Improving genetic diagnosis in Mendelian disease with transcriptome sequencing

• Type: Article in International Scientific Journal
• Date: 2017

Authors

Cummings, BB (Author) Other; Marshall, JL (Author) Other; Tukiainen, T (Author) Other; Lek, M (Author) Other; Donkervoort, S (Author) Other; Foley, AR (Author) Other; Bolduc, V (Author) Other; Waddell, LB (Author) Other; Sandaradura, SA (Author) Other; O'Grady, GL (Author) Other; Estrella, E (Author) Other; Reddy, HM (Author) Other; Zhao, F (Author) Other; Weisburd, B (Author) Other; Karczewski, KJ (Author) Other; O'Donnell Luria, AH (Author) Other; Birnbaum, D (Author) Other; Sarkozy, A (Author) Other; Hu, Y (Author) Other; Gonorazky, H (Author) Other; Claeys, K (Author) Other; Joshi, H (Author) Other; Bournazos, A (Author) Other; Oates, EC (Author) Other; Ghaoui, R (Author) Other; Davis, MR (Author) Other; Laing, NG (Author) Other; Topf, A (Author) Other; Kang, PB (Author) Other; Beggs, AH (Author) Other; North, KN (Author) Other; Straub, V (Author) Other; Dowling, JJ (Author) Other; Muntoni, F (Author) Other; Clarke, NF (Author) Other; Cooper, ST (Author) Other; Bönnemann, CG (Author) Other; MacArthur, DG (Author) Other; Ardlie, KG (Author) Other; Getz, G (Author) Other; Gelfand, ET (Author) Other; Segrè, AV (Author) Other; Aguet, F (Author) Other; Sullivan, TJ (Author) Other; Li, X (Author) Other; Nedzel, JL (Author) Other; Trowbridge, CA (Author) Other; Hadley, K (Author) Other; Huang, KH (Author) Other; Noble, MS (Author) Other; Nguyen, DT (Author) Other; Nobel, AB (Author) Other; Wright, FA (Author) Other; Shabalin, AA (Author) Other; Palowitch, JJ (Author) Other; Zhou, YH (Author) Other; Dermitzakis, ET (Author) Other; McCarthy, MI (Author) Other; Payne, AJ (Author) Other; Lappalainen, T (Author) Other; Castel, S (Author) Other; Kim Hellmuth, S (Author) Other; Mohammadi, P (Author) Other; Battle, A (Author) Other; Parsana, P (Author) Other; Mostafavi, S (Author) Other; Brown, A (Author) Other; Ongen, H (Author) Other; Delaneau, O (Author) Other; Panousis, N (Author) Other; Howald, C (Author) Other; Van De Bunt, M (Author) Other; Guigo, R (Author) Other; Monlong, J (Author) Other; Reverter, F (Author) Other; Garrido, D (Author) Other; Munoz, M (Author) Other; Bogu, G (Author) Other; Sodaei, R (Author) Other; Papasaikas, P (Author) Other; Ndungu, AW (Author) Other; Montgomery, SB (Author) Other; Li, X (Author) Other; Fresard, L (Author) Other; Davis, JR (Author) Other; Tsang, EK (Author) Other; Zappala, Z (Author) Other; Abell, NS (Author) Other; Gloudemans, MJ (Author) Other; Liu, B (Author) Other; Damani, FN (Author) Other; Saha, A (Author) Other; Kim, Y (Author) Other; Strober, BJ (Author) Other; He, Y (Author) Other; Stephens, M (Author) Other; Pritchard, JK (Author) Other; Wen, X (Author) Other; Urbut, S (Author) Other; Cox, NJ (Author) Other; Nicolae, DL (Author) Other; Gamazon, ER (Author) Other; Im, HK (Author) Other; Brown, CD (Author) Other; Engelhardt, BE (Author) Other; Park, Y (Author) Other; Jo, B (Author) Other; McDowell, IC (Author) Other; Gewirtz, A (Author) Other; Gliner, G (Author) Other; Conrad, D (Author) Other; Hall, I (Author) Other; Chiang, C (Author) Other; Scott, A (Author) Other; Sabatti, C (Author) Other; Eskin, E (Author) Other; Peterson, C (Author) Other; Hormozdiari, F (Author) Other; Kang, EY (Author) Other; Mangul, S (Author) Other; Han, B (Author) Other; Sul, JH (Author) Other; Feinberg, AP (Author) Other; Rizzardi, LF (Author) Other; Hansen, KD (Author) Other; Hickey, P (Author) Other; Akey, J (Author) Other; Kellis, M (Author) Other; Li, JB (Author) Other; Snyder, M (Author) Other; Tang, H (Author) Other; Jiang, L (Author) Other; Lin, S (Author) Other; Stranger, BE (Author) Other; Fernando, M (Author) Other; Oliva, M (Author) Other; Stamatoyannopoulos, J (Author) Other; Kaul, R (Author) Other; Halow, J (Author) Other; Sandstrom, R (Author) Other; Haugen, E (Author) Other; Johnson, A (Author) Other; Lee, K (Author) Other; Bates, D (Author) Other; Diegel, M (Author) Other; Pierce, BL (Author) Other; Chen, L (Author) Other; Kibriya, MG (Author) Other; Jasmine, F (Author) Other; Doherty, J (Author) Other; Demanelis, K (Author) Other; Smith, KS (Author) Other; Li, Q (Author) Other; Zhang, R (Author) Other; Nierras, CR (Author) Other; Moore, HM (Author) Other; Rao, A (Author) Other; Guan, P (Author) Other; Vaught, JB (Author) Other; Branton, PA (Author) Other; Carithers, LJ (Author) Other; Volpi, S (Author) Other; Struewing, JP (Author) Other; Martin, CG (Author) Other; Nicole, LC (Author) Other; Koester, SE (Author) Other; Addington, AM (Author) Other; Little, AR (Author) Other; Leinweber, WF (Author) Other; Thomas, JA (Author) Other; Kopen, G (Author) Other; McDonald, A (Author) Other; Mestichelli, B (Author) Other; Shad, S (Author) Other; Lonsdale, JT (Author) Other; Salvatore, M (Author) Other; Hasz, R (Author) Other; Walters, G (Author) Other; Johnson, M (Author) Other; Washington, M (Author) Other; Brigham, LE (Author) Other; Johns, C (Author) Other; Wheeler, J (Author) Other; Roe, B (Author) Other; Hunter, M (Author) Other; Myer, K (Author) Other; Foster, BA (Author) Other; Moser, MT (Author) Other; Karasik, E (Author) Other; Gillard, BM (Author) Other; Kumar, R (Author) Other; Bridge, J (Author) Other; Miklos, M (Author) Other; Jewell, SD (Author) Other; Rohrer, DC (Author) Other; Valley, D (Author) Other; Montroy, RG (Author) Other; Mash, DC (Author) Other; Davis, DA (Author) Other; Undale, AH (Author) Other; Smith, AM (Author) Other; Tabor, DE (Author) Other; Roche, NV (Author) Other; McLean, JA (Author) Other; Vatanian, N (Author) Other; Robinson, KL (Author) Other; Sobin, L (Author) Other; Barcus, ME (Author) Other; Valentino, KM (Author) Other; Qi, L (Author) Other; Hunter, S (Author) Other; Hariharan, P (Author) Other; Singh, S (Author) Other; Um, KS (Author) Other; Matose, T (Author) Other; Tomadzewski, MM (Author) Other; Siminoff, LA (Author) Other; Traino, HM (Author) Other; Mosavel, M (Author) Other; Barker, LK (Author) Other; Zerbino, DR (Author) Other; Juettmann, T (Author) Other; Taylor, K (Author) Other; Ruffier, M (Author) Other; Sheppard, D (Author) Other; Trevanion, S (Author) Other; Flicek, P (Author) Other; Kent, WJ (Author) Other; Rosenbloom, KR (Author) Other; Haeussler, M (Author) Other; Lee, CM (Author) Other; Paten, B (Author) Other; Vivan, J (Author) Other; Zhu, J (Author) Other; Goldman, M (Author) Other; Craft, B (Author) Other; Li, G (Author) Other; Ferreira, PG (Author) Other; Yeger Lotem, E (Author) Other; Maurano, MT (Author) Other; Barshir, R (Author) Other; Basha, O (Author) Other; Xi, HS (Author) Other; Quan, J (Author) Other; Sammeth, M (Author) Other; Zaugg, JB (Author) Other

Journal

Title: Science Translational Medicine

Vol. 9

ISSN: 1946-6234

Publisher: American Association for the Advancement of Science

Indexing

Scopus - 278 Citations

Scientific classification

CORDIS: Natural sciences > Biological sciences > Biology > Computational biology

FOS: Natural sciences > Biological sciences ; Natural sciences > Computer and information sciences

Other information

Authenticus ID: P-00M-Q75

DOI: 10.1126/scitranslmed.aal5209

Abstract (EN): Exome and whole-genome sequencing are becoming increasingly routine approaches in Mendelian disease diagnosis. Despite their success, the current diagnostic rate for genomic analyses across a variety of rare diseases is approximately 25 to 50%. We explore the utility of transcriptome sequencing [RNA sequencing (RNA-seq)] as a complementary diagnostic tool in a cohort of 50 patients with genetically undiagnosed rare muscle disorders. We describe an integrated approach to analyze patient muscle RNA-seq, leveraging an analysis framework focused on the detection of transcript-level changes that are unique to the patient compared to more than 180 control skeletal muscle samples. We demonstrate the power of RNA-seq to validate candidate splice-disrupting mutations and to identify splice-altering variants in both exonic and deep intronic regions, yielding an overall diagnosis rate of 35%. We also report the discovery of a highly recurrent de novo intronic mutation in COL6A1 that results in a dominantly acting splice-gain event, disrupting the critical glycine repeat motif of the triple helical domain. We identify this pathogenic variant in a total of 27 genetically unsolved patients in an external collagen VI-like dystrophy cohort, thus explaining approximately 25% of patients clinically suggestive of having collagen VI dystrophy in whom prior genetic analysis is negative. Overall, this study represents a large systematic application of transcriptome sequencing to rare disease diagnosis and highlights its utility for the detection and interpretation of variants missed by current standard diagnostic approaches. 2017 © The Authors.

Language: English

Type (Professor's evaluation): Scientific