当前位置:
X-MOL 学术
›
Clin. Genet.
›
论文详情
Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)
A BBS1 SVA F retrotransposon insertion is a frequent cause of Bardet‐Biedl syndrome
Clinical Genetics ( IF 3.5 ) Pub Date : 2020-11-09 , DOI: 10.1111/cge.13878 Clarisse Delvallée 1 , Samuel Nicaise 1 , Manuela Antin 2 , Anne-Sophie Leuvrey 2 , Elsa Nourisson 2 , Carmen C Leitch 3 , Georgios Kellaris 3 , Corinne Stoetzel 1 , Véronique Geoffroy 1 , Sophie Scheidecker 1, 2 , Boris Keren 4, 5 , Christel Depienne 4, 6 , Joakim Klar 7 , Niklas Dahl 7 , Jean-François Deleuze 8 , Emmanuelle Génin 9 , Richard Redon 10 , Florence Demurger 11 , Koenraad Devriendt 12 , Michèle Mathieu-Dramard 13 , Christine Poitou-Bernert 14 , Sylvie Odent 15, 16 , Nicholas Katsanis 3, 17 , Jean-Louis Mandel 2, 18 , Erica E Davis 3, 17 , Hélène Dollfus 1, 19, 20 , Jean Muller 1, 2
Clinical Genetics ( IF 3.5 ) Pub Date : 2020-11-09 , DOI: 10.1111/cge.13878 Clarisse Delvallée 1 , Samuel Nicaise 1 , Manuela Antin 2 , Anne-Sophie Leuvrey 2 , Elsa Nourisson 2 , Carmen C Leitch 3 , Georgios Kellaris 3 , Corinne Stoetzel 1 , Véronique Geoffroy 1 , Sophie Scheidecker 1, 2 , Boris Keren 4, 5 , Christel Depienne 4, 6 , Joakim Klar 7 , Niklas Dahl 7 , Jean-François Deleuze 8 , Emmanuelle Génin 9 , Richard Redon 10 , Florence Demurger 11 , Koenraad Devriendt 12 , Michèle Mathieu-Dramard 13 , Christine Poitou-Bernert 14 , Sylvie Odent 15, 16 , Nicholas Katsanis 3, 17 , Jean-Louis Mandel 2, 18 , Erica E Davis 3, 17 , Hélène Dollfus 1, 19, 20 , Jean Muller 1, 2
Affiliation
Bardet‐Biedl syndrome (BBS) is a ciliopathy characterized by retinitis pigmentosa, obesity, polydactyly, cognitive impairment and renal failure. Pathogenic variants in 24 genes account for the molecular basis of >80% of cases. Toward saturated discovery of the mutational basis of the disorder, we carefully explored our cohorts and identified a hominid‐specific SINE‐R/VNTR/Alu type F (SVA‐F) insertion in exon 13 of BBS1 in eight families. In six families, the repeat insertion was found in trans with c.1169 T > G, p.Met390Arg and in two families the insertion was found in addition to other recessive BBS loci. Whole genome sequencing, de novo assembly and SNP array analysis were performed to characterize the genomic event. This insertion is extremely rare in the general population (found in 8 alleles of 8 BBS cases but not in >10 800 control individuals from gnomAD‐SV) and due to a founder effect. Its 2435 bp sequence contains hallmarks of LINE1 mediated retrotransposition. Functional studies with patient‐derived cell lines confirmed that the BBS1 SVA‐F is deleterious as evidenced by a significant depletion of both mRNA and protein levels. Such findings highlight the importance of dedicated bioinformatics pipelines to identify all types of variation.
中文翻译:
BBS1 SVA F 逆转录转座子插入是 Bardet-Biedl 综合征的常见原因
Bardet-Biedl 综合征 (BBS) 是一种纤毛病,其特征是视网膜色素变性、肥胖、多指畸形、认知障碍和肾功能衰竭。24 种基因的致病变异占> 80% 病例的分子基础。为了充分发现该疾病的突变基础,我们仔细研究了我们的队列,并在 8 个家族的BBS1外显子 13 中确定了一个人科特异性 SINE-R/VNTR/ Alu型 F(SVA-F)插入。在六个家族中,在反式中发现了重复插入,c.1169 T > G,p.Met390Arg,在两个家族中,除了其他隐性 BBS 基因座外,还发现了插入。全基因组测序,从头进行组装和 SNP 阵列分析以表征基因组事件。这种插入在一般人群中极为罕见(在 8 个 BBS 病例的 8 个等位基因中发现,但在来自 gnomAD-SV 的 >10800 个对照个体中没有发现)并且由于创始人效应。其 2435 bp 序列包含 LINE1 介导的逆转录转座的标志。对源自患者的细胞系的功能研究证实,BBS1 SVA-F 是有害的,这可以通过 mRNA 和蛋白质水平的显着消耗来证明。这些发现突出了专用生物信息学管道在识别所有类型变异方面的重要性。
更新日期:2021-01-14
中文翻译:
BBS1 SVA F 逆转录转座子插入是 Bardet-Biedl 综合征的常见原因
Bardet-Biedl 综合征 (BBS) 是一种纤毛病,其特征是视网膜色素变性、肥胖、多指畸形、认知障碍和肾功能衰竭。24 种基因的致病变异占> 80% 病例的分子基础。为了充分发现该疾病的突变基础,我们仔细研究了我们的队列,并在 8 个家族的BBS1外显子 13 中确定了一个人科特异性 SINE-R/VNTR/ Alu型 F(SVA-F)插入。在六个家族中,在反式中发现了重复插入,c.1169 T > G,p.Met390Arg,在两个家族中,除了其他隐性 BBS 基因座外,还发现了插入。全基因组测序,从头进行组装和 SNP 阵列分析以表征基因组事件。这种插入在一般人群中极为罕见(在 8 个 BBS 病例的 8 个等位基因中发现,但在来自 gnomAD-SV 的 >10800 个对照个体中没有发现)并且由于创始人效应。其 2435 bp 序列包含 LINE1 介导的逆转录转座的标志。对源自患者的细胞系的功能研究证实,BBS1 SVA-F 是有害的,这可以通过 mRNA 和蛋白质水平的显着消耗来证明。这些发现突出了专用生物信息学管道在识别所有类型变异方面的重要性。