Exome Sequencing Reveals Novel Rare Variants in the Ryanodine Receptor and Calcium Channel Genes in Malignant Hyperthermia Families

被引:43
作者
Kim, Jerry H. [1 ]
Jarvik, Gail P. [1 ]
Browning, Brian L. [1 ]
Rajagopalan, Ramakrishnan [1 ]
Gordon, Adam S. [1 ,2 ]
Rieder, Mark J. [1 ,2 ]
Robertson, Peggy D. [1 ,2 ]
Nickerson, Deborah A. [1 ,2 ]
Fisher, Nickla A. [1 ]
Hopkins, Philip M. [1 ]
机构
[1] Univ Washington, Dept Anesthesiol & Pain Med, Seattle, WA 98195 USA
[2] Univ Washington, Dept Genome Sci, Seattle, WA 98195 USA
基金
美国国家卫生研究院;
关键词
SUSCEPTIBILITY LOCUS; HUMAN TRANSCRIPTOME; MISSENSE MUTATIONS; WIDESPREAD RNA; POPULATION; GENERATION; RYR1; PREDISPOSITION; LOCALIZATION; EVOLUTION;
D O I
10.1097/ALN.0b013e3182a8a998
中图分类号
R614 [麻醉学];
学科分类号
100217 ;
摘要
Background: About half of malignant hyperthermia (MH) cases are associated with skeletal muscle ryanodine receptor 1 (RYR1) and calcium channel, voltage-dependent, L type, 1S subunit (CACNA1S) gene mutations, leaving many with an unknown cause. The authors chose to apply a sequencing approach to uncover causal variants in unknown cases. Sequencing the exome, the protein-coding region of the genome, has power at low sample sizes and identified the cause of over a dozen Mendelian disorders. Methods: The authors considered four families with multiple MH cases lacking mutations in RYR1 and CACNA1S by Sanger sequencing of complementary DNA. Exome sequencing in two affecteds per family, chosen for maximum genetic distance, were compared. Variants were ranked by allele frequency, protein change, and measures of conservation among mammals to assess likelihood of causation. Finally, putative pathogenic mutations were genotyped in other family members to verify cosegregation with MH. Results: Exome sequencing revealed one rare RYR1 nonsynonymous variant in each of three families (Asp1056His, Val2627Met, Val4234Leu), and one CACNA1S variant (Thr1009Lys) in the fourth family. These were not seen in variant databases or in our control population sample of 5,379 exomes. Follow-up sequencing in other family members verified cosegregation of alleles with MH. Conclusions: The authors found that using both exome sequencing and allele frequency data from large sequencing efforts may aid genetic diagnosis of MH. In a sample selected by the authors, this technique was more sensitive for variant detection in known genes than Sanger sequencing of complementary DNA, and allows for the possibility of novel gene discovery.
引用
收藏
页码:1054 / 1065
页数:12
相关论文
共 41 条
  • [1] A method and server for predicting damaging missense mutations
    Adzhubei, Ivan A.
    Schmidt, Steffen
    Peshkin, Leonid
    Ramensky, Vasily E.
    Gerasimova, Anna
    Bork, Peer
    Kondrashov, Alexey S.
    Sunyaev, Shamil R.
    [J]. NATURE METHODS, 2010, 7 (04) : 248 - 249
  • [2] A map of human genome variation from population-scale sequencing
    Altshuler, David
    Durbin, Richard M.
    Abecasis, Goncalo R.
    Bentley, David R.
    Chakravarti, Aravinda
    Clark, Andrew G.
    Collins, Francis S.
    De la Vega, Francisco M.
    Donnelly, Peter
    Egholm, Michael
    Flicek, Paul
    Gabriel, Stacey B.
    Gibbs, Richard A.
    Knoppers, Bartha M.
    Lander, Eric S.
    Lehrach, Hans
    Mardis, Elaine R.
    McVean, Gil A.
    Nickerson, DebbieA.
    Peltonen, Leena
    Schafer, Alan J.
    Sherry, Stephen T.
    Wang, Jun
    Wilson, Richard K.
    Gibbs, Richard A.
    Deiros, David
    Metzker, Mike
    Muzny, Donna
    Reid, Jeff
    Wheeler, David
    Wang, Jun
    Li, Jingxiang
    Jian, Min
    Li, Guoqing
    Li, Ruiqiang
    Liang, Huiqing
    Tian, Geng
    Wang, Bo
    Wang, Jian
    Wang, Wei
    Yang, Huanming
    Zhang, Xiuqing
    Zheng, Huisong
    Lander, Eric S.
    Altshuler, David L.
    Ambrogio, Lauren
    Bloom, Toby
    Cibulskis, Kristian
    Fennell, Tim J.
    Gabriel, Stacey B.
    [J]. NATURE, 2010, 467 (7319) : 1061 - 1073
  • [3] [Anonymous], 2012, LANG ENV STAT COMP
  • [4] Prevalence of Malignant Hyperthermia Due to Anesthesia in New York State, 2001-2005
    Brady, Joanne E.
    Sun, Lena S.
    Rosenberg, Henry
    Li, Guohua
    [J]. ANESTHESIA AND ANALGESIA, 2009, 109 (04) : 1162 - 1166
  • [5] A Fast, Powerful Method for Detecting Identity by Descent
    Browning, Brian L.
    Browning, Sharon R.
    [J]. AMERICAN JOURNAL OF HUMAN GENETICS, 2011, 88 (02) : 173 - 182
  • [6] Genetic variation in RYR1 and malignant hyperthermia phenotypes
    Carpenter, D.
    Robinson, R. L.
    Quinnell, R. J.
    Ringrose, C.
    Hogg, M.
    Casson, F.
    Booms, P.
    Iles, D. E.
    Halsall, P. J.
    Steele, D. S.
    Shaw, M. -A.
    Hopkins, P. M.
    [J]. BRITISH JOURNAL OF ANAESTHESIA, 2009, 103 (04) : 538 - 548
  • [7] The role of CACNA1S in predisposition to malignant hyperthermia
    Carpenter, Danielle
    Ringrose, Christopher
    Leo, Vincenzo
    Morris, Andrew
    Robinson, Rachel L.
    Halsall, P. Jane
    Hopkins, Philip M.
    Shaw, Marie-Anne
    [J]. BMC MEDICAL GENETICS, 2009, 10 : 104
  • [8] Distribution and intensity of constraint in mammalian genomic sequence
    Cooper, GM
    Stone, EA
    Asimenos, G
    Green, ED
    Batzoglou, S
    Sidow, A
    [J]. GENOME RESEARCH, 2005, 15 (07) : 901 - 913
  • [9] DAVIES W, 1988, ANIM GENET, V19, P203, DOI 10.1111/j.1365-2052.1988.tb00809.x
  • [10] Identifying a High Fraction of the Human Genome to be under Selective Constraint Using GERP plus
    Davydov, Eugene V.
    Goode, David L.
    Sirota, Marina
    Cooper, Gregory M.
    Sidow, Arend
    Batzoglou, Serafim
    [J]. PLOS COMPUTATIONAL BIOLOGY, 2010, 6 (12)