannot be detected by the diagnostic tests usually performed, such as array CGH or sequencing methods (Sanger, panel, or exome sequencing). With the future perspective of WGS as a diagnostic tool, it will be important to include a structural variation analysis in order to detect balanced rearrangements and gene disruption.

中文翻译:

由家族染色体7倒位引起的瓣膜上主动脉瓣狭窄破坏了全基因组测序发现的ELN基因。

显然,平衡的染色体重排通常对载体没有表型的影响。但是,在某些情况下,它们可能与异常的表型有关。我们在这里报告一个4岁男孩的临床孤立的瓣膜上主动脉瓣狭窄(SVAS)的情况。阵列CGH未检测到染色体失衡。核型显示出平衡的副中心染色体7倒位。使用双末端全基因组测序(WGS)进行的断点表征揭示了内含子1中的ELN基因破坏,这说明了表型。家庭研究表明,倒立是遗传性的,外et不完全。据我们所知,这是第一个以WGS为特征的ELN基因被破坏的情况。它有助于改善ELN破坏中的基因型-表型相关性。尽管这种破坏是SVAS的罕见病因,但无法通过通常执行的诊断测试(例如阵列CGH或测序方法(Sanger,panel或exome测序))检测到。使用WGS作为诊断工具的未来前景,包括结构变异分析以检测平衡的重排和基因破坏将非常重要。
更新日期:2019-11-01
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