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1. P154 The generation of a GNE myopathy patient-derived biobank enables the study of disease-relevant cellular phenotypes across multiple pathogenic variants

Author

Koczwara, K., primary, Lake, N., additional, Huang, S., additional, DeSimone, A., additional, Pajusalu, S., additional, Branford, K., additional, Hallak, D., additional, Woodman, K., additional, Xu, J., additional, Lek, A., additional, Best, H., additional, Habib, A., additional, Avelar, J., additional, Martin, V., additional, Mozaffar, T., additional, Shieh, P., additional, Weisleder, N., additional, and Lek, M., additional

Published
2023
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5. Genome-Wide Association Study in 2,140 Patients and Subtype Meta-analyses of Barlow's Disease and Fibroelastic Deficiency Identify Novel Risk Loci for Mitral Valve Prolapse.

Author

Feirer, N., Weber, M., Knoll, K., Miranda, L., Yu, M., Lahm, H., Kameric, M., Doppler, S., Neb, I., Lichtner, P., Lek, M., Lange, R., Schunkert, H., Hagége, A., Bouatia-Naji, N., Müller-Myhsok, B., Trenkwalder, T., Gruber, P., Krane, M., and Dreßen, M.

Subjects
GENOME-wide association studies, MITRAL valve prolapse, LOCUS (Genetics), DEFICIENCY diseases, HEART valve diseases, MITRAL valve surgery
Abstract

This article discusses a genome-wide association study (GWAS) conducted on patients with mitral valve prolapse (MVP), a cardiac valve disease with a genetic component. The study aimed to identify genetic variants associated with MVP, specifically focusing on the subtypes fibroelastic deficiency (FED) and Barlow's Disease (BD). The cohort included 2,140 MVP patients, and the GWAS identified 40 loci associated with MVP. Subgroup analyses revealed two loci associated with FED and eight highly significant SNPs associated with BD. These findings may contribute to the development of personalized therapeutic approaches for MVP patients. [Extracted from the article]

Published
2024
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7. Multi-omics identifies large mitoribosomal subunit instability caused by pathogenic MRPL39 variants as a cause of pediatric onset mitochondrial disease

Author

Amarasekera, SSC, Hock, DH, Lake, NJ, Calvo, SE, Gronborg, SW, Krzesinski, E, Amor, DJ, Fahey, MC, Simons, C, Wibrand, F, Mootha, VK, Lek, M, Lunke, S, Stark, Z, ostergaard, E, Christodoulou, J, Thorburn, DR, Stroud, DA, Compton, AG, Amarasekera, SSC, Hock, DH, Lake, NJ, Calvo, SE, Gronborg, SW, Krzesinski, E, Amor, DJ, Fahey, MC, Simons, C, Wibrand, F, Mootha, VK, Lek, M, Lunke, S, Stark, Z, ostergaard, E, Christodoulou, J, Thorburn, DR, Stroud, DA, and Compton, AG

Abstract

MRPL39 encodes one of 52 proteins comprising the large subunit of the mitochondrial ribosome (mitoribosome). In conjunction with 30 proteins in the small subunit, the mitoribosome synthesizes the 13 subunits of the mitochondrial oxidative phosphorylation (OXPHOS) system encoded by mitochondrial Deoxyribonucleic acid (DNA). We used multi-omics and gene matching to identify three unrelated individuals with biallelic variants in MRPL39 presenting with multisystem diseases with severity ranging from lethal, infantile-onset (Leigh syndrome spectrum) to milder with survival into adulthood. Clinical exome sequencing of known disease genes failed to diagnose these patients; however quantitative proteomics identified a specific decrease in the abundance of large but not small mitoribosomal subunits in fibroblasts from the two patients with severe phenotype. Re-analysis of exome sequencing led to the identification of candidate single heterozygous variants in mitoribosomal genes MRPL39 (both patients) and MRPL15. Genome sequencing identified a shared deep intronic MRPL39 variant predicted to generate a cryptic exon, with transcriptomics and targeted studies providing further functional evidence for causation. The patient with the milder disease was homozygous for a missense variant identified through trio exome sequencing. Our study highlights the utility of quantitative proteomics in detecting protein signatures and in characterizing gene-disease associations in exome-unsolved patients. We describe Relative Complex Abundance analysis of proteomics data, a sensitive method that can identify defects in OXPHOS disorders to a similar or greater sensitivity to the traditional enzymology. Relative Complex Abundance has potential utility for functional validation or prioritization in many hundreds of inherited rare diseases where protein complex assembly is disrupted.

Published
2023

8. Noncoding variants alter GATA2 expression in rhombomere 4 motor neurons and cause dominant hereditary congenital facial paresis.

Author

Tenney, A.P., Gioia, S.A. Di, Webb, B.D., Chan, W.M., Boer, E. de, Garnai, S.J., Barry, B.J., Ray, T., Kosicki, M., Robson, C.D., Zhang, Zhongyang, Collins, T.E., Gelber, A., Pratt, B.M., Fujiwara, Y., Varshney, A., Lek, M., Warburton, P.E., Ryzin, C. Van, Lehky, T.J., Zalewski, C., King, K.A., Brewer, C.C., Thurm, A., Snow, J., Facio, F.M., Narisu, N., Bonnycastle, L.L., Swift, A., Chines, P.S., Bell, J.L., Mohan, S., Whitman, M.C., Staffieri, S.E., Elder, J.E., Demer, J.L., Torres, A., Rachid, E., Al-Haddad, C., Boustany, R.M., Mackey, D.A., Brady, A.F., Fenollar-Cortés, M., Fradin, M., Kleefstra, T., Padberg, G.W., Raskin, S., Sato, M.T., Orkin, S.H., Parker, S.C.J., Hadlock, T.A., Vissers, L.E.L.M., Bokhoven, H. van, Jabs, E.W., Collins, F.S., Pennacchio, L.A., Manoli, I., Engle, E.C., Tenney, A.P., Gioia, S.A. Di, Webb, B.D., Chan, W.M., Boer, E. de, Garnai, S.J., Barry, B.J., Ray, T., Kosicki, M., Robson, C.D., Zhang, Zhongyang, Collins, T.E., Gelber, A., Pratt, B.M., Fujiwara, Y., Varshney, A., Lek, M., Warburton, P.E., Ryzin, C. Van, Lehky, T.J., Zalewski, C., King, K.A., Brewer, C.C., Thurm, A., Snow, J., Facio, F.M., Narisu, N., Bonnycastle, L.L., Swift, A., Chines, P.S., Bell, J.L., Mohan, S., Whitman, M.C., Staffieri, S.E., Elder, J.E., Demer, J.L., Torres, A., Rachid, E., Al-Haddad, C., Boustany, R.M., Mackey, D.A., Brady, A.F., Fenollar-Cortés, M., Fradin, M., Kleefstra, T., Padberg, G.W., Raskin, S., Sato, M.T., Orkin, S.H., Parker, S.C.J., Hadlock, T.A., Vissers, L.E.L.M., Bokhoven, H. van, Jabs, E.W., Collins, F.S., Pennacchio, L.A., Manoli, I., and Engle, E.C.

Abstract

01 juli 2023, Item does not contain fulltext, Hereditary congenital facial paresis type 1 (HCFP1) is an autosomal dominant disorder of absent or limited facial movement that maps to chromosome 3q21-q22 and is hypothesized to result from facial branchial motor neuron (FBMN) maldevelopment. In the present study, we report that HCFP1 results from heterozygous duplications within a neuron-specific GATA2 regulatory region that includes two enhancers and one silencer, and from noncoding single-nucleotide variants (SNVs) within the silencer. Some SNVs impair binding of NR2F1 to the silencer in vitro and in vivo and attenuate in vivo enhancer reporter expression in FBMNs. Gata2 and its effector Gata3 are essential for inner-ear efferent neuron (IEE) but not FBMN development. A humanized HCFP1 mouse model extends Gata2 expression, favors the formation of IEEs over FBMNs and is rescued by conditional loss of Gata3. These findings highlight the importance of temporal gene regulation in development and of noncoding variation in rare mendelian disease.

Published
2023

9. Data safety prediction using YOLOv7+G3HN for traffic roads

Author

Lek Ming Lim, Lu Yang, Ahmad Sufril Azlan Mohamed, and Majid Khan Majahar Ali

Subjects
Vehicle detection, Near miss detection, YOLOv7+G3HN, Machine Learning, Physics, QC1-999
Abstract

Pulau Pinang has introduced several measures to enhance traffic safety and promote sustainability, including the installation of CCTV systems and the implementation of smart solutions and green technology as part of the Penang 2030 vision, aligning with the Sustainable Development Goals (SDGs). However, despite these efforts, road accidents persist due to non-optimised detection models, incomplete data from manual reporting, and technological constraints in real-time video analysis and predictive modelling. This study evaluates the effectiveness of the YOLOv7+G3HN framework for vehicle detection and near-miss analysis, with a focus on the influence of video quality on detection performance. The research aims to understand how high- and low-quality video inputs affect the accuracy and computational efficiency of detection algorithms. High[1]quality videos resulted in significantly faster computation times for vehicle detection than low-quality videos, highlighting the importance of video resolution in optimising detection processes. Despite the robustness of the algorithm, with no errors detected in both video qualities, higher miss detection rates in low-quality videos suggest that lower resolution may compromise detection accuracy and the effectiveness of monitoring systems. Near-miss analysis revealed that high-quality videos had a lower probability of near-miss occurrences than low-quality videos, highlighting the importance of video resolution for detection efficacy. These findings emphasise the critical role of high-resolution video inputs in enhancing detection accuracy and reliability, advocating for their implementation to optimise vehicle detection and improve road safety. Additionally, YOLOv7+G3HN outperforms YOLOv7 in both accuracy and speed. The study concludes that the YOLOv7+G3HN framework is effective for vehicle detection and near-miss analysis, provided that video quality is considered in system design and implementation.

Published
2024
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10. Testing the performance of the Milankovi�� telescope

Author

Vudragovi��, A., B��lek, M., M��ller, O., Samurovi��, S., and Jovanovi��, M.

Subjects
Astrophysics of Galaxies (astro-ph.GA), FOS: Physical sciences
Abstract

We have undertaken a multi-band imaging campaign of several galaxies to study their low surface brightness features such as shells and streams. Using the 1.4-m Milankovi�� telescope, we measured the surface brightness limits in various bands depending on the exposure time. Remarkably, within three to four hours of observations with the $L$-filter we reached the surface brightness limit of $��_g$=28.5-29.0 mag/arcsec$^2$. We have confirmed the faint stream of the elliptical galaxy NGC\,474 discovered with MegaCam. The comparison to other deep photometric surveys has revealed that within few hours of observations we can produce competitive results, showing that the Milankovi�� telescope can be a valuable asset in the study of the low-surface brightness Universe., Accepted for publication by the Publications de l'Observatoire Astronomique de Belgrade

Published
2021
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11. The mutational constraint spectrum quantified from variation in 141,456 humans

Author

Karczewski, KJ, Francioli, LC, Tiao, G, Cummings, BB, Alföldi, J, Wang, Q, Collins, RL, Laricchia, KM, Ganna, A, Birnbaum, DP, Gauthier, LD, Brand, H, Solomonson, M, Watts, NA, Rhodes, D, Singer-Berk, M, England, EM, Seaby, EG, Kosmicki, JA, Walters, RK, Tashman, K, Farjoun, Y, Banks, E, Poterba, T, Wang, A, Seed, C, Whiffin, N, Chong, JX, Samocha, KE, Pierce-Hoffman, E, Zappala, Z, O’Donnell-Luria, AH, Vallabh Minikel, E, Weisburd, B, Lek, M, Ware, JS, Vittal, C, Armean, IM, Bergelson, L, Cibulskis, K, Connolly, JM, Covarrubias, M, Donnelly, S, Ferriera, S, Gabriel, S, Gentry, J, Gupta, N, Jeandet, T, Kaplan, D, Llanwarne, C, Munshi, J, Novod, S, Petrillo, N, Roazen, D, Ruano-Rubio, V, Saltzman, A, Schleicher, M, Soto, J, Tibbetts, K, Tolonen, C, Wade, G, Talkowski, ME, Genome Aggregation Database (gnomAD) Consortium, Neale, BM, Daly, MJ, MacArthur, DG, Tampere University, Clinical Medicine, Department of Clinical Chemistry, Wellcome Trust, Rosetrees Trust, Institute for Molecular Medicine Finland, Data Science Genetic Epidemiology Lab, Centre of Excellence in Complex Disease Genetics, Department of Medicine, Clinicum, Gastroenterologian yksikkö, HUS Abdominal Center, University Management, HUS Psychiatry, Department of Psychiatry, HUS Neurocenter, Department of Neurosciences, Neurologian yksikkö, Department of Public Health, Aarno Palotie / Principal Investigator, Genomics of Neurological and Neuropsychiatric Disorders, Samuli Olli Ripatti / Principal Investigator, Complex Disease Genetics, Biostatistics Helsinki, Doctoral Programme in Clinical Research, and Biosciences

Subjects
Male, Mutation rate, ved/biology.organism_classification_rank.species, VARIANTS, Genome, Whole Exome Sequencing, Cohort Studies, 0302 clinical medicine, Mutation Rate, Loss of Function Mutation, Databases, Genetic, Exome, Organism, Exome sequencing, 0303 health sciences, Genes, Essential, Multidisciplinary, 1184 Genetics, developmental biology, physiology, Brain, Phenotype, Multidisciplinary Sciences, Cardiovascular Diseases, Science & Technology - Other Topics, Female, Proprotein Convertase 9, BURDEN, Medical genomics, Adult, General Science & Technology, Computational biology, Biology, 3121 Internal medicine, Article, 03 medical and health sciences, Humans, Genetic Predisposition to Disease, RNA, Messenger, Model organism, Gene, 030304 developmental biology, Science & Technology, Whole Genome Sequencing, Genome, Human, ved/biology, Genetic Variation, Reproducibility of Results, Rare variants, MODEL, DE-NOVO MUTATIONS, Genome Aggregation Database Consortium, 3111 Biomedicine, 030217 neurology & neurosurgery, Function (biology), Genome-Wide Association Study
Abstract

Genetic variants that inactivate protein-coding genes are a powerful source of information about the phenotypic consequences of gene disruption: genes that are crucial for the function of an organism will be depleted of such variants in natural populations, whereas non-essential genes will tolerate their accumulation. However, predicted loss-of-function variants are enriched for annotation errors, and tend to be found at extremely low frequencies, so their analysis requires careful variant annotation and very large sample sizes1. Here we describe the aggregation of 125,748 exomes and 15,708 genomes from human sequencing studies into the Genome Aggregation Database (gnomAD). We identify 443,769 high-confidence predicted loss-of-function variants in this cohort after filtering for artefacts caused by sequencing and annotation errors. Using an improved model of human mutation rates, we classify human protein-coding genes along a spectrum that represents tolerance to inactivation, validate this classification using data from model organisms and engineered human cells, and show that it can be used to improve the power of gene discovery for both common and rare diseases., A catalogue of predicted loss-of-function variants in 125,748 whole-exome and 15,708 whole-genome sequencing datasets from the Genome Aggregation Database (gnomAD) reveals the spectrum of mutational constraints that affect these human protein-coding genes.

Published
2020

12. The mutational constraint spectrum quantified from variation in 141,456 humans (vol 581, pg 434, 2020)

Author

Gudmundsson, S, Karczewski, KJ, Francioli, LC, Tiao, G, Cummings, BB, Alfoldi, J, Wang, Q, Collins, RL, Laricchia, KM, Ganna, A, Birnbaum, DP, Gauthier, LD, Brand, H, Solomonson, M, Watts, NA, Rhodes, D, Singer-Berk, M, England, EM, Seaby, EG, Kosmicki, JA, Walters, RK, Tashman, K, Farjoun, Y, Banks, E, Poterba, T, Wang, A, Seed, C, Whiffin, N, Chong, JX, Samocha, KE, Pierce-Hoffman, E, Zappala, Z, O'Donnell-Luria, AH, Minikel, EV, Weisburd, B, Lek, M, Ware, JS, Vittal, C, Armean, IM, Bergelson, L, Cibulskis, K, Connolly, KM, Covarrubias, M, Donnelly, S, Ferriera, S, Gabriel, S, Gentry, J, Gupta, N, Jeandet, T, Kaplan, D, Llanwarne, C, Munshi, R, Novod, S, Petrillo, N, Roazen, D, Ruano-Rubio, V, Saltzman, A, Schleicher, M, Soto, J, Tibbetts, K, Tolonen, C, Wade, G, Talkowski, ME, Neale, BM, Daly, MJ, and MacArthur, DG

Subjects
Multidisciplinary Sciences, Science & Technology, General Science & Technology, Genome Aggregation Database Consortium, Science & Technology - Other Topics, OF-FUNCTION VARIANTS
Published
2020

13. Low-frequency variation in TP53 has large effects on head circumference and intracranial volume

Author

Haworth, S, Shapland, CY, Hayward, C, Prins, BP, Felix, JF, Medina-Gomez, C, Rivadeneira, F, Wang, C, Ahluwalia, TS, Vrijheid, M, Guxens, M, Sunyer, J, Tachmazidou, I, Walter, K, Iotchkova, V, Jackson, A, Cleal, L, Huffmann, J, Min, JL, Sass, L, Timmers, PRHJ, Al Turki, S, Anderson, CA, Anney, R, Antony, D, Artigas, MS, Ayub, M, Bala, S, Barrett, JC, Barroso, I, Beales, P, Bentham, J, Bhattacharya, S, Birney, E, Blackwood, D, Bobrow, M, Bochukova, E, Bolton, PF, Bounds, R, Boustred, C, Breen, G, Calissano, M, Carss, K, Charlton, R, Chatterjee, K, Chen, L, Ciampi, A, Cirak, S, Clapham, P, Clement, G, Coates, G, Cocca, M, Collier, DA, Cosgrove, C, Cox, T, Craddock, N, Crooks, L, Curran, S, Curtis, D, Daly, A, Danecek, P, Day, INM, Day-Williams, A, Dominiczak, A, Down, T, Du, Y, Dunham, I, Durbin, R, Edkins, S, Ekong, R, Ellis, P, Evans, DM, Farooqi, IS, Fitzpatrick, DR, Flicek, P, Floyd, J, Foley, AR, Franklin, CS, Futema, M, Gallagher, L, Gaunt, TR, Geihs, M, Geschwind, D, Greenwood, CMT, Griffin, H, Grozeva, D, Guo, X, Gurling, H, Hart, D, Hendricks, AE, Holmans, P, Howie, B, Huang, J, Huang, L, Hubbard, T, Humphries, SE, Hurles, ME, Hysi, P, Jackson, DK, Jamshidi, Y, Joyce, C, Karczewski, KJ, Kaye, J, Keane, T, Kemp, JP, Kennedy, K, Kent, A, Keogh, J, Khawaja, F, van Kogelenberg, M, Kolb-Kokocinski, A, Lachance, G, Langford, C, Lawson, D, Lee, I, Lek, M, Li, R, Li, Y, Liang, J, Lin, H, Liu, R, Lonnqvist, J, Lopes, LR, Lopes, M, MacArthur, DG, Mangino, M, Marchini, J, Marenne, G, Maslen, J, Mathieson, I, McCarthy, S, McGuffin, P, McIntosh, AM, McKechanie, AG, McQuillin, A, Memari, Y, Metrustry, S, Migone, N, Mitchison, HM, Moayyeri, A, Morris, A, Morris, J, Muddyman, D, Muntoni, F, Northstone, K, O'Donovan, MC, O'Rahilly, S, Onoufriadis, A, Oualkacha, K, Owen, MJ, Palotie, A, Panoutsopoulou, K, Parker, V, Parr, JR, Paternoster, L, Paunio, T, Payne, F, Payne, SJ, Perry, JRB, Pietilainen, O, Plagnol, V, Pollitt, RC, Porteous, DJ, Povey, S, Quail, MA, Quaye, L, Raymond, FL, Rehnstrom, K, Richards, JB, Ridout, CK, Ring, S, Ritchie, GRS, Roberts, N, Robinson, RL, Savage, DB, Scambler, P, Schiffels, S, Schmidts, M, Schoenmakers, N, Scott, RH, Semple, RK, Serra, E, Sharp, SI, Shaw, A, Shihab, HA, Shin, S-Y, Skuse, D, Small, KS, Smee, C, Smith, BH, Soranzo, N, Southam, L, Spasic-Boskovic, O, Spector, TD, St Clair, D, Stalker, J, Stevens, E, Sun, J, Surdulescu, G, Suvisaari, J, Syrris, P, Taylor, R, Tian, J, Tobin, MD, Valdes, AM, Vandersteen, AM, Vijayarangakannan, P, Visscher, PM, Wain, LV, Walters, JTR, Wang, G, Wang, J, Wang, Y, Ward, K, Wheeler, E, Whyte, T, Williams, HJ, Williamson, KA, Wilson, C, Wilson, SG, Wong, K, Xu, C, Yang, J, Zhang, F, Zhang, P, Zheng, H-F, Smith, GD, Fisher, SE, Wilson, JF, Cole, TJ, Fernandez-Orth, D, Bonnelykke, K, Bisgaard, H, Pennell, CE, Jaddoe, VWV, Dedoussis, G, Timpson, N, Zeggini, E, Vitart, V, St Pourcain, B, UK10K Consortium, Epidemiology, Erasmus MC other, Pediatrics, Internal Medicine, and Child and Adolescent Psychiatry / Psychology

Abstract

Cranial growth and development is a complex process which affects the closely related traits of head circumference (HC) and intracranial volume (ICV). The underlying genetic influences shaping these traits during the transition from childhood to adulthood are little understood, but might include both age-specific genetic factors and low-frequency genetic variation. Here, we model the developmental genetic architecture of HC, showing this is genetically stable and correlated with genetic determinants of ICV. Investigating up to 46,000 children and adults of European descent, we identify association with final HC and/or final ICV + HC at 9 novel common and low-frequency loci, illustrating that genetic variation from a wide allele frequency spectrum contributes to cranial growth. The largest effects are reported for low-frequency variants within TP53, with 0.5 cm wider heads in increaser-allele carriers versus non-carriers during mid-childhood, suggesting a previously unrecognized role of TP53 transcripts in human cranial development.

Published
2019

14. A recurrent COL6A1 pseudoexon insertion causes muscular dystrophy and is effectively targeted by splice-correction therapies

Author

Bolduc V, Foley AR, Solomon-Degefa H, Sarathy A, Donkervoort S, Hu Y, Chen GS, Sizov K, Nalls M, Zhou H, Aguti S, Cummings BB, Lek M, Tukiainen T, Marshall JL, Regev O, Marek-Yagel D, Sarkozy A, Butterfield RJ, Jou-Munoz C, Jimenez-Mallebrera C, Li Y, Gartioux C, Mamchaoui K, Allamand V, Gualandi F, Ferlini A, Hanssen E, COL6A1 Intron 11 Study Group, Wilton SD, Lamandé SR, MacArthur DG, Wagener R, Muntoni F, and Bönnemann CG

Subjects
Collagens, Neuromuscular disease, Muscle Biology, Extracellular matrix, Therapeutics
Abstract

The clinical application of advanced next-generation sequencing technologies is increasingly uncovering novel classes of mutations that may serve as potential targets for precision medicine therapeutics. Here, we show that a deep intronic splice defect in the COL6A1 gene, originally discovered by applying muscle RNA sequencing in patients with clinical findings of collagen VI-related dystrophy (COL6-RD), inserts an in-frame pseudoexon into COL6A1 mRNA, encodes a mutant collagen a1(VI) protein that exerts a dominant-negative effect on collagen VI matrix assembly, and provides a unique opportunity for splice-correction approaches aimed at restoring normal gene expression. Using splice-modulating antisense oligomers, we efficiently skipped the pseudoexon in patient-derived fibroblast cultures and restored a wild-type matrix. Similarly, we used CRISPR/Cas9 to precisely delete an intronic sequence containing the pseudoexon and efficiently abolish its inclusion while preserving wild-type splicing. Considering that this splice defect is emerging as one of the single most frequent mutations in COL6-RD, the design of specific and effective splice-correction therapies offers a promising path for clinical translation.

Published
2019

15. A recurrent COL6A1 pseudoexon insertion causes muscular dystrophy and is effectively targeted by splice-correction therapies

Author

Bolduc, V, Foley, A.R., Solomon-Degefa, H., Sarathy, A., Donkervoort, S., Hu, Y., Chen, G.S., Sizov, K., Nalls, M., Zhou, H., Aguti, S., Cummings, B.B., Lek, M., Tukiainen, T., Marshall, J.L., Regev, O., Marek-Yagel, D., Sarkozy, A., Butterfield, R.J., Jou, C., Jimenez-Mallebrera, C., Li, Y., Gartioux, C., Mamchaoui, K., Allamand, V., Gualandi, F., Ferlini, A., Hanssen, E., Wilton, S.D., Lamandé, S.R., MacArthur, D.G., Wagener, R., Muntoni, F., Bönnemann, C.G., Bolduc, V, Foley, A.R., Solomon-Degefa, H., Sarathy, A., Donkervoort, S., Hu, Y., Chen, G.S., Sizov, K., Nalls, M., Zhou, H., Aguti, S., Cummings, B.B., Lek, M., Tukiainen, T., Marshall, J.L., Regev, O., Marek-Yagel, D., Sarkozy, A., Butterfield, R.J., Jou, C., Jimenez-Mallebrera, C., Li, Y., Gartioux, C., Mamchaoui, K., Allamand, V., Gualandi, F., Ferlini, A., Hanssen, E., Wilton, S.D., Lamandé, S.R., MacArthur, D.G., Wagener, R., Muntoni, F., and Bönnemann, C.G.

Abstract

The clinical application of advanced next-generation sequencing technologies is increasingly uncovering novel classes of mutations that may serve as potential targets for precision medicine therapeutics. Here, we show that a deep intronic splice defect in the COL6A1 gene, originally discovered by applying muscle RNA sequencing in patients with clinical findings of collagen VI–related dystrophy (COL6-RD), inserts an in-frame pseudoexon into COL6A1 mRNA, encodes a mutant collagen α1(VI) protein that exerts a dominant-negative effect on collagen VI matrix assembly, and provides a unique opportunity for splice-correction approaches aimed at restoring normal gene expression. Using splice-modulating antisense oligomers, we efficiently skipped the pseudoexon in patient-derived fibroblast cultures and restored a wild-type matrix. Similarly, we used CRISPR/Cas9 to precisely delete an intronic sequence containing the pseudoexon and efficiently abolish its inclusion while preserving wild-type splicing. Considering that this splice defect is emerging as one of the single most frequent mutations in COL6-RD, the design of specific and effective splice-correction therapies offers a promising path for clinical translation.

Published
2019

16. Low-frequency variation in TP53 has large effects on head circumference and intracranial volume

Author

Haworth, S., Shapland, C.Y., Hayward, C. (Caroline), Prins, B.P. (Bram), Felix, J.F. (Janine), Medina-Gomez, M.C. (Carolina), Rivadeneira Ramirez, F. (Fernando), Wang, C., Ahluwalia, TS, Vrijheid, M. (Martine), Guxens Junyent, M. (Mònica), Sunyer, J. (Jordi), Tachmazidou, I, Walter, K., Iotchkova, V, Jackson, A.U. (Anne), Cleal, L., Huffmann, J., Min, J. (Josine), Sass, L., Timmers, P, Al Turki, S., Anderson, CA, Anney, R. (Richard), Antony, D, Soler Artigas, M. (Maria), Ayub, M, Bala, S, Barrett, JC, Barroso, I.E. (Inês), Beales, P., Bentham, J, Bhattacharya, S. (Shoumo), Birney, E. (Ewan), Blackwood, D, Bobrow, M, Bochukova, E, Bolton, PF, Bounds, R, Boustred, C, Breen, G. (Gerome), Calissano, M, Carss, K, Charlton, R, Chatterjee, K. (Krishna), Chen, L. (Leslie), Ciampi, A. (Antonio), Cirak, S, Clapham, P, Clement, G, Coates, G, Cocca, M, Collier, D.A. (David), Cosgrove, C, Cox, T. (Tessa), Craddock, N.J. (Nick), Crooks, L, Curran, S, Curtis, D. (David), Daly, A, Danecek, P, Day, I.N.M. (Ian), Day-Williams, A, Dominiczak, A. (Anna), Down, T, Li, Y. (Yingrui), Dunham, D.M. (David), Durbin, R, Edkins, T. (Ted), Ekong, R. (Rosemary), Ellis, P. (Paul), Evans, D.M. (David), Farooqi, I.S. (Sadaf), Fitzpatrick, D.R. (David), Flicek, P, Floyd, J. (Jamie), Foley, AR, Franklin, C.S. (Christopher), Futema, M, Gallagher, L. (Louise), Gaunt, T.R. (Tom), Geihs, M, Geschwind, D., Greenwood, J.P. (John), Griffin, H, Grozeva, D. (Detelina), Guo, X.S., Guo, X. (Xiuqing), Gurling, H. (Hugh), Hart, D.J. (Deborah), Hendricks, AE, Holmans, P.A. (Peter), Howie, B, Huang, J. (Jian), Huang, L.R., Hubbard, T., Humphries, S.E. (Steve), Hurles, M.E. (Matthew), Hysi, P.G. (Pirro), Jackson, DK, Jamshidi, Y. (Yalda), Joyce, C, Karczewski, KJ, Kaye, J. (Jane), Keane, T, Kemp, J.P., Kennedy, K. (Karen), Kent, A. (Alistair), Keogh, J, Khawaja, F, van Kogelenberg, M., Kolb-Kokocinski, A, Lachance, G, Langford, C. (Cordelia), Lawson, D, Lee, I. van der, Lek, M, Li, R. (Rui), Li, Y.R. (Yun), Liang, J.Q., Lin, H., Liu, R, Lonnqvist, J, Lopes, LR, Lopes, M., MacArthur, DG, Mangino, M. (Massimo), Marchini, J. (Jonathan), Marenne, G., Maslen, J., Mathieson, I. (Iain), McCarthy, S. (Sean), Mcguffin, P. (Peter), Mcintosh, A.M. (Andrew), McKechanie, AG, McQuillin, A. (Andrew), Memari, Y, Metrustry, S. (Sarah), Migone, N, Mitchison, H.M. (Hannah), Moayyeri, A. (Alireza), Morris, A.D. (Andrew), Morris, J, Muddyman, D, Muntoni, F., Northstone, K. (Kate), O'Donovan, M. (Michael), O'Rahilly, S. (Stephen), Onoufriadis, A, Oualkacha, K., Owen, M.J., Palotie, A. (Aarno), Panoutsopoulou, K, Parker, V., Parr, D., Paternoster, L. (Lavinia), Paunio, T, Payne, F. (Felicity), Payne, SJ, Perry, J.B. (John), Pietiläinen, O.P.H. (Olli), Plagnol, V, Pollitt, RC, Porteous, D.J. (David J.), Povey, S. (Sue), Quail, MA, Quaye, L. (Lydia), Raymond, FL, Rehnström, K. (Karola), Richards, J.B. (Brent), Ridout, CK, Ring, S.M. (Susan), Ritchie, GRS, Roberts, N. (Nicola), Robinson, RL, Savage, D.B. (David), Scambler, P., Schiffels, S, Schmidts, M, Schoenmakers, N. (Nadia), Scott, RH, Semple, R.K. (Robert), Serra, E, Sharp, S.I., Shaw, A. (Alison), Shihab, HA, Shin, S.-Y., Skuse, D, Small, K.S. (Kerrin), Smee, C, Smith, B.H. (Blair), Soranzo, N. (Nicole), Southam, L. (Lorraine), Spasic-Boskovic, O, Spector, T.D. (Timothy), St. Clair, D. (David), Stalker, J, Stevens, E, Sun, J.P., Surdulescu, G, Suvisaari, J. (Jaana), Syrris, P, R. Taylor (Rohan), Tian, J., Tobin, M.D. (Martin), Valdes, A.M. (Ana Maria), Vandersteen, AM, Vijayarangakannan, P, Visscher, P.M. (Peter), Wain, L.V. (Louise), Walters, JTR, Wang, G. B., Wang, J. (Jinxia), Wang, Y. (Ying), Ward, K, Wheeler, E. (Eleanor), Whyte, T, Williams, HJ, Williamson, K.A., Wilson, C, Wilson, S.G. (Scott), Wong, K. (Kenny), Xu, CJ, Yang, J. (Jian), Zhang, F. (Feng), Zhang, P.B., Zheng, H.-F. (Hou-Feng), Smith, A.V. (Davey), Fisher, SE, Wilson, J.F. (James F), Cole, T.J. (T.), Fernandez-Orth, D., Bønnelykke, K. (Klaus), Bisgaard, H. (Hans), Pennell, C.E. (Craig), Jaddoe, V.W.V. (Vincent), Dedoussis, G, Timpson, N.J. (Nicholas), Zeggini, E. (Eleftheria), Vitart, V. (Veronique), Pourcain, B.S. (Beate), Haworth, S., Shapland, C.Y., Hayward, C. (Caroline), Prins, B.P. (Bram), Felix, J.F. (Janine), Medina-Gomez, M.C. (Carolina), Rivadeneira Ramirez, F. (Fernando), Wang, C., Ahluwalia, TS, Vrijheid, M. (Martine), Guxens Junyent, M. (Mònica), Sunyer, J. (Jordi), Tachmazidou, I, Walter, K., Iotchkova, V, Jackson, A.U. (Anne), Cleal, L., Huffmann, J., Min, J. (Josine), Sass, L., Timmers, P, Al Turki, S., Anderson, CA, Anney, R. (Richard), Antony, D, Soler Artigas, M. (Maria), Ayub, M, Bala, S, Barrett, JC, Barroso, I.E. (Inês), Beales, P., Bentham, J, Bhattacharya, S. (Shoumo), Birney, E. (Ewan), Blackwood, D, Bobrow, M, Bochukova, E, Bolton, PF, Bounds, R, Boustred, C, Breen, G. (Gerome), Calissano, M, Carss, K, Charlton, R, Chatterjee, K. (Krishna), Chen, L. (Leslie), Ciampi, A. (Antonio), Cirak, S, Clapham, P, Clement, G, Coates, G, Cocca, M, Collier, D.A. (David), Cosgrove, C, Cox, T. (Tessa), Craddock, N.J. (Nick), Crooks, L, Curran, S, Curtis, D. (David), Daly, A, Danecek, P, Day, I.N.M. (Ian), Day-Williams, A, Dominiczak, A. (Anna), Down, T, Li, Y. (Yingrui), Dunham, D.M. (David), Durbin, R, Edkins, T. (Ted), Ekong, R. (Rosemary), Ellis, P. (Paul), Evans, D.M. (David), Farooqi, I.S. (Sadaf), Fitzpatrick, D.R. (David), Flicek, P, Floyd, J. (Jamie), Foley, AR, Franklin, C.S. (Christopher), Futema, M, Gallagher, L. (Louise), Gaunt, T.R. (Tom), Geihs, M, Geschwind, D., Greenwood, J.P. (John), Griffin, H, Grozeva, D. (Detelina), Guo, X.S., Guo, X. (Xiuqing), Gurling, H. (Hugh), Hart, D.J. (Deborah), Hendricks, AE, Holmans, P.A. (Peter), Howie, B, Huang, J. (Jian), Huang, L.R., Hubbard, T., Humphries, S.E. (Steve), Hurles, M.E. (Matthew), Hysi, P.G. (Pirro), Jackson, DK, Jamshidi, Y. (Yalda), Joyce, C, Karczewski, KJ, Kaye, J. (Jane), Keane, T, Kemp, J.P., Kennedy, K. (Karen), Kent, A. (Alistair), Keogh, J, Khawaja, F, van Kogelenberg, M., Kolb-Kokocinski, A, Lachance, G, Langford, C. (Cordelia), Lawson, D, Lee, I. van der, Lek, M, Li, R. (Rui), Li, Y.R. (Yun), Liang, J.Q., Lin, H., Liu, R, Lonnqvist, J, Lopes, LR, Lopes, M., MacArthur, DG, Mangino, M. (Massimo), Marchini, J. (Jonathan), Marenne, G., Maslen, J., Mathieson, I. (Iain), McCarthy, S. (Sean), Mcguffin, P. (Peter), Mcintosh, A.M. (Andrew), McKechanie, AG, McQuillin, A. (Andrew), Memari, Y, Metrustry, S. (Sarah), Migone, N, Mitchison, H.M. (Hannah), Moayyeri, A. (Alireza), Morris, A.D. (Andrew), Morris, J, Muddyman, D, Muntoni, F., Northstone, K. (Kate), O'Donovan, M. (Michael), O'Rahilly, S. (Stephen), Onoufriadis, A, Oualkacha, K., Owen, M.J., Palotie, A. (Aarno), Panoutsopoulou, K, Parker, V., Parr, D., Paternoster, L. (Lavinia), Paunio, T, Payne, F. (Felicity), Payne, SJ, Perry, J.B. (John), Pietiläinen, O.P.H. (Olli), Plagnol, V, Pollitt, RC, Porteous, D.J. (David J.), Povey, S. (Sue), Quail, MA, Quaye, L. (Lydia), Raymond, FL, Rehnström, K. (Karola), Richards, J.B. (Brent), Ridout, CK, Ring, S.M. (Susan), Ritchie, GRS, Roberts, N. (Nicola), Robinson, RL, Savage, D.B. (David), Scambler, P., Schiffels, S, Schmidts, M, Schoenmakers, N. (Nadia), Scott, RH, Semple, R.K. (Robert), Serra, E, Sharp, S.I., Shaw, A. (Alison), Shihab, HA, Shin, S.-Y., Skuse, D, Small, K.S. (Kerrin), Smee, C, Smith, B.H. (Blair), Soranzo, N. (Nicole), Southam, L. (Lorraine), Spasic-Boskovic, O, Spector, T.D. (Timothy), St. Clair, D. (David), Stalker, J, Stevens, E, Sun, J.P., Surdulescu, G, Suvisaari, J. (Jaana), Syrris, P, R. Taylor (Rohan), Tian, J., Tobin, M.D. (Martin), Valdes, A.M. (Ana Maria), Vandersteen, AM, Vijayarangakannan, P, Visscher, P.M. (Peter), Wain, L.V. (Louise), Walters, JTR, Wang, G. B., Wang, J. (Jinxia), Wang, Y. (Ying), Ward, K, Wheeler, E. (Eleanor), Whyte, T, Williams, HJ, Williamson, K.A., Wilson, C, Wilson, S.G. (Scott), Wong, K. (Kenny), Xu, CJ, Yang, J. (Jian), Zhang, F. (Feng), Zhang, P.B., Zheng, H.-F. (Hou-Feng), Smith, A.V. (Davey), Fisher, SE, Wilson, J.F. (James F), Cole, T.J. (T.), Fernandez-Orth, D., Bønnelykke, K. (Klaus), Bisgaard, H. (Hans), Pennell, C.E. (Craig), Jaddoe, V.W.V. (Vincent), Dedoussis, G, Timpson, N.J. (Nicholas), Zeggini, E. (Eleftheria), Vitart, V. (Veronique), and Pourcain, B.S. (Beate)

Abstract

Cranial growth and development is a complex process which affects the closely related traits of head circumference (HC) and intracranial volume (ICV). The underlying genetic influences shaping these traits during the transition from childhood to adulthood are little understood, but might include both age-specific genetic factors and low-frequency genetic variation. Here, we model the developmental genetic architecture of HC, showing this is genetically stable and correlated with genetic determinants of ICV. Investigating up to 46,000 children and adults of European descent, we identify association with final HC and/or final ICV + HC at 9 novel common and low-frequency loci, illustrating that genetic variation from a wide allele frequency spectrum contributes to cranial growth. The largest effects are reported for lowfrequency variants within TP53, with 0.5 cm wider heads in increaser-allele carriers versus non-carrie

Published
2019
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17. MOLECULAR THERAPEUTIC APPROACHES

Author

Best, H., primary, Woodman, K., additional, Lek, A., additional, Koczwara, K., additional, Xu, E., additional, Aykanat, A., additional, Jiang, Y., additional, Saltzman, M., additional, Beggs, A., additional, and Lek, M., additional

Published
2019
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18. O.10A novel target for splice-modulating therapies: a common pseudoexon-inducing mutation that causes a severe collagen VI-related muscular dystrophy

Author

Bolduc, V., primary, Foley, A., additional, Solomon Degefa, H., additional, Sarathy, A., additional, Donkervoort, S., additional, Hu, Y., additional, Zhou, H., additional, Cummings, B., additional, Lek, M., additional, Regev, O., additional, Jimenez-Mallebrera, C., additional, Allamand, V., additional, Ferlini, A., additional, Wilton, S., additional, Hanssen, E., additional, Lamandé, S., additional, MacArthur, D., additional, Wagener, R., additional, Muntoni, F., additional, and Bönnemann, C., additional

Published
2019
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19. Whole-Exome Sequencing Identifies Causative Mutations in Families with Congenital Anomalies of the Kidney and Urinary Tract.

Author

Ven, A.T. van der, Connaughton, D.M., Ityel, H., Mann, N., Nakayama, M., Chen, J., Vivante, A., Hwang, D.Y., Schulz, J, Braun, D.A., Schmidt, J.M., Schapiro, D., Schneider, R., Warejko, J.K., Daga, A., Majmundar, A.J., Tan, W., Jobst-Schwan, T., Hermle, T., Widmeier, E., Ashraf, S., Amar, A., Hoogstraten, C.A., Hugo, H., Kitzler, T.M., Kause, F., Kolvenbach, C.M., Dai, R., Spaneas, L., Amann, K., Stein, D.R., Baum, M.A., Somers, M.J.G., Rodig, N.M., Ferguson, M.A., Traum, A.Z., Daouk, G.H., Bogdanovic, R., Stajic, N., Soliman, N.A., Kari, J.A., Desoky, S. El, Fathy, H.M., Milosevic, D., Al-Saffar, M., Awad, H.S., Eid, L.A., Selvin, A., Senguttuvan, P., Sanna-Cherchi, S., Rehm, H.L., MacArthur, D.G., Lek, M., Laricchia, K.M., Wilson, M.W., Mane, S.M., Lifton, R.P., Lee, R.S., Bauer, S.B., Lu, W., Reutter, H.M., Tasic, V., Shril, S., Hildebrandt, F., Ven, A.T. van der, Connaughton, D.M., Ityel, H., Mann, N., Nakayama, M., Chen, J., Vivante, A., Hwang, D.Y., Schulz, J, Braun, D.A., Schmidt, J.M., Schapiro, D., Schneider, R., Warejko, J.K., Daga, A., Majmundar, A.J., Tan, W., Jobst-Schwan, T., Hermle, T., Widmeier, E., Ashraf, S., Amar, A., Hoogstraten, C.A., Hugo, H., Kitzler, T.M., Kause, F., Kolvenbach, C.M., Dai, R., Spaneas, L., Amann, K., Stein, D.R., Baum, M.A., Somers, M.J.G., Rodig, N.M., Ferguson, M.A., Traum, A.Z., Daouk, G.H., Bogdanovic, R., Stajic, N., Soliman, N.A., Kari, J.A., Desoky, S. El, Fathy, H.M., Milosevic, D., Al-Saffar, M., Awad, H.S., Eid, L.A., Selvin, A., Senguttuvan, P., Sanna-Cherchi, S., Rehm, H.L., MacArthur, D.G., Lek, M., Laricchia, K.M., Wilson, M.W., Mane, S.M., Lifton, R.P., Lee, R.S., Bauer, S.B., Lu, W., Reutter, H.M., Tasic, V., Shril, S., and Hildebrandt, F.

Abstract

1 september 2018, Item does not contain fulltext, BACKGROUND: Congenital anomalies of the kidney and urinary tract (CAKUT) are the most prevalent cause of kidney disease in the first three decades of life. Previous gene panel studies showed monogenic causation in up to 12% of patients with CAKUT. METHODS: We applied whole-exome sequencing to analyze the genotypes of individuals from 232 families with CAKUT, evaluating for mutations in single genes known to cause human CAKUT and genes known to cause CAKUT in mice. In consanguineous or multiplex families, we additionally performed a search for novel monogenic causes of CAKUT. RESULTS: In 29 families (13%), we detected a causative mutation in a known gene for isolated or syndromic CAKUT that sufficiently explained the patient's CAKUT phenotype. In three families (1%), we detected a mutation in a gene reported to cause a phenocopy of CAKUT. In 15 of 155 families with isolated CAKUT, we detected deleterious mutations in syndromic CAKUT genes. Our additional search for novel monogenic causes of CAKUT in consanguineous and multiplex families revealed a potential single, novel monogenic CAKUT gene in 19 of 232 families (8%). CONCLUSIONS: We identified monogenic mutations in a known human CAKUT gene or CAKUT phenocopy gene as the cause of disease in 14% of the CAKUT families in this study. Whole-exome sequencing provides an etiologic diagnosis in a high fraction of patients with CAKUT and will provide a new basis for the mechanistic understanding of CAKUT.

Published
2018

20. Congenital Titinopathy: Comprehensive characterization and pathogenic insights

Author

Oates, E.C., Jones, K.J., Donkervoort, S., Charlton, A., Brammah, S., Smith, J.E., Ware, J.S., Yau, K.S., Swanson, L.C., Whiffin, N., Peduto, A.J., Bournazos, A., Waddell, L.B., Farrar, M.A., Sampaio, H.A., Teoh, H.L., Lamont, P.J., Mowat, D., Fitzsimons, R.B., Corbett, A.J., Ryan, M.M., O'Grady, G.L., Sandaradura, S.A., Ghaoui, R., Joshi, H., Marshall, J.L., Nolan, M.A., Kaur, S., Punetha, J., Topf, A., Harris, E., Bakshi, M., Genetti, C.A., Marttila, M., Werlauff, U., Streichenberger, N., Pestronk, A., Mazanti, I., Pinner, J.R., Vuillerot, C., Grosmann, C., Camacho, A., Mohassel, P., Leach, M.E., Foley, A.R., Bharucha-Goebel, D., Collins, J., Connolly, A.M., Gilbreath, H.R., Iannaccone, S.T., Castro, D., Cummings, B.B., Webster, R.I., Lazaro, L., Vissing, J., Coppens, S., Deconinck, N., Luk, H.M., Thomas, N.H., Foulds, N.C., Illingworth, M.A., Ellard, S., McLean, C.A., Phadke, R., Ravenscroft, G., Witting, N., Hackman, P., Richard, I., Cooper, S.T., Kamsteeg, E.J., Hoffman, E.P., Bushby, K., Straub, V., Udd, B., Ferreiro, A., North, K.N., Clarke, N.F., Lek, M., Beggs, A.H., Bonnemann, C.G., MacArthur, D.G., Granzier, H., Davis, M.R., Laing, N.G., Oates, E.C., Jones, K.J., Donkervoort, S., Charlton, A., Brammah, S., Smith, J.E., Ware, J.S., Yau, K.S., Swanson, L.C., Whiffin, N., Peduto, A.J., Bournazos, A., Waddell, L.B., Farrar, M.A., Sampaio, H.A., Teoh, H.L., Lamont, P.J., Mowat, D., Fitzsimons, R.B., Corbett, A.J., Ryan, M.M., O'Grady, G.L., Sandaradura, S.A., Ghaoui, R., Joshi, H., Marshall, J.L., Nolan, M.A., Kaur, S., Punetha, J., Topf, A., Harris, E., Bakshi, M., Genetti, C.A., Marttila, M., Werlauff, U., Streichenberger, N., Pestronk, A., Mazanti, I., Pinner, J.R., Vuillerot, C., Grosmann, C., Camacho, A., Mohassel, P., Leach, M.E., Foley, A.R., Bharucha-Goebel, D., Collins, J., Connolly, A.M., Gilbreath, H.R., Iannaccone, S.T., Castro, D., Cummings, B.B., Webster, R.I., Lazaro, L., Vissing, J., Coppens, S., Deconinck, N., Luk, H.M., Thomas, N.H., Foulds, N.C., Illingworth, M.A., Ellard, S., McLean, C.A., Phadke, R., Ravenscroft, G., Witting, N., Hackman, P., Richard, I., Cooper, S.T., Kamsteeg, E.J., Hoffman, E.P., Bushby, K., Straub, V., Udd, B., Ferreiro, A., North, K.N., Clarke, N.F., Lek, M., Beggs, A.H., Bonnemann, C.G., MacArthur, D.G., Granzier, H., Davis, M.R., and Laing, N.G.

Abstract

Contains fulltext : 196367.pdf (Publisher’s version ) (Open Access), OBJECTIVE: Comprehensive clinical characterization of congenital titinopathy to facilitate diagnosis and management of this important emerging disorder. METHODS: Using massively parallel sequencing we identified 30 patients from 27 families with 2 pathogenic nonsense, frameshift and/or splice site TTN mutations in trans. We then undertook a detailed analysis of the clinical, histopathological and imaging features of these patients. RESULTS: All patients had prenatal or early onset hypotonia and/or congenital contractures. None had ophthalmoplegia. Scoliosis and respiratory insufficiency typically developed early and progressed rapidly, whereas limb weakness was often slowly progressive, and usually did not prevent independent walking. Cardiac involvement was present in 46% of patients. Relatives of 2 patients had dilated cardiomyopathy. Creatine kinase levels were normal to moderately elevated. Increased fiber size variation, internalized nuclei and cores were common histopathological abnormalities. Cap-like regions, whorled or ring fibers, and mitochondrial accumulations were also observed. Muscle magnetic resonance imaging showed gluteal, hamstring and calf muscle involvement. Western blot analysis showed a near-normal sized titin protein in all samples. The presence of 2 mutations predicted to impact both N2BA and N2B cardiac isoforms appeared to be associated with greatest risk of cardiac involvement. One-third of patients had 1 mutation predicted to impact exons present in fetal skeletal muscle, but not included within the mature skeletal muscle isoform transcript. This strongly suggests developmental isoforms are involved in the pathogenesis of this congenital/early onset disorder. INTERPRETATION: This detailed clinical reference dataset will greatly facilitate diagnostic confirmation and management of patients, and has provided important insights into disease pathogenesis. Ann Neurol 2018;83:1105-1124.

Published
2018

21. Mutations in WDR4 as a new cause of Galloway-Mowat syndrome

Author

Braun, D.A., Shril, S., Sinha, A., Schneider, R., Tan, W., Ashraf, S., Hermle, T., Jobst-Schwan, T., Widmeier, E., Majmundar, A.J., Daga, A., Warejko, J.K., Nakayama, M., Schapiro, D., Chen, J., Airik, M., Rao, J., Schmidt, J.M., Hoogstraten, C.A., Hugo, H., Meena, J., Lek, M., Laricchia, K.M., Bagga, A., Hildebrandt, F., Braun, D.A., Shril, S., Sinha, A., Schneider, R., Tan, W., Ashraf, S., Hermle, T., Jobst-Schwan, T., Widmeier, E., Majmundar, A.J., Daga, A., Warejko, J.K., Nakayama, M., Schapiro, D., Chen, J., Airik, M., Rao, J., Schmidt, J.M., Hoogstraten, C.A., Hugo, H., Meena, J., Lek, M., Laricchia, K.M., Bagga, A., and Hildebrandt, F.

Abstract

Item does not contain fulltext, Galloway-Mowat syndrome (GAMOS) is a phenotypically heterogeneous disorder characterized by neurodevelopmental defects combined with renal-glomerular disease, manifesting with proteinuria. To identify additional monogenic disease causes, we here performed whole exome sequencing (WES), linkage analysis, and homozygosity mapping in three affected siblings of an Indian family with GAMOS. Applying established criteria for variant filtering, we identify a novel homozygous splice site mutation in the gene WDR4 as the likely disease-causing mutation in this family. In line with previous reports, we observe growth deficiency, microcephaly, developmental delay, and intellectual disability as phenotypic features resulting from WDR4 mutations. However, the newly identified allele additionally gives rise to proteinuria and nephrotic syndrome, a phenotype that was never reported in patients with WDR4 mutations. Our data thus expand the phenotypic spectrum of WDR4 mutations by demonstrating that, depending on the specific mutated allele, a renal phenotype may be present. This finding suggests that GAMOS may occupy a phenotypic spectrum with other microcephalic diseases. Furthermore, WDR4 is an additional example of a gene that encodes a tRNA modifying enzyme and gives rise to GAMOS, if mutated. Our findings thereby support the recent observation that, like neurons, podocytes of the renal glomerulus are particularly vulnerable to cellular defects resulting from altered tRNA modifications.

Published
2018

22. Congenital titinopathy: comprehensive characterisation & pathogenic insights

Author

Oates, E, Jones, K, Donkervoort, S, Charlton, A, Brammah, S, Smith, J, Ware, J, Yau, K, Swanson, L, Whiffin, N, Peduto, A, Bournazos, A, Waddell, L, Farrar, M, Sampaio, H, Teoh, H, Lamont, P, Mowat, D, Fitzsimmons, R, Corbett, A, Ryan, M, O'Grady, G, Sandaradura, S, Ghaoui, R, Joshi, H, Marshall, J, Nolan, M, Kaur, S, Punetha, J, Topf, A, Harris, E, Bakshi, M, Genetti, C, Marttila, M, Werkauff, U, Streichenberger, N, Pestronk, A, Mazanti, I, Pinner, J, Vuillerot, C, Grosmann, C, Camacho, A, Mohassel, P, Leach, M, Foley, A, Bharucha-Goeber, D, Collins, J, Connolly, A, Gilbreath, H, Iannaccone, S, Castro, D, Cummings, B, Webster, R, Lazaro, L, Vissing, J, Coppens, S, Deconinck, N, Luk, H, Thomas, N, Foulds, N, Illingworth, M, Ellard, S, McLean, C, Phadke, R, Ravenscroft, G, Witting, N, Hackman, P, Clarke, N, Lek, M, Beggs, A, Bonnemann, C, MacArthur, D, Granzier, H, Davis, M, Laing, N, Oates, E, Jones, K, Donkervoort, S, Charlton, A, Brammah, S, Smith, J, Ware, J, Yau, K, Swanson, L, Whiffin, N, Peduto, A, Bournazos, A, Waddell, L, Farrar, M, Sampaio, H, Teoh, H, Lamont, P, Mowat, D, Fitzsimmons, R, Corbett, A, Ryan, M, O'Grady, G, Sandaradura, S, Ghaoui, R, Joshi, H, Marshall, J, Nolan, M, Kaur, S, Punetha, J, Topf, A, Harris, E, Bakshi, M, Genetti, C, Marttila, M, Werkauff, U, Streichenberger, N, Pestronk, A, Mazanti, I, Pinner, J, Vuillerot, C, Grosmann, C, Camacho, A, Mohassel, P, Leach, M, Foley, A, Bharucha-Goeber, D, Collins, J, Connolly, A, Gilbreath, H, Iannaccone, S, Castro, D, Cummings, B, Webster, R, Lazaro, L, Vissing, J, Coppens, S, Deconinck, N, Luk, H, Thomas, N, Foulds, N, Illingworth, M, Ellard, S, McLean, C, Phadke, R, Ravenscroft, G, Witting, N, Hackman, P, Clarke, N, Lek, M, Beggs, A, Bonnemann, C, MacArthur, D, Granzier, H, Davis, M, and Laing, N

Published
2018

23. STRetch: detecting and discovering pathogenic short tandem repeat expansions

Author

Dashnow, H, Lek, M, Phipson, B, Halman, A, Sadedin, S, Lonsdale, A, Davis, M, Lamont, P, Clayton, JS, Laing, NG, MacArthur, DG, Oshlack, A, Dashnow, H, Lek, M, Phipson, B, Halman, A, Sadedin, S, Lonsdale, A, Davis, M, Lamont, P, Clayton, JS, Laing, NG, MacArthur, DG, and Oshlack, A

Abstract

Short tandem repeat (STR) expansions have been identified as the causal DNA mutation in dozens of Mendelian diseases. Most existing tools for detecting STR variation with short reads do so within the read length and so are unable to detect the majority of pathogenic expansions. Here we present STRetch, a new genome-wide method to scan for STR expansions at all loci across the human genome. We demonstrate the use of STRetch for detecting STR expansions using short-read whole-genome sequencing data at known pathogenic loci as well as novel STR loci. STRetch is open source software, available from github.com/Oshlack/STRetch .

Published
2018

24. Congenital Titinopathy: Comprehensive characterization and pathogenic insights

Author

Oates, EC, Jones, KJ, Donkervoort, S, Charlton, A, Brammah, S, Smith, JE, Ware, JS, Yau, KS, Swanson, LC, Whiffin, N, Peduto, AJ, Bournazos, A, Waddell, LB, Farrar, MA, Sampaio, HA, Teoh, HL, Lamont, PJ, Mowat, D, Fitzsimons, RB, Corbett, AJ, Ryan, MM, O'Grady, GL, Sandaradura, SA, Ghaoui, R, Joshi, H, Marshall, JL, Nolan, MA, Kaur, S, Punetha, J, Toepf, A, Harris, E, Bakshi, M, Genetti, CA, Marttila, M, Werlauff, U, Streichenberger, N, Pestronk, A, Mazanti, I, Pinner, JR, Vuillerot, C, Grosmann, C, Camacho, A, Mohassel, P, Leach, ME, Foley, AR, Bharucha-Goebel, D, Collins, J, Connolly, AM, Gilbreath, HR, Iannaccone, ST, Castro, D, Cummings, BB, Webster, RI, Lazaro, L, Vissing, J, Coppens, S, Deconinck, N, Luk, H-M, Thomas, NH, Foulds, NC, Illingworth, MA, Ellard, S, McLean, CA, Phadke, R, Ravenscroft, G, Witting, N, Hackman, P, Richard, I, Cooper, ST, Kamsteeg, E-J, Hoffman, EP, Bushby, K, Straub, V, Udd, B, Ferreiro, A, North, KN, Clarke, NF, Lek, M, Beggs, AH, Boennemann, CG, MacArthur, DG, Granzier, H, Davis, MR, Laing, NG, Oates, EC, Jones, KJ, Donkervoort, S, Charlton, A, Brammah, S, Smith, JE, Ware, JS, Yau, KS, Swanson, LC, Whiffin, N, Peduto, AJ, Bournazos, A, Waddell, LB, Farrar, MA, Sampaio, HA, Teoh, HL, Lamont, PJ, Mowat, D, Fitzsimons, RB, Corbett, AJ, Ryan, MM, O'Grady, GL, Sandaradura, SA, Ghaoui, R, Joshi, H, Marshall, JL, Nolan, MA, Kaur, S, Punetha, J, Toepf, A, Harris, E, Bakshi, M, Genetti, CA, Marttila, M, Werlauff, U, Streichenberger, N, Pestronk, A, Mazanti, I, Pinner, JR, Vuillerot, C, Grosmann, C, Camacho, A, Mohassel, P, Leach, ME, Foley, AR, Bharucha-Goebel, D, Collins, J, Connolly, AM, Gilbreath, HR, Iannaccone, ST, Castro, D, Cummings, BB, Webster, RI, Lazaro, L, Vissing, J, Coppens, S, Deconinck, N, Luk, H-M, Thomas, NH, Foulds, NC, Illingworth, MA, Ellard, S, McLean, CA, Phadke, R, Ravenscroft, G, Witting, N, Hackman, P, Richard, I, Cooper, ST, Kamsteeg, E-J, Hoffman, EP, Bushby, K, Straub, V, Udd, B, Ferreiro, A, North, KN, Clarke, NF, Lek, M, Beggs, AH, Boennemann, CG, MacArthur, DG, Granzier, H, Davis, MR, and Laing, NG

Abstract

OBJECTIVE: Comprehensive clinical characterization of congenital titinopathy to facilitate diagnosis and management of this important emerging disorder. METHODS: Using massively parallel sequencing we identified 30 patients from 27 families with 2 pathogenic nonsense, frameshift and/or splice site TTN mutations in trans. We then undertook a detailed analysis of the clinical, histopathological and imaging features of these patients. RESULTS: All patients had prenatal or early onset hypotonia and/or congenital contractures. None had ophthalmoplegia. Scoliosis and respiratory insufficiency typically developed early and progressed rapidly, whereas limb weakness was often slowly progressive, and usually did not prevent independent walking. Cardiac involvement was present in 46% of patients. Relatives of 2 patients had dilated cardiomyopathy. Creatine kinase levels were normal to moderately elevated. Increased fiber size variation, internalized nuclei and cores were common histopathological abnormalities. Cap-like regions, whorled or ring fibers, and mitochondrial accumulations were also observed. Muscle magnetic resonance imaging showed gluteal, hamstring and calf muscle involvement. Western blot analysis showed a near-normal sized titin protein in all samples. The presence of 2 mutations predicted to impact both N2BA and N2B cardiac isoforms appeared to be associated with greatest risk of cardiac involvement. One-third of patients had 1 mutation predicted to impact exons present in fetal skeletal muscle, but not included within the mature skeletal muscle isoform transcript. This strongly suggests developmental isoforms are involved in the pathogenesis of this congenital/early onset disorder. INTERPRETATION: This detailed clinical reference dataset will greatly facilitate diagnostic confirmation and management of patients, and has provided important insights into disease pathogenesis. Ann Neurol 2018;83:1105-1124.

Published
2018

25. Insights into the genetic epidemiology of Crohn's and rare diseases in the Ashkenazi Jewish population.

Author

Williams, SM, Rivas, MA, Avila, BE, Koskela, J, Huang, H, Stevens, C, Pirinen, M, Haritunians, T, Neale, BM, Kurki, M, Ganna, A, Graham, D, Glaser, B, Peter, I, Atzmon, G, Barzilai, N, Levine, AP, Schiff, E, Pontikos, N, Weisburd, B, Lek, M, Karczewski, KJ, Bloom, J, Minikel, EV, Petersen, B-S, Beaugerie, L, Seksik, P, Cosnes, J, Schreiber, S, Bokemeyer, B, Bethge, J, International IBD Genetics Consortium, NIDDK IBD Genetics Consortium, T2D-GENES Consortium, Heap, G, Ahmad, T, Plagnol, V, Segal, AW, Targan, S, Turner, D, Saavalainen, P, Farkkila, M, Kontula, K, Palotie, A, Brant, SR, Duerr, RH, Silverberg, MS, Rioux, JD, Weersma, RK, Franke, A, Jostins, L, Anderson, CA, Barrett, JC, MacArthur, DG, Jalas, C, Sokol, H, Xavier, RJ, Pulver, A, Cho, JH, McGovern, DPB, Daly, MJ, Williams, SM, Rivas, MA, Avila, BE, Koskela, J, Huang, H, Stevens, C, Pirinen, M, Haritunians, T, Neale, BM, Kurki, M, Ganna, A, Graham, D, Glaser, B, Peter, I, Atzmon, G, Barzilai, N, Levine, AP, Schiff, E, Pontikos, N, Weisburd, B, Lek, M, Karczewski, KJ, Bloom, J, Minikel, EV, Petersen, B-S, Beaugerie, L, Seksik, P, Cosnes, J, Schreiber, S, Bokemeyer, B, Bethge, J, International IBD Genetics Consortium, NIDDK IBD Genetics Consortium, T2D-GENES Consortium, Heap, G, Ahmad, T, Plagnol, V, Segal, AW, Targan, S, Turner, D, Saavalainen, P, Farkkila, M, Kontula, K, Palotie, A, Brant, SR, Duerr, RH, Silverberg, MS, Rioux, JD, Weersma, RK, Franke, A, Jostins, L, Anderson, CA, Barrett, JC, MacArthur, DG, Jalas, C, Sokol, H, Xavier, RJ, Pulver, A, Cho, JH, McGovern, DPB, and Daly, MJ

Abstract

As part of a broader collaborative network of exome sequencing studies, we developed a jointly called data set of 5,685 Ashkenazi Jewish exomes. We make publicly available a resource of site and allele frequencies, which should serve as a reference for medical genetics in the Ashkenazim (hosted in part at https://ibd.broadinstitute.org, also available in gnomAD at http://gnomad.broadinstitute.org). We estimate that 34% of protein-coding alleles present in the Ashkenazi Jewish population at frequencies greater than 0.2% are significantly more frequent (mean 15-fold) than their maximum frequency observed in other reference populations. Arising via a well-described founder effect approximately 30 generations ago, this catalog of enriched alleles can contribute to differences in genetic risk and overall prevalence of diseases between populations. As validation we document 148 AJ enriched protein-altering alleles that overlap with "pathogenic" ClinVar alleles (table available at https://github.com/macarthur-lab/clinvar/blob/master/output/clinvar.tsv), including those that account for 10-100 fold differences in prevalence between AJ and non-AJ populations of some rare diseases, especially recessive conditions, including Gaucher disease (GBA, p.Asn409Ser, 8-fold enrichment); Canavan disease (ASPA, p.Glu285Ala, 12-fold enrichment); and Tay-Sachs disease (HEXA, c.1421+1G>C, 27-fold enrichment; p.Tyr427IlefsTer5, 12-fold enrichment). We next sought to use this catalog, of well-established relevance to Mendelian disease, to explore Crohn's disease, a common disease with an estimated two to four-fold excess prevalence in AJ. We specifically attempt to evaluate whether strong acting rare alleles, particularly protein-truncating or otherwise large effect-size alleles, enriched by the same founder-effect, contribute excess genetic risk to Crohn's disease in AJ, and find that ten rare genetic risk factors in NOD2 and LRRK2 are enriched in AJ (p < 0.005), including several novel con

Published
2018

26. Genome-wide common and rare variant analysis provides novel insights into clozapine-associated neutropenia

Author

Legge, S. E., Hamshere, M. L., Ripke, S., Pardinas, A. F., Goldstein, J. I., Rees, E., Richards, A. L., Leonenko, G., Jorskog, L. F., Jarskog, L. F., Hilliard, C., Alfirevic, A., Duncan, L., Fourches, D., Huang, H., Lek, M., Neale, B. M., Shianna, K., Szatkiewicz, J. P., Tropsha, A., van den Oord, E. J. C. G., Cascorbi, I., Dettling, M., Gazit, E., Goff, D. C., Holden, A. L., Kelly, D. L., Malhotra, A. K, Nielsen, J., Pirmohamed, M., Rujescu, D., Werge, T., Levy, D. L., Josiassen, R. C., Kennedy, J. L., Lieberman, J. A., Daly, M. J., Sullivan, P. F., Chambert, K. D., Collier, D. A., Genovese, G., Giegling, I., Holmans, P., Jonasdottir, A., Kirov, G., McCarroll, S. A., MacCabe, J. H., Mantripragada, K, Moran, J. L., Stefansson, H., Owen, M. J., O'Donovan, M. C., Walters, J.T. R, and Clozapine-Induced Agranulocytosis Consortium

Subjects
0301 basic medicine, Male, Published Erratum, Neutropenia, Section (typography), Genome-wide association study, Human leukocyte antigen, Computational biology, Pharmacology, Bioinformatics, Genome, 03 medical and health sciences, Cellular and Molecular Neuroscience, Solute Carrier Organic Anion Transporter Family Member 1B3, 0302 clinical medicine, medicine, Odds Ratio, SNP, HLA-DQ beta-Chains, Humans, Exome, Molecular Biology, Clozapine, 030304 developmental biology, 0303 health sciences, HLA-DQB1, business.industry, Case-control study, Odds ratio, medicine.disease, 3. Good health, Psychiatry and Mental health, 030104 developmental biology, Case-Control Studies, Schizophrenia, RC0321, Original Article, Female, business, Carrier Proteins, Corrigendum, 030217 neurology & neurosurgery, medicine.drug, Genome-Wide Association Study
Abstract

The antipsychotic clozapine is uniquely effective in the management of schizophrenia; however, its use is limited by its potential to induce agranulocytosis. The causes of this, and of its precursor neutropenia, are largely unknown, although genetic factors have an important role. We sought risk alleles for clozapine-associated neutropenia in a sample of 66 cases and 5583 clozapine-treated controls, through a genome-wide association study (GWAS), imputed human leukocyte antigen (HLA) alleles, exome array and copy-number variation (CNV) analyses. We then combined associated variants in a meta-analysis with data from the Clozapine-Induced Agranulocytosis Consortium (up to 163 cases and 7970 controls). In the largest combined sample to date, we identified a novel association with rs149104283 (odds ratio (OR)=4.32, P=1.79 × 10−8), intronic to transcripts of SLCO1B3 and SLCO1B7, members of a family of hepatic transporter genes previously implicated in adverse drug reactions including simvastatin-induced myopathy and docetaxel-induced neutropenia. Exome array analysis identified gene-wide associations of uncommon non-synonymous variants within UBAP2 and STARD9. We additionally provide independent replication of a previously identified variant in HLA-DQB1 (OR=15.6, P=0.015, positive predictive value=35.1%). These results implicate biological pathways through which clozapine may act to cause this serious adverse effect.

Published
2017

27. Rare Variant Analysis of Human and Rodent Obesity Genes in Individuals with Severe Childhood Obesity

Author

Hendricks, A.E. Bochukova, E.G. Marenne, G. Keogh, J.M. Atanassova, N. Bounds, R. Wheeler, E. Mistry, V. Henning, E. Körner, A. Muddyman, D. McCarthy, S. Hinney, A. Hebebrand, J. Scott, R.A. Langenberg, C. Wareham, N.J. Surendran, P. Howson, J.M. Butterworth, A.S. Danesh, J. Nordestgaard, Bø.G. Nielsen, S.F. Afzal, S. Papadia, S. Ashford, S. Garg, S. Millhauser, G.L. Palomino, R.I. Kwasniewska, A. Tachmazidou, I. O'Rahilly, S. Zeggini, E. Barroso, I. Farooqi, I.S. Benzeval, M. Burton, J. Buck, N. Jäckle, A. Kumari, M. Laurie, H. Lynn, P. Pudney, S. Rabe, B. Wolke, D. Overvad, K. Tjønneland, A. Clavel-Chapelon, F. Kaaks, R. Boeing, H. Trichopoulou, A. Ferrari, P. Palli, D. Krogha, V. Panico, S. Tuminoa, R. Matullo, G. Boer, J. Van Der Schouw, Y. Weiderpass, E. Quiros, J.R. Sánchez, M.-J. Navarro, C. Moreno-Iribas, C. Arriola, L. Melander, O. Wennberg, P. Key, T.J. Riboli, E. Turki, S.A. Anderson, C.A. Anney, R. Antony, D. Soler Artigas, M. Ayub, M. Bala, S. Barrett, J.C. Beales, P. Bentham, J. Bhattacharyaa, S. Birney, E. Blackwooda, D. Bobrow, M. Bolton, P.F. Boustred, C. Breen, G. Calissanoa, M. Carss, K. Charlton, R. Chatterjee, K. Chen, L. Ciampia, A. Cirak, S. Clapham, P. Clement, G. Coates, G. Coccaa, M. Collier, D.A. Cosgrove, C. Coxa, T. Craddock, N. Crooks, L. Curran, S. Curtis, D. Daly, A. Danecek, P. Day, I.N.M. Day-Williams, A. Dominiczak, A. Down, T. Du, Y. Dunham, I. Durbin, R. Edkins, S. Ekong, R. Ellis, P. Evansa, D.M. Fitzpatrick, D.R. Flicek, P. Floyd, J. Foley, A.R. Franklin, C.S. Futema, M. Gallagher, L. Gaunt, T.R. Geihs, M. Geschwind, D. Greenwood, C.M.T. Griffin, H. Grozeva, D. Guo, X. Guo, X. Gurling, H. Hart, D. Holmans, P. Howie, B. Huang, J. Huang, L. Hubbard, T. Humphries, S.E. Hurles, M.E. Hysi, P. Iotchkova, V. Jackson, D.K. Jamshidi, Y. Joyce, C. Karczewski, K.J. Kaye, J. Keane, T. Kemp, J.P. Kennedy, K. Kent, A. Khawaja, F. Van Kogelenberg, M. Kolb-Kokocinski, A. Lachance, G. Langford, C. Lawson, D. Lee, I. Lek, M. Li, R. Li, Y. Liang, J. Lin, H. Liu, R. Lönnqvist, J. Lopes, L.R. Lopes, M. MacArthur, D.G. Mangino, M. Marchini, J. Maslen, J. Mathieson, I. McGuffin, P. McIntosh, A.M. McKechanie, A.G. McQuillin, A. Memari, Y. Metrustry, S. Migone, N. Min, J.L. Mitchison, H.M. Moayyeri, A. Morris, A. Morris, J. Muntoni, F. Northstone, K. O'Donovan, M.C. Onoufriadis, A. Oualkacha, K. Owen, M.J. Palotie, A. Panoutsopoulou, K. Parker, V. Parr, J.R. Paternoster, L. Paunio, T. Payne, F. Payne, S.J. Perry, J.R.B. Pietilainen, O. Plagnol, V. Pollitt, R.C. Porteous, D.J. Povey, S. Quail, M.A. Quaye, L. Raymond, F.L. Rehnström, K. Richards, J.B. Ridout, C.K. Ring, S. Ritchie, G.R.S. Roberts, N. Robinson, R.L. Savage, D.B. Scambler, P. Schiffels, S. Schmidts, M. Schoenmakers, N. Scott, R.H. Semple, R.K. Serra, E. Sharp, S.I. Shaw, A. Shihab, H.A. Shin, S.-Y. Skuse, D. Small, K.S. Smee, C. Smith, B.H. Davey Smith, G. Soranzo, N. Southam, L. Spasic-Boskovic, O. Spector, T.D. St Clair, D. St Pourcain, B. Stalker, J. Stevens, E. Sun, J. Surdulescu, G. Suvisaari, J. Syrris, P. Taylor, R. Tian, J. Timpson, N.J. Tobin, M.D. Valdes, A.M. Vandersteen, A.M. Vijayarangakannan, P. Visscher, P.M. Wain, L.V. Walter, K. Walters, J.T.R. Wang, G. Wang, J. Wang, Y. Ward, K. Whyte, T. Williams, H.J. Williamson, K.A. Wilson, C. Wilson, S.G. Wong, K. Xu, C. Yang, J. Zhang, F. Zhang, P. Zheng, H.-F.

Abstract

Obesity is a genetically heterogeneous disorder. Using targeted and whole-exome sequencing, we studied 32 human and 87 rodent obesity genes in 2,548 severely obese children and 1,117 controls. We identified 52 variants contributing to obesity in 2% of cases including multiple novel variants in GNAS, which were sometimes found with accelerated growth rather than short stature as described previously. Nominally significant associations were found for rare functional variants in BBS1, BBS9, GNAS, MKKS, CLOCK and ANGPTL6. The p.S284X variant in ANGPTL6 drives the association signal (rs201622589, MAF∼0.1%, odds ratio = 10.13, p-value = 0.042) and results in complete loss of secretion in cells. Further analysis including additional case-control studies and population controls (N = 260,642) did not support association of this variant with obesity (odds ratio = 2.34, p-value = 2.59 × 10-3), highlighting the challenges of testing rare variant associations and the need for very large sample sizes. Further validation in cohorts with severe obesity and engineering the variants in model organisms will be needed to explore whether human variants in ANGPTL6 and other genes that lead to obesity when deleted in mice, do contribute to obesity. Such studies may yield druggable targets for weight loss therapies. © 2017 The Author(s).

Published
2017

28. Large-scale GWAS identifies multiple loci for hand grip strength providing biological insights into muscular fitness

Author

Willems, SM, Wright, DJ, Day, FR, Trajanoska, K, Joshi, PK, Morris, JA, Matteini, AM, Garton, FC, Grarup, N, Oskolkov, N, Thalamuthu, A, Mangino, M, Liu, J, Demirkan, A, Lek, M, Xu, L, Wang, G, Oldmeadow, C, Gaulton, KJ, Lotta, LA, Miyamoto-Mikami, E, Rivas, MA, White, T, Loh, P-R, Aadahl, M, Amin, N, Attia, JR, Austin, K, Benyamin, B, Brage, S, Cheng, Y-C, Cięszczyk, P, Derave, W, Eriksson, K-F, Eynon, N, Linneberg, A, Lucia, A, Massidda, M, Mitchell, BD, Miyachi, M, Murakami, H, Padmanabhan, S, Pandey, A, Papadimitriou, I, Rajpal, DK, Sale, C, Schnurr, TM, Sessa, F, Shrine, N, Tobin, MD, Varley, I, Wain, LV, Wray, NR, Lindgren, CM, MacArthur, DG, Waterworth, DM, McCarthy, MI, Pedersen, O, Khaw, K-T, Kiel, DP, Oei, L, Zheng, H-F, Forgetta, V, Leong, A, Ahmad, OS, Laurin, C, Mokry, LE, Ross, S, Elks, CE, Bowden, J, Warrington, NM, Murray, A, Ruth, KS, Tsilidis, KK, Medina-Gómez, C, Estrada, K, Bis, JC, Chasman, DI, Demissie, S, Enneman, AW, Hsu, Y-H, Ingvarsson, T, Kähönen, M, Kammerer, C, Lacroix, AZ, Li, G, Liu, C-T, Liu, Y, Lorentzon, M, Mägi, R, Mihailov, E, Milani, L, Moayyeri, A, Nielson, CM, Sham, PC, Siggeirsdotir, K, Sigurdsson, G, Stefansson, K, Trompet, S, Thorleifsson, G, Vandenput, L, van der Velde, N, Viikari, J, Xiao, S-M, Zhao, JH, Evans, DS, Cummings, SR, Cauley, J, Duncan, EL, de Groot, LCPGM, Esko, T, Gudnason, V, Harris, TB, Jackson, RD, Jukema, JW, Ikram, AMA, Karasik, D, Kaptoge, S, Kung, AWC, Lehtimäki, T, Lyytikäinen, L-P, Lips, P, Luben, R, Metspalu, A, van Meurs, JBJ, Minster, RL, Orwoll, E, Oei, E, Psaty, BM, Raitakari, OT, Ralston, SW, Ridker, PM, Robbins, JA, Smith, AV, Styrkarsdottir, U, Tranah, GJ, Thorstensdottir, U, Uitterlinden, AG, Zmuda, J, Zillikens, MC, Ntzani, EE, Evangelou, E, Ioannidis, JPA, Evans, DM, Ohlsson, C, Pitsiladis, Y, Fuku, N, Franks, PW, North, KN, van Duijn, CM, Mather, KA, Hansen, T, Hansson, O, Spector, T, Murabito, JM, Richards, JB, Rivadeneira, F, Langenberg, C, Perry, JRB, Wareham, NJ, Scott, RA, Willems, Sara M, Wright, Daniel J, Day, Felix R, Trajanoska, Katerina, Benyamin, Beben, Scott, Robert A, GEFOS Anytype Fracture Consortium, Wright, Daniel [0000-0003-3983-2093], Day, Felix [0000-0003-3789-7651], White, Thomas [0000-0001-8456-0803], Brage, Soren [0000-0002-1265-7355], Khaw, Kay-Tee [0000-0002-8802-2903], Langenberg, Claudia [0000-0002-5017-7344], Perry, John [0000-0001-6483-3771], Wareham, Nicholas [0000-0003-1422-2993], Apollo - University of Cambridge Repository, Epidemiology, and Internal Medicine

Subjects
Male, Genome-wide association study, VARIANTS, Physical strength, DISEASE, Grip strength, 0302 clinical medicine, Neoplasm Proteins/genetics, GENETIC INFLUENCES, European Continental Ancestry Group/genetics, Aetiology, education.field_of_study, Hand Strength, Deporte, 3. Good health, Neoplasm Proteins, muscular fitness, Science & Technology - Other Topics, Medical genetics, medicine.medical_specialty, Science, 1.1 Normal biological development and functioning, European Continental Ancestry Group, ta3111, Article, White People, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, FRACTURES, Genetics, Humans, GENOME-WIDE ASSOCIATION, Genetik, Polymorphism, education, METAANALYSIS, Aged, VLAG, Global Nutrition, Wereldvoeding, Science & Technology, ta1184, Prevention, Hand/physiology, Biology and Life Sciences, INSTRUMENTS, Hand, GEFOS Any-Type of Fracture Consortium, Nuclear Proteins/genetics, Genetics, Population, 030104 developmental biology, Genetic Loci, 030217 neurology & neurosurgery, 0301 basic medicine, Transforming Growth Factor alpha/genetics, General Physics and Astronomy, Bioinformatics, GROWTH-FACTOR-ALPHA, Cohort Studies, Medicine and Health Sciences, 2.1 Biological and endogenous factors, ta315, Multidisciplinary, Nuclear Proteins, Single Nucleotide, Middle Aged, Multidisciplinary Sciences, MENDELIAN RANDOMIZATION, SKELETAL-MUSCLE, Female, Medical Genetics, Adult, Population, Quantitative trait locus, Biology, Polymorphism, Single Nucleotide, Underpinning research, Hand strength, MD Multidisciplinary, Mendelian randomization, medicine, Life Science, Membrane Proteins/genetics, Deportes, Medicinsk genetik, Repressor Proteins/genetics, Whites, Actins/genetics, Membrane Proteins, General Chemistry, Transforming Growth Factor alpha, Genética, Actins, United Kingdom, Repressor Proteins, Good Health and Well Being, Exercise Physiology and nutrition, Musculoskeletal, genome-wide association, Genome-Wide Association Study
Abstract

Hand grip strength is a widely used proxy of muscular fitness, a marker of frailty, and predictor of a range of morbidities and all-cause mortality. To investigate the genetic determinants of variation in grip strength, we perform a large-scale genetic discovery analysis in a combined sample of 195,180 individuals and identify 16 loci associated with grip strength (P, Hand grip strength as a proxy of muscular fitness is a clinical predictor of mortality and morbidity. In a large-scale GWA study, the authors find 16 robustly associated genetic loci that highlight roles in muscle fibre structure and function, neuronal maintenance and nervous system signal transduction.

Published
2017

29. NEXT GENERATION SEQUENCING AND EXPERIMENTAL MYOLOGY

Author

Donkervoort, S., primary, Foley, A.R., additional, Saade, D., additional, Neuhaus, S., additional, Mohassel, P., additional, Bharucha-Goebel, D., additional, Chao, K., additional, Cummings, B., additional, Lek, M., additional, MacArthur, D., additional, and Bönnemann, C., additional

Published
2018
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30. An international collaboration applying targeted whole exome sequencing to detect causative variants in 1001 patients affected by limb-girdle weakness of unknown origin

Author

Johnson, K., primary, Bertoli, M., additional, Phillips, L., additional, Blain, A., additional, Ensini, M., additional, Töpf, A., additional, Lek, M., additional, Xu, L., additional, Mullen, T., additional, Valkanas, E., additional, MacArthur, D.G., additional, and Straub, V., additional

Published
2018
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31. Corrigendum to “A homozygous DPM3 mutation in a patient with alpha-dystroglycan-related limb girdle muscular dystrophy” [Neuromuscular disorders 27/11 (2017) 1043–1046]

Author

Van den Bergh, P.Y.K., primary, Sznajer, Y., additional, Van Parys, V., additional, van Tol, W., additional, Wevers, R.A., additional, Lefeber, D.J., additional, Xu, L., additional, Lek, M., additional, MacArthur, D.G., additional, Johnson, K., additional, Phillips, L., additional, Töpf, A., additional, and Straub, V., additional

Published
2018
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32. SMCHD1 mutations associated with a rare muscular dystrophy can also cause isolated arhinia and Bosma arhinia microphthalmia syndrome

Author

Shaw, N.D., Brand, H., Kupchinsky, Z.A., Bengani, H., Plummer, L., Jones, T.I., Erdin, S., Williamson, K.A., Rainger, J., Stortchevoi, A., Samocha, K., Currall, B.B., Dunican, D.S., Collins, R.L., Willer, J.R., Lek, A., Lek, M., Nassan, M., Pereira, S., Kammin, T., Lucente, D., Silva, A., Seabra, C.M., Chiang, C., An, Y., Ansari, M., Rainger, J.K., Joss, S., Smith, J.C., Lippincott, M.F., Singh, S.S., Patel, N., Jing, J.W., Law, J.R., Ferraro, N., Verloes, A., Rauch, A., Steindl, K., Zweier, M., Scheer, I., Sato, D., Okamoto, N., Jacobsen, C., Tryggestad, J., Chernausek, S., Schimmenti, L.A., Brasseur, B., Cesaretti, C., Garcia-Ortiz, J.E., Buitrago, T.P., Silva, O.P., Hoffman, J.D., Muhlbauer, W., Ruprecht, K.W., Loeys, B.L., Shino, M., Kaindl, A.M., Cho, C.H., Morton, C.C., Meehan, R.R., Heyningen, V. van, Liao, E.C., Balasubramanian, R., Hall, J.E., Seminara, S.B., Macarthur, D., Moore, S.A., Yoshiura, K.I., Gusella, J.F., Marsh, J.A., Graham, J.M., Lin, A.E., Katsanis, N., Jones, P.L., Crowley, W.F., Davis, E.E., FitzPatrick, D.R., Talkowski, M.E., Shaw, N.D., Brand, H., Kupchinsky, Z.A., Bengani, H., Plummer, L., Jones, T.I., Erdin, S., Williamson, K.A., Rainger, J., Stortchevoi, A., Samocha, K., Currall, B.B., Dunican, D.S., Collins, R.L., Willer, J.R., Lek, A., Lek, M., Nassan, M., Pereira, S., Kammin, T., Lucente, D., Silva, A., Seabra, C.M., Chiang, C., An, Y., Ansari, M., Rainger, J.K., Joss, S., Smith, J.C., Lippincott, M.F., Singh, S.S., Patel, N., Jing, J.W., Law, J.R., Ferraro, N., Verloes, A., Rauch, A., Steindl, K., Zweier, M., Scheer, I., Sato, D., Okamoto, N., Jacobsen, C., Tryggestad, J., Chernausek, S., Schimmenti, L.A., Brasseur, B., Cesaretti, C., Garcia-Ortiz, J.E., Buitrago, T.P., Silva, O.P., Hoffman, J.D., Muhlbauer, W., Ruprecht, K.W., Loeys, B.L., Shino, M., Kaindl, A.M., Cho, C.H., Morton, C.C., Meehan, R.R., Heyningen, V. van, Liao, E.C., Balasubramanian, R., Hall, J.E., Seminara, S.B., Macarthur, D., Moore, S.A., Yoshiura, K.I., Gusella, J.F., Marsh, J.A., Graham, J.M., Lin, A.E., Katsanis, N., Jones, P.L., Crowley, W.F., Davis, E.E., FitzPatrick, D.R., and Talkowski, M.E.

Abstract

Item does not contain fulltext, Arhinia, or absence of the nose, is a rare malformation of unknown etiology that is often accompanied by ocular and reproductive defects. Sequencing of 40 people with arhinia revealed that 84% of probands harbor a missense mutation localized to a constrained region of SMCHD1 encompassing the ATPase domain. SMCHD1 mutations cause facioscapulohumeral muscular dystrophy type 2 (FSHD2) via a trans-acting loss-of-function epigenetic mechanism. We discovered shared mutations and comparable DNA hypomethylation patterning between these distinct disorders. CRISPR/Cas9-mediated alteration of smchd1 in zebrafish yielded arhinia-relevant phenotypes. Transcriptome and protein analyses in arhinia probands and controls showed no differences in SMCHD1 mRNA or protein abundance but revealed regulatory changes in genes and pathways associated with craniofacial patterning. Mutations in SMCHD1 thus contribute to distinct phenotypic spectra, from craniofacial malformation and reproductive disorders to muscular dystrophy, which we speculate to be consistent with oligogenic mechanisms resulting in pleiotropic outcomes.

Published
2017

33. Exploring the relationship between α-actinin-3 deficiency and obesity in mice and humans

Author

Houweling, PJ, Berman, YD, Turner, N, Quinlan, KGR, Seto, JT, Yang, N, Lek, M, MacArthur, DG, Cooney, G, North, KN, Houweling, PJ, Berman, YD, Turner, N, Quinlan, KGR, Seto, JT, Yang, N, Lek, M, MacArthur, DG, Cooney, G, and North, KN

Abstract

Obesity is a worldwide health crisis, and the identification of genetic modifiers of weight gain is crucial in understanding this complex disorder. A common null polymorphism in the fast fiber-specific gene ACTN3 (R577X) is known to influence skeletal muscle function and metabolism. α-Actinin-3 deficiency occurs in an estimated 1.5 billion people worldwide, and results in reduced muscle strength and a shift towards a more efficient oxidative metabolism. The X-allele has undergone strong positive selection during recent human evolution, and in this study, we sought to determine whether ACTN3 genotype influences weight gain and obesity in mice and humans. An Actn3 KO mouse has been generated on two genetic backgrounds (129X1/SvJ and C57BL/6J) and fed a high-fat diet (HFD, 45% calories from fat). Anthropomorphic features (including body weight) were examined and show that Actn3 KO 129X1/SvJ mice gained less weight compared to WT. In addition, six independent human cohorts were genotyped for ACTN3 R577X (Rs1815739) and body mass index (BMI), waist-to-hip ratio-adjusted BMI (WHRadjBMI) and obesity-related traits were assessed. In humans, ACTN3 genotype alone does not contribute to alterations in BMI or obesity.

Published
2017

34. A common dominant-negative COL6A1 pseudo-exon insertion is skippable using splice-modulating oligonucleotides

Author

Bolduc, V., Foley, A., Donkervoort, S., Hu, Y., Cummings, B., Lek, M., Sarathy, A., Sizov, K., Degefa, H., Wagener, R., Hennig, G., Hanssen, E., Lamande, S., Muntoni, F., Wilton, S., MacArthur, D., Bonnemann, C., Bolduc, V., Foley, A., Donkervoort, S., Hu, Y., Cummings, B., Lek, M., Sarathy, A., Sizov, K., Degefa, H., Wagener, R., Hennig, G., Hanssen, E., Lamande, S., Muntoni, F., Wilton, S., MacArthur, D., and Bonnemann, C.

Published
2017

35. A peculiar case of LGMD with rimmed vacuoles

Author

Ponzalino, Valentina, Vercelli, Liliana, Chiadò Piat, L., Vittonatto, Elisa, Boschi, Silvia, Bortolani, Sara, Xu, L., Lek, M., Johnson, K., Topf, A., Macarthur, D., Straub, V., and Mongini, Tiziana Enrica

Published
2016

37. A common dominant-negative COL6A1 pseudo-exon insertion is skippable using splice-modulating oligonucleotides

Author

Bolduc, V., primary, Foley, A., additional, Donkervoort, S., additional, Hu, Y., additional, Cummings, B., additional, Lek, M., additional, Sarathy, A., additional, Sizov, K., additional, Degefa, H., additional, Wagener, R., additional, Hennig, G., additional, Hanssen, E., additional, Lamande, S., additional, Muntoni, F., additional, Wilton, S., additional, MacArthur, D., additional, and Bönnemann, C., additional

Published
2017
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38. Identification and characterisation of ATP2A1 variants through whole exome sequencing

Author

Johnson, K., primary, Arroyo, A. Martinez, additional, Zulaica, M., additional, Fernández-Torrón, R., additional, de Munain, A. Lopez, additional, Töpf, A., additional, Bertoli, M., additional, Phillips, L., additional, Blain, A., additional, Ensini, M., additional, Lek, M., additional, Mullen, T., additional, Valkanas, E., additional, Xu, L., additional, MacArthur, D., additional, and Straub, V., additional

Published
2017
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39. Do titin developmental isoforms contribute to the pathogenesis of congenital titinopathy?

Author

Oates, E., primary, Yau, K., additional, Jones, K., additional, Smith, J., additional, Cummings, B., additional, Farrar, M., additional, Cooper, S., additional, Lek, M., additional, Hoffman, E., additional, Straub, V., additional, Ferreiro, A., additional, Udd, B., additional, Beggs, A., additional, Bönnemann, C., additional, North, K., additional, MacArthur, D., additional, Granzier, H., additional, Muntoni, F., additional, Davis, M., additional, and Laing, N., additional

Published
2017
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41. Detection of TRIM32 variants associated with LGMD2H in a large cohort of patients with unexplained limb-girdle weakness

Author

Johnson, K., primary, Töpf, A., additional, Bertoli, M., additional, Phillips, L., additional, De Ridder, W., additional, Baets, J., additional, De Jonghe, P., additional, Deconinck, T., additional, Rakocevic Stojanovic, V., additional, Perić, S., additional, Durmus, H., additional, Jamal-Omidi, S., additional, Nafissi, S., additional, Łusakowska, A., additional, Mongini, T., additional, Lek, M., additional, Valkanas, E., additional, Mullen, T., additional, Xu, L., additional, MacArthur, D., additional, and Straub, V., additional

Published
2017
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42. A common COL6A1 deep-intronic pseudo-exon inserting mutation causes a distinct phenotype of Ullrich congenital muscular dystrophy

Author

Reghan Foley, A., primary, Donkervoort, S., additional, Bolduc, V., additional, Hu, Y., additional, Cummings, B., additional, Lek, M., additional, Sarkozy, A., additional, Jimenez-Mallebrera, C., additional, Butterfield, R., additional, Lamande, S., additional, Kirschner, J., additional, Allamand, V., additional, Stojkovic, T., additional, Quijano-Roy, S., additional, Gualandi, F., additional, Ferlini, A., additional, Bertini, E., additional, MacArthur, D., additional, Muntoni, F., additional, and Bönnemann, C., additional

Published
2017
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44. The MYO-SEQ project: application of exome sequencing technologies to 1000 patients affected by limb-girdle weakness of unknown origin

Author

Johnson, K., primary, Bertoli, M., additional, Phillips, L., additional, Blain, A., additional, Ensini, M., additional, Bushby, K., additional, Lochmüller, H., additional, Töpf, A., additional, Lek, M., additional, Xu, L., additional, Mullen, T., additional, Valkanas, E., additional, MacArthur, D.G., additional, and Straub, V., additional

Published
2017
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45. Clinical characterisation of a large international congenital titinopathy cohort

Author

Oates, E.C., primary, Yau, K.S., additional, Jones, K., additional, Smith, J.E., additional, Donkervoort, S., additional, Swanson, L., additional, Charlton, A., additional, Brammah, S., additional, Peduto, A.J., additional, Richard, I., additional, Ferreiro, A., additional, Hoffman, E., additional, Bushby, K., additional, Straub, V., additional, Udd, B., additional, Lek, M., additional, MacArthur, D.G., additional, Granzier, H., additional, Beggs, A., additional, Bönnemann, C.G., additional, North, K.N., additional, Davis, M.R., additional, and Laing, N.G., additional

Published
2017
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46. Mutations in PIGY: expanding the phenotype of inherited glycosylphosphatidylinositol deficiencies

Author

Ilkovski, B, Pagnamenta, AT, O'Grady, GL, Kinoshita, T, Howard, MF, Lek, M, Thomas, B, Turner, A, Christodoulou, J, Sillence, D, Knight, SJ, Popitsch, N, Keays, DA, Anzilotti, C, Goriely, A, Waddell, LB, Brilot, F, North, KN, Kanzawa, N, Macarthur, DG, Taylor, JC, Kini, U, Murakami, Y, and Clarke, NF

Subjects
Male, CD55 Antigens, Glycosylphosphatidylinositols, DNA Mutational Analysis, Infant, Newborn, Gene Expression, Infant, Membrane Proteins, CD59 Antigens, Articles, Transfection, Phenotype, Seizures, Cell Line, Tumor, Child, Preschool, Mutation, Humans, Female
Abstract

Glycosylphosphatidylinositol (GPI)-anchored proteins are ubiquitously expressed in the human body and are important for various functions at the cell surface. Mutations in many GPI biosynthesis genes have been described to date in patients with multi-system disease and together these constitute a subtype of congenital disorders of glycosylation. We used whole exome sequencing in two families to investigate the genetic basis of disease and used RNA and cellular studies to investigate the functional consequences of sequence variants in the PIGY gene. Two families with different phenotypes had homozygous recessive sequence variants in the GPI biosynthesis gene PIGY. Two sisters with c.137T>C (p.Leu46Pro) PIGY variants had multi-system disease including dysmorphism, seizures, severe developmental delay, cataracts and early death. There were significantly reduced levels of GPI-anchored proteins (CD55 and CD59) on the surface of patient-derived skin fibroblasts (∼20-50% compared with controls). In a second, consanguineous family, two siblings had moderate development delay and microcephaly. A homozygous PIGY promoter variant (c.-540G>A) was detected within a 7.7 Mb region of autozygosity. This variant was predicted to disrupt a SP1 consensus binding site and was shown to be associated with reduced gene expression. Mutations in PIGY can occur in coding and non-coding regions of the gene and cause variable phenotypes. This article contributes to understanding of the range of disease phenotypes and disease genes associated with deficiencies of the GPI-anchor biosynthesis pathway and also serves to highlight the potential importance of analysing variants detected in 5'-UTR regions despite their typically low coverage in exome data.

Published
2015

47. Effect of predicted protein-truncating genetic variants on the human transcriptome

Author

Rivas, M.A., Pirinen, M., Conrad, D.F., Lek, M., Tsang, E.K., Karczewski, K.J., Maller, J.B., Kukurba, K.R., DeLuca, D.S., Fromer, M., Ferreira, P.G., Smith, K.S., Zhang, R., Zhao, F.M., Banks, E., Poplin, R., Ruderfer, D.M., Purcell, S.M., Tukiainen, T., Minikel, E.V., Stenson, P.D., Cooper, D.N., Huang, K.H., Sullivan, T.J., Nedzel, J., Bustamante, C.D., Li, J.B., Daly, M.J., Guigo, R., Donnelly, P., Ardlie, K., Sammeth, M., Dermitzakis, E.T., McCarthy, M.I., Montgomery, S.B., Lappalainen, T., MacArthur, D.G., GTEx Consortium, and Geuvadis Consortium

Subjects
Genetics, Gene expression profiling, Transcriptome, Multidisciplinary, Alternative splicing, Genetic variation, Robustness (evolution), Human genome, Biology, Gene, Human genetics
Abstract

Expression, genetic variation, and tissues Human genomes show extensive genetic variation across individuals, but we have only just started documenting the effects of this variation on the regulation of gene expression. Furthermore, only a few tissues have been examined per genetic variant. In order to examine how genetic expression varies among tissues within individuals, the Genotype-Tissue Expression (GTEx) Consortium collected 1641 postmortem samples covering 54 body sites from 175 individuals. They identified quantitative genetic traits that affect gene expression and determined which of these exhibit tissue-specific expression patterns. Melé et al. measured how transcription varies among tissues, and Rivas et al. looked at how truncated protein variants affect expression across tissues. Science , this issue p. 648 , p. 660 , p. 666 ; see also p. 640

Published
2015

48. The Genotype-Tissue Expression (GTEx) pilot analysis: Multitissue gene regulation in humans

Author

Ardlie, K. G., Getz, G., Ferreira, P. G., Segre, A. V., Ward, L. D., Young, T. R., Lappalainen, T., Sullivan, T. J., Winckler, W., Li, G., Kheradpour, P., Lek, M., Shabalin, A. A., Hirschhorn, J. N., Deluca, D. S., MacArthur, D. G., Kellis, M., Rusyn, I., Wright, F. A., Nobel, A. B., Tukiainen, T., Esko, T., Iriarte, B., Gelfand, E. T., Maller, J. B., Zhou, Y.-H., Palmer, C. D., Meng, Y., Trowbridge, C. A., Ongen, H., Rivas, M. A., and Battle, A.

Abstract

Understanding the functional consequences of genetic variation, and how it affects complex human disease and quantitative traits, remains a critical challenge for biomedicine. We present an analysis of RNA sequencing data from 1641 samples across 43 tissues from 175 individuals, generated as part of the pilot phase of the Genotype-Tissue Expression (GTEx) project. We describe the landscape of gene expression across tissues, catalog thousands of tissue-specific and shared regulatory expression quantitative trait loci (eQTL) variants, describe complex network relationships, and identify signals from genome-wide association studies explained by eQTLs. These findings provide a systematic understanding of the cellular and biological consequences of human genetic variation and of the heterogeneity of such effects among a diverse set of human tissues.

Published
2015
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49. Improved imputation of low-frequency and rare variants using the UK10K haplotype reference panel

Author

Huang, J, Howie, B, Mccarthy, S, Memari, Y, Walter, K, Min, Jl, Danecek, P, Malerba, Giovanni, Trabetti, Elisabetta, Zheng, Hf, Gambaro, G, Richards, Jb, Durbin, R, Timpson, Nj, Marchini, J, Soranzo, N, Al Turki, S, Amuzu, A, Anderson, Ca, Anney, R, Antony, D, Artigas, Ms, Ayub, M, Bala, S, Barrett, Jc, Barroso, I, Beales, P, Benn, M, Bentham, J, Bhattacharya, S, Birney, E, Blackwood, D, Bobrow, M, Bochukova, E, Bolton, Pf, Bounds, R, Boustred, C, Breen, G, Calissano, M, Carss, K, Casas, Jp, Chambers, Jc, Charlton, R, Chatterjee, K, Chen, L, Ciampi, A, Cirak, S, Clapham, P, Clement, G, Coates, G, Cocca, M, Collier, Da, Cosgrove, C, Cox, T, Craddock, N, Crooks, L, Curran, S, Curtis, D, Daly, A, Day, In, Day Williams, A, Dedoussis, G, Down, T, Du, Y, van Duijn, Cm, Dunham, I, Edkins, S, Ekong, R, Ellis, P, Evans, Dm, Farooqi, Is, Fitzpatrick, Dr, Flicek, P, Floyd, J, Foley, Ar, Franklin, Cs, Futema, M, Gallagher, L, Gasparini, P, Gaunt, Tr, Geihs, M, Geschwind, D, Greenwood, C, Griffin, H, Grozeva, D, Guo, X, Gurling, H, Hart, D, Hendricks, Ae, Holmans, P, Huang, L, Hubbard, T, Humphries, Se, Hurles, Me, Hysi, P, Iotchkova, V, Isaacs, A, Jackson, Dk, Jamshidi, Y, Johnson, J, Joyce, C, Karczewski, Kj, Kaye, J, Keane, T, Kemp, Jp, Kennedy, K, Kent, A, Keogh, J, Khawaja, F, Kleber, Me, van Kogelenberg, M, Kolb Kokocinski, A, Kooner, Js, Lachance, G, Langenberg, C, Langford, C, Lawson, D, Lee, I, van Leeuwen, Em, Lek, M, Li, R, Li, Y, Liang, J, Lin, H, Liu, R, Lönnqvist, J, Lopes, Lr, Lopes, M, Luan, J, Macarthur, Dg, Mangino, M, Marenne, G, März, W, Maslen, J, Matchan, A, Mathieson, I, Mcguffin, P, Mcintosh, Am, Mckechanie, Ag, Mcquillin, A, Metrustry, S, Migone, N, Mitchison, Hm, Moayyeri, A, Morris, J, Morris, R, Muddyman, D, Muntoni, F, Nordestgaard, Bg, Northstone, K, O'Donovan, Mc, O'Rahilly, S, Onoufriadis, A, Oualkacha, K, Owen, Mj, Palotie, A, Panoutsopoulou, K, Parker, V, Parr, Jr, Paternoster, L, Paunio, T, Payne, F, Payne, Sj, Perry, Jr, Pietilainen, O, Plagnol, V, Pollitt, Rc, Povey, S, Quail, Ma, Quaye, L, Raymond, L, Rehnström, K, Ridout, Ck, Ring, S, Ritchie, Gr, Roberts, N, Robinson, Rl, Savage, Db, Scambler, P, Schiffels, S, Schmidts, M, Schoenmakers, N, Scott, Rh, Scott, Ra, Semple, Rk, Serra, E, Sharp, Si, Shaw, A, Shihab, Ha, Shin, Sy, Skuse, D, Small, Ks, Smee, C, Smith, Gd, Southam, L, Spasic Boskovic, O, Spector, Td, St Clair, D, St Pourcain, B, Stalker, J, Stevens, E, Sun, J, Surdulescu, G, Suvisaari, J, Syrris, P, Tachmazidou, I, Taylor, R, Tian, J, Tobin, Md, Toniolo, D, Traglia, M, Tybjaerg Hansen, A, Valdes, Am, Vandersteen, Am, Varbo, A, Vijayarangakannan, P, Visscher, Pm, Wain, Lv, Walters, Jt, Wang, G, Wang, J, Wang, Y, Ward, K, Wheeler, E, Whincup, P, Whyte, T, Williams, Hj, Williamson, Ka, Wilson, C, Wilson, Sg, Wong, K, Xu, C, Yang, J, Zaza, Gianluigi, Zeggini, E, Zhang, F, Zhang, P, Zhang, W., Clinicum, Department of Psychiatry, Jie, Huang, Bryan, Howie, Shane, Mccarthy, Yasin, Memari, Klaudia, Walter, Josine L., Min, Petr, Danecek, Giovanni, Malerba, Elisabetta, Trabetti, Hou Feng, Zheng, Saeed Al, Turki, Antoinette, Amuzu, Carl A., Anderson, Richard, Anney, Dinu, Antony, María Soler, Artiga, Muhammad, Ayub, Senduran, Bala, Jeffrey C., Barrett, Inês, Barroso, Phil, Beale, Marianne, Benn, Jamie, Bentham, Shoumo, Bhattacharya, Ewan, Birney, Douglas, Blackwood, Martin, Bobrow, Elena, Bochukova, Patrick F., Bolton, Rebecca, Bound, Chris, Boustred, Gerome, Breen, Mattia, Calissano, Keren, Car, Juan Pablo, Casa, John C., Chamber, Ruth, Charlton, Krishna, Chatterjee, Lu, Chen, Antonio, Ciampi, Sebahattin, Cirak, Peter, Clapham, Gail, Clement, Guy, Coate, Cocca, Massimiliano, David A., Collier, Catherine, Cosgrove, Tony, Cox, Nick, Craddock, Lucy, Crook, Sarah, Curran, David, Curti, Allan, Daly, Ian N. M., Day, Aaron Day, William, George, Dedoussi, Thomas, Down, Yuanping, Du, Cornelia M., van Duijn, Ian, Dunham, Sarah, Edkin, Rosemary, Ekong, Peter, Elli, David M., Evan, I., Sadaf Farooqi, David R., Fitzpatrick, Paul, Flicek, James, Floyd, A., Reghan Foley, Christopher S., Franklin, Marta, Futema, Louise, Gallagher, Gasparini, Paolo, Tom R., Gaunt, Matthias, Geih, Daniel, Geschwind, Celia, Greenwood, Heather, Griffin, Detelina, Grozeva, Xiaosen, Guo, Xueqin, Guo, Hugh, Gurling, Deborah, Hart, Audrey E., Hendrick, Peter, Holman, Liren, Huang, Tim, Hubbard, Steve E., Humphrie, Matthew E., Hurle, Pirro, Hysi, Valentina, Iotchkova, Aaron, Isaac, David K., Jackson, Yalda, Jamshidi, Jon, Johnson, Chris, Joyce, Konrad J., Karczewski, Jane, Kaye, Thomas, Keane, John P., Kemp, Karen, Kennedy, Alastair, Kent, Julia, Keogh, Farrah, Khawaja, Marcus E., Kleber, Margriet van, Kogelenberg, Anja Kolb, Kokocinski, Jaspal S., Kooner, Genevieve, Lachance, Claudia, Langenberg, Cordelia, Langford, Daniel, Lawson, Irene, Lee, Elisabeth M., van Leeuwen, Monkol, Lek, Rui, Li, Yingrui, Li, Jieqin, Liang, Hong, Lin, Ryan, Liu, Jouko, Lönnqvist, Luis R., Lope, Margarida, Lope, Jian'An, Luan, Daniel G., Macarthur, Massimo, Mangino, Gaëlle, Marenne, Winfried, März, John, Maslen, Angela, Matchan, Iain, Mathieson, Peter, Mcguffin, Andrew M., Mcintosh, Andrew G., Mckechanie, Andrew, Mcquillin, Sarah, Metrustry, Nicola, Migone, Hannah M., Mitchison, Alireza, Moayyeri, James, Morri, Richard, Morri, Dawn, Muddyman, Francesco, Muntoni, Børge G., Nordestgaard, Kate, Northstone, Michael C., O'Donovan, Stephen, O'Rahilly, Alexandros, Onoufriadi, Karim, Oualkacha, Michael J., Owen, Aarno, Palotie, Kalliope, Panoutsopoulou, Victoria, Parker, Jeremy R., Parr, Lavinia, Paternoster, Tiina, Paunio, Felicity, Payne, Stewart J., Payne, John R. B., Perry, Olli, Pietilainen, Vincent, Plagnol, Rebecca C., Pollitt, Sue, Povey, Michael A., Quail, Lydia, Quaye, Lucy, Raymond, Karola, Rehnström, Cheryl K., Ridout, Susan, Ring, Graham R. S., Ritchie, Nicola, Robert, Rachel L., Robinson, David B., Savage, Peter, Scambler, Stephan, Schiffel, Miriam, Schmidt, Nadia, Schoenmaker, Richard H., Scott, Robert A., Scott, Robert K., Semple, Eva, Serra, Sally I., Sharp, Adam, Shaw, Hashem A., Shihab, So Youn, Shin, David, Skuse, Kerrin S., Small, Carol, Smee, George Davey, Smith, Lorraine, Southam, Olivera Spasic, Boskovic, Timothy D., Spector, David St, Clair, Beate St, Pourcain, Jim, Stalker, Elizabeth, Steven, Jianping, Sun, Gabriela, Surdulescu, Jaana, Suvisaari, Petros, Syrri, Ioanna, Tachmazidou, Rohan, Taylor, Jing, Tian, Martin D., Tobin, Daniela, Toniolo, Michela, Traglia, Anne Tybjaerg, Hansen, Ana M., Valde, Anthony M., Vandersteen, Anette, Varbo, Parthiban, Vijayarangakannan, Peter M., Visscher, Louise V., Wain, James T. R., Walter, Guangbiao, Wang, Jun, Wang, Yu, Wang, Kirsten, Ward, Eleanor, Wheeler, Peter, Whincup, Tamieka, Whyte, Hywel J., William, Kathleen A., Williamson, Crispian, Wilson, Scott G., Wilson, Kim, Wong, Changjiang, Xu, Jian, Yang, Gianluigi, Zaza, Eleftheria, Zeggini, Feng, Zhang, Pingbo, Zhang, Weihua, Zhang, Giovanni, Gambaro, J., Brent Richard, Richard, Durbin, Nicholas J., Timpson, Jonathan, Marchini, and Nicole, Soranzo

Subjects
Computer science, General Physics and Astronomy, Genome-wide association study, 0302 clinical medicine, Gene Frequency, Haplotype, Genetics,Biological sciences, Settore MED/14 - NEFROLOGIA, Aged, 80 and over, Genetics, 0303 health sciences, education.field_of_study, Multidisciplinary, TWINSUK, Middle Aged, single-nucleotide polymorphism, Whole-genome sequencing, WGS imputation panel, single-nucleotide polymorphism, Biological sciences, Italy, MAP, Adult, Adolescent, Genotype, WGS imputation panel, Population, Single-nucleotide polymorphism, FORMAT, Computational biology, GENOTYPE IMPUTATION, Polymorphism, Single Nucleotide, Article, White People, General Biochemistry, Genetics and Molecular Biology, Young Adult, 03 medical and health sciences, Humans, GENOME-WIDE ASSOCIATION, 1000 Genomes Project, education, Allele frequency, Alleles, Aged, 030304 developmental biology, Whole-genome sequencing, Models, Statistical, Models, Genetic, Genome, Human, Genetic Variation, General Chemistry, United Kingdom, Minor allele frequency, Renal disorders Radboud Institute for Molecular Life Sciences [Radboudumc 11], Haplotypes, 3111 Biomedicine, 030217 neurology & neurosurgery, Imputation (genetics)
Abstract

Imputing genotypes from reference panels created by whole-genome sequencing (WGS) provides a cost-effective strategy for augmenting the single-nucleotide polymorphism (SNP) content of genome-wide arrays. The UK10K Cohorts project has generated a data set of 3,781 whole genomes sequenced at low depth (average 7x), aiming to exhaustively characterize genetic variation down to 0.1% minor allele frequency in the British population. Here we demonstrate the value of this resource for improving imputation accuracy at rare and low-frequency variants in both a UK and an Italian population. We show that large increases in imputation accuracy can be achieved by re-phasing WGS reference panels after initial genotype calling. We also present a method for combining WGS panels to improve variant coverage and downstream imputation accuracy, which we illustrate by integrating 7,562 WGS haplotypes from the UK10K project with 2,184 haplotypes from the 1000 Genomes Project. Finally, we introduce a novel approximation that maintains speed without sacrificing imputation accuracy for rare variants., Imputation uses genotype information from SNP arrays to infer the genotypes of missing markers. Here, the authors show that an imputation reference panel derived from whole-genome sequencing of 3,781 samples from the UK10K project improves the imputation accuracy and coverage of low frequency variants compared to existing methods.

Published
2015

50. Variants in SLC18A3, vesicular acetylcholine transporter, cause congenital myasthenic syndrome

Author

O'Grady, G.L., Verschuuren, C., Yuen, M., Webster, R., Menezes, M., Fock, J.M., Pride, N., Best, H.A., Benavides Damm, T., Turner, C., Lek, M., Engel, A.G., North, K.N., Clarke, N.F., MacArthur, D.G., Kamsteeg, E.J., Cooper, S.T., O'Grady, G.L., Verschuuren, C., Yuen, M., Webster, R., Menezes, M., Fock, J.M., Pride, N., Best, H.A., Benavides Damm, T., Turner, C., Lek, M., Engel, A.G., North, K.N., Clarke, N.F., MacArthur, D.G., Kamsteeg, E.J., and Cooper, S.T.

Abstract

Item does not contain fulltext, OBJECTIVE: To describe the clinical and genetic characteristics of presynaptic congenital myasthenic syndrome secondary to biallelic variants in SLC18A3. METHODS: Individuals from 2 families were identified with biallelic variants in SLC18A3, the gene encoding the vesicular acetylcholine transporter (VAChT), through whole-exome sequencing. RESULTS: The patients demonstrated features seen in presynaptic congenital myasthenic syndrome, including ptosis, ophthalmoplegia, fatigable weakness, apneic crises, and deterioration of symptoms in cold water for patient 1. Both patients demonstrated moderate clinical improvement on pyridostigmine. Patient 1 had a broader phenotype, including learning difficulties and left ventricular dysfunction. Electrophysiologic studies were typical for a presynaptic defect. Both patients showed profound electrodecrement on low-frequency repetitive stimulation followed by a prolonged period of postactivation exhaustion. In patient 1, this was unmasked only after isometric contraction, a recognized feature of presynaptic disease, emphasizing the importance of activation procedures. CONCLUSIONS: VAChT is responsible for uptake of acetylcholine into presynaptic vesicles. The clinical and electrographic characteristics of the patients described are consistent with previously reported mouse models of VAChT deficiency. These findings make it very likely that defects in VAChT due to variants in SLC18A3 are a cause of congenital myasthenic syndrome in humans.

Published
2016

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