Research Departments & Organizations
The lab is focused on understanding the genetic mechanism of rare diseases that may lead to rational approaches for therapies. Initially we are aimed at improving the diagnosis of rare neuromuscular diseases through the following approaches:
In recent years, large genomic data sets such as ExAC have been made publicly available and are a powerful resource for methods development. Our goal is to use these resources to build computational methods to improve our interpretation and prioritization of near-coding variants that are captured by exome sequencing but are often filtered or not considered due to difficulties in their interpretation. Further understanding of these classes of variants may contribute to improving the diagnosis rate in rare diseases.
Novel disease gene discovery
In collaboration with the Center of Mendelian Genomics, we aim to build and sequence a large cohort of undiagnosed neuromuscular disease patients to identify novel genes from exome and genome sequencing. These cohorts will be mainly non-European with a particular focus on patients from East Asia and South Asia. As part of these projects, we aim to develop and share tools and methods specific to rare disease analysis.
Detection of non-coding variants associated with disease
We aim to develop a cohort of recessive disease patients with only one pathogenic variant identified and based on several lines of evidence are likely to harbor another pathogenic mutation. Genome sequencing of these patients is likely to reveal non-coding, structural variants or novel mechanisms that were undetected by exome sequencing.
As a complementary approach, we will use saturating mutagenesis (i.e. tiling of sgRNA) to systematically disrupt regions in the vicinity of disease genes to identify non-coding regions that may impact gene function.
Interpretation of variants of unknown significance
A large challenge of rare disease diagnosis is the interpretation or correcting misinterpretations of rare missense variants in well established disease genes. Computational and analytical approaches take several lines of evidence in to consideration such as allele frequency and conservation but rarely physiologically relevant functional assays. Using cells from patients and healthy controls, we will design scalable high-throughput assays that can distinguish pathogenic from benign variants in muscle disease.
The methods and models to better understand the genetic underpinnings of rare disease can then be used to design and test therapies for neuromuscular disease patients.
|Children's Health, Genetics - Pediatric||Pediatric Genomics Discovery Program (PGDP)|
Analysis of protein-coding genetic variation in 60,706 humans.
Lek M, Karczewski KJ, Minikel EV, Samocha KE, Banks E, Fennell T, O'Donnell-Luria AH, Ware JS, Hill AJ, Cummings BB, Tukiainen T, Birnbaum DP, Kosmicki JA, Duncan LE, Estrada K, Zhao F, Zou J, Pierce-Hoffman E, Berghout J, Cooper DN, Deflaux N, DePristo M, Do R, Flannick J, Fromer M, Gauthier L, Goldstein J, Gupta N, Howrigan D, Kiezun A, Kurki MI, Moonshine AL, Natarajan P, Orozco L, Peloso GM, Poplin R, Rivas MA, Ruano-Rubio V, Rose SA, Ruderfer DM, Shakir K, Stenson PD, Stevens C, Thomas BP, Tiao G, Tusie-Luna MT, Weisburd B, Won HH, Yu D, Altshuler DM, Ardissino D, Boehnke M, Danesh J, Donnelly S, Elosua R, Florez JC, Gabriel SB, Getz G, Glatt SJ, Hultman CM, Kathiresan S, Laakso M, McCarroll S, McCarthy MI, McGovern D, McPherson R, Neale BM, Palotie A, Purcell SM, Saleheen D, Scharf JM, Sklar P, Sullivan PF, Tuomilehto J, Tsuang MT, Watkins HC, Wilson JG, Daly MJ, MacArthur DG. Analysis of protein-coding genetic variation in 60,706 humans. Nature 2016, 536:285-91. 2016
Patterns of genic intolerance of rare copy number variation in 59,898 human exomes.
Ruderfer DM, Hamamsy T, Lek M, Karczewski KJ, Kavanagh D, Samocha KE, Daly MJ, MacArthur DG, Fromer M, Purcell SM. Patterns of genic intolerance of rare copy number variation in 59,898 human exomes. Nature Genetics 2016, 48:1107-11. 2016
Quantifying prion disease penetrance using large population control cohorts.
Minikel EV, Vallabh SM, Lek M, Estrada K, Samocha KE, Sathirapongsasuti JF, McLean CY, Tung JY, Yu LP, Gambetti P, Blevins J, Zhang S, Cohen Y, Chen W, Yamada M, Hamaguchi T, Sanjo N, Mizusawa H, Nakamura Y, Kitamoto T, Collins SJ, Boyd A, Will RG, Knight R, Ponto C, Zerr I, Kraus TF, Eigenbrod S, Giese A, Calero M, de Pedro-Cuesta J, Haïk S, Laplanche JL, Bouaziz-Amar E, Brandel JP, Capellari S, Parchi P, Poleggi A, Ladogana A, O'Donnell-Luria AH, Karczewski KJ, Marshall JL, Boehnke M, Laakso M, Mohlke KL, Kähler A, Chambert K, McCarroll S, Sullivan PF, Hultman CM, Purcell SM, Sklar P, van der Lee SJ, Rozemuller A, Jansen C, Hofman A, Kraaij R, van Rooij JG, Ikram MA, Uitterlinden AG, van Duijn CM, Daly MJ, MacArthur DG. Quantifying prion disease penetrance using large population control cohorts. Science Translational Medicine 2016, 8:322ra9. 2016
Human genomics. Effect of predicted protein-truncating genetic variants on the human transcriptome.
Rivas MA, Pirinen M, Conrad DF, Lek M, Tsang EK, Karczewski KJ, Maller JB, Kukurba KR, DeLuca DS, Fromer M, Ferreira PG, Smith KS, Zhang R, Zhao F, Banks E, Poplin R, Ruderfer DM, Purcell SM, Tukiainen T, Minikel EV, Stenson PD, Cooper DN, Huang KH, Sullivan TJ, Nedzel J, Bustamante CD, Li JB, Daly MJ, Guigo R, Donnelly P, Ardlie K, Sammeth M, Dermitzakis ET, McCarthy MI, Montgomery SB, Lappalainen T, MacArthur DG. Human genomics. Effect of predicted protein-truncating genetic variants on the human transcriptome. Science (New York, N.Y.) 2015, 348:666-9. 2015
Improving genetic diagnosis in Mendelian disease with transcriptome sequencing.
Cummings BB, Marshall JL, Tukiainen T, Lek M, Donkervoort S, Foley AR, Bolduc V, Waddell LB, Sandaradura SA, O'Grady GL, Estrella E, Reddy HM, Zhao F, Weisburd B, Karczewski KJ, O'Donnell-Luria AH, Birnbaum D, Sarkozy A, Hu Y, Gonorazky H, Claeys K, Joshi H, Bournazos A, Oates EC, Ghaoui R, Davis MR, Laing NG, Topf A, Kang PB, Beggs AH, North KN, Straub V, Dowling JJ, Muntoni F, Clarke NF, Cooper ST, Bönnemann CG, MacArthur DG. Improving genetic diagnosis in Mendelian disease with transcriptome sequencing. Science Translational Medicine 2017, 9. 2017
Use of Whole-Exome Sequencing for Diagnosis of Limb-Girdle Muscular Dystrophy: Outcomes and Lessons Learned.
Ghaoui R, Cooper ST, Lek M, Jones K, Corbett A, Reddel SW, Needham M, Liang C, Waddell LB, Nicholson G, O'Grady G, Kaur S, Ong R, Davis M, Sue CM, Laing NG, North KN, MacArthur DG, Clarke NF. Use of Whole-Exome Sequencing for Diagnosis of Limb-Girdle Muscular Dystrophy: Outcomes and Lessons Learned. JAMA Neurology 2015, 72:1424-32. 2015
Diagnosis and etiology of congenital muscular dystrophy: We are halfway there.
O'Grady GL, Lek M, Lamande SR, Waddell L, Oates EC, Punetha J, Ghaoui R, Sandaradura SA, Best H, Kaur S, Davis M, Laing NG, Muntoni F, Hoffman E, MacArthur DG, Clarke NF, Cooper S, North K. Diagnosis and etiology of congenital muscular dystrophy: We are halfway there. Annals Of Neurology 2016, 80:101-11. 2016
The Challenge of Next Generation Sequencing in the Context of Neuromuscular Diseases.
Lek M, MacArthur D. The Challenge of Next Generation Sequencing in the Context of Neuromuscular Diseases. Journal Of Neuromuscular Diseases 2014, 1:135-149. 2014
The uncertain road towards genomic medicine.
MacArthur DG, Lek M. The uncertain road towards genomic medicine. Trends In Genetics : TIG 2012, 28:303-5. 2012