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      Revisiting the complex architecture of ALS in Turkey: expanding genotypes, shared phenotypes, molecular networks, and a public variant database

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      Embargo Lift Date: 2021-08-01
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      Author(s)
      Tunca, C.
      Şeker, T.
      Akçimen, F.
      Coşkun, C.
      Bayraktar, E.
      Palvadeau, R.
      Zor, S.
      Koçoğlu, C.
      Kartal, E.
      Şen, N. E.
      Hamzeiy, H.
      Özoğuz-Erimiş, A.
      Norman, Utku
      Karakahya, Oğuzhan
      Olgun, Gülden
      Akgün, T.
      Durmuş, H.
      Şahin, E.
      Çakar, A.
      Başar-Gürsoy, E.
      Babacan-Yıldız, G.
      İşak, B.
      Uluç, K.
      Hanağası, H.
      Bilgiç, B.
      Turgut, N.
      Aysal, F.
      Ertaş, M.
      Boz, C.
      Kotan, D.
      İdrisoğlu, H.
      Soysal, A.
      Uzun-Adatepe, N.
      Akalın, M. A.
      Koç, F.
      Tan, E.
      Oflazer, P.
      Deymeer, F.
      Taştan, Ö.
      Çiçek, A. Ercüment
      Kavak, E.
      Parman, Y.
      Başak, A. N.
      Date
      2020
      Source Title
      Human Mutation
      Print ISSN
      1059-7794
      Publisher
      John Wiley and Sons
      Volume
      41
      Issue
      8
      Pages
      e7 - e45
      Language
      English
      Type
      Article
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      Abstract
      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).
      Keywords
      ALS
      ALS variant database
      Genetics
      Clinical exome sequencing
      Coexpression network analysis
      Genome-wide association study
      Motor neuron disease
      Next generation sequencing
      Turkish peninsula
      Permalink
      http://hdl.handle.net/11693/55039
      Published Version (Please cite this version)
      https://dx.doi.org/10.1002/humu.24055
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      • Department of Computer Engineering 1561
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