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Revisiting the complex architecture of ALS in Turkey: Expanding genotypes, shared phenotypes, molecular networks, and a public variant database.
Human Mutation ( IF 3.9 ) Pub Date : 2020-06-24 , DOI: 10.1002/humu.24055 Ceren Tunca 1, 2 , Tuncay Şeker 3 , Fulya Akçimen 2 , Cemre Coşkun 2 , Elif Bayraktar 1 , Robin Palvadeau 1 , Seyit Zor 3 , Cemile Koçoğlu 2 , Ece Kartal 2 , Nesli Ece Şen 2 , Hamid Hamzeiy 2 , Aslıhan Özoğuz Erimiş 2 , Utku Norman 4 , Oğuzhan Karakahya 4 , Gülden Olgun 4 , Tahsin Akgün 5 , Hacer Durmuş 6 , Erdi Şahin 6 , Arman Çakar 6 , Esra Başar Gürsoy 7 , Gülsen Babacan Yıldız 7 , Barış İşak 8 , Kayıhan Uluç 8 , Haşmet Hanağası 6 , Başar Bilgiç 6 , Nilda Turgut 9 , Fikret Aysal 10 , Mustafa Ertaş 6 , Cavit Boz 11 , Dilcan Kotan 12 , Halil İdrisoğlu 6 , Aysun Soysal 13 , Nurten Uzun Adatepe 14 , Mehmet Ali Akalın 14 , Filiz Koç 15 , Ersin Tan 16 , Piraye Oflazer 6 , Feza Deymeer 6 , Öznur Taştan 17 , A Ercüment Çiçek 4, 18 , Erşen Kavak 3 , Yeşim Parman 6 , A Nazlı Başak 1, 2
Human Mutation ( IF 3.9 ) Pub Date : 2020-06-24 , DOI: 10.1002/humu.24055 Ceren Tunca 1, 2 , Tuncay Şeker 3 , Fulya Akçimen 2 , Cemre Coşkun 2 , Elif Bayraktar 1 , Robin Palvadeau 1 , Seyit Zor 3 , Cemile Koçoğlu 2 , Ece Kartal 2 , Nesli Ece Şen 2 , Hamid Hamzeiy 2 , Aslıhan Özoğuz Erimiş 2 , Utku Norman 4 , Oğuzhan Karakahya 4 , Gülden Olgun 4 , Tahsin Akgün 5 , Hacer Durmuş 6 , Erdi Şahin 6 , Arman Çakar 6 , Esra Başar Gürsoy 7 , Gülsen Babacan Yıldız 7 , Barış İşak 8 , Kayıhan Uluç 8 , Haşmet Hanağası 6 , Başar Bilgiç 6 , Nilda Turgut 9 , Fikret Aysal 10 , Mustafa Ertaş 6 , Cavit Boz 11 , Dilcan Kotan 12 , Halil İdrisoğlu 6 , Aysun Soysal 13 , Nurten Uzun Adatepe 14 , Mehmet Ali Akalın 14 , Filiz Koç 15 , Ersin Tan 16 , Piraye Oflazer 6 , Feza Deymeer 6 , Öznur Taştan 17 , A Ercüment Çiçek 4, 18 , Erşen Kavak 3 , Yeşim Parman 6 , A Nazlı Başak 1, 2
Affiliation
The last decade has proven that amyotrophic lateral sclerosis (ALS) is clinically and genetically heterogeneous, and that the genetic component in sporadic cases might be stronger than expected. This study investigates 1,200 patients to revisit ALS in the ethnically heterogeneous yet inbred Turkish population. Familial ALS (fALS) accounts for 20% of our cases. The rates of consanguinity are 30% in fALS and 23% in sporadic ALS (sALS). Major ALS genes explained the disease cause in only 35% of fALS, as compared with ~70% in Europe and North America. Whole exome sequencing resulted in a discovery rate of 42% (53/127). Whole genome analyses in 623 sALS cases and 142 population controls, sequenced within Project MinE, revealed well‐established fALS gene variants, solidifying the concept of incomplete penetrance in ALS. Genome‐wide association studies (GWAS) with whole genome sequencing data did not indicate a new risk locus. Coupling GWAS with a coexpression network of disease‐associated candidates, points to a significant enrichment for cell cycle‐ and division‐related genes. Within this network, literature text‐mining highlights DECR1 , ATL1 , HDAC2 , GEMIN4 , and HNRNPA3 as important genes. Finally, information on ALS‐related gene variants in the Turkish cohort sequenced within Project MinE was compiled in the GeNDAL variant browser (www.gendal.org).
中文翻译:
重新审视土耳其 ALS 的复杂架构:扩展基因型、共享表型、分子网络和公共变异数据库。
过去十年已经证明肌萎缩侧索硬化 (ALS) 在临床和遗传上具有异质性,并且散发病例的遗传成分可能比预期的要强。本研究调查了 1,200 名患者,以重新审视种族异质但近交的土耳其人群中的 ALS。家族性 ALS (fALS) 占我们病例的 20%。fALS 中的血亲率为 30%,散发性 ALS (sALS) 中为 23%。主要 ALS 基因仅在 35% 的 fALS 中解释了该疾病的原因,而在欧洲和北美则为约 70%。全外显子组测序的发现率为 42% (53/127)。在 Project MinE 中测序的 623 个 sALS 病例和 142 个人群对照的全基因组分析揭示了完善的 fALS 基因变异,巩固了 ALS 中不完全外显率的概念。使用全基因组测序数据进行的全基因组关联研究 (GWAS) 并未显示新的风险位点。将 GWAS 与疾病相关候选基因的共表达网络结合,表明细胞周期和分裂相关基因的显着富集。在这个网络中,文献文本挖掘亮点DECR1、ATL1、HDAC2、GEMIN4和HNRNPA3作为重要基因。最后,在 GeNDAL 变异浏览器 (www.gendal.org) 中编译了在 Project MinE 中测序的土耳其队列中 ALS 相关基因变异的信息。
更新日期:2020-07-28
中文翻译:
重新审视土耳其 ALS 的复杂架构:扩展基因型、共享表型、分子网络和公共变异数据库。
过去十年已经证明肌萎缩侧索硬化 (ALS) 在临床和遗传上具有异质性,并且散发病例的遗传成分可能比预期的要强。本研究调查了 1,200 名患者,以重新审视种族异质但近交的土耳其人群中的 ALS。家族性 ALS (fALS) 占我们病例的 20%。fALS 中的血亲率为 30%,散发性 ALS (sALS) 中为 23%。主要 ALS 基因仅在 35% 的 fALS 中解释了该疾病的原因,而在欧洲和北美则为约 70%。全外显子组测序的发现率为 42% (53/127)。在 Project MinE 中测序的 623 个 sALS 病例和 142 个人群对照的全基因组分析揭示了完善的 fALS 基因变异,巩固了 ALS 中不完全外显率的概念。使用全基因组测序数据进行的全基因组关联研究 (GWAS) 并未显示新的风险位点。将 GWAS 与疾病相关候选基因的共表达网络结合,表明细胞周期和分裂相关基因的显着富集。在这个网络中,文献文本挖掘亮点DECR1、ATL1、HDAC2、GEMIN4和HNRNPA3作为重要基因。最后,在 GeNDAL 变异浏览器 (www.gendal.org) 中编译了在 Project MinE 中测序的土耳其队列中 ALS 相关基因变异的信息。