Rare disease genetics- UCL exomes consortium


Rare disease genetics has been revolutionized by the widespread use of exome sequencing. However, the interpretation of sequence data on a large scale raises two major issues. The first issue is technical, related to the limits of short read sequencing, and the artifacts that these tools can generate. The second limitation is the difficulty to interpret rare variants without the knowledge of the genetic variation in large cohorts of individuals.

These issues can be addressed to a large extent by sharing of clinical sequence data across multiple groups. This allows the identification of shared traits and variants, and the verification of hypotheses by comparing clinical data. Another advantage is the improvement in calling accuracy when the same variants are detected across multiple samples.

To this end, we have assembled the UCL-exomes (or UCL-ex) consortium. UCL-ex groups together a dozen clinical investigators (most at UCL but not only) with an analytical lead based at the UGI. Rules are in place to facilitate data sharing while respecting patient privacy. As of now, UCL-ex consists of 1,500 exome samples and this set grows regularly. Data are stored on the UCL computer science cluster and analysis, including a monthly joint calling of the entire set, is centralized at the UCL Genetics Consortium. Owing to an average of 10 Gb size per exome, these sequence data add up to 15 Tb of required storage. This analysis creates significant computational challenges, and technical solutions (hardware/storage) are being developed as the sample size grows to accommodate this analysis. A key tool is the reduced reads format developed by the GATK team.

Funding for analytical staff is currently provided mainly by NIHR (UCL-Moorfields Eyes Hospital Biomedical Research Center) and in part by the UK Medical Research Council and the British Heart Foundation. Consumables funding originates from a variety of sources (charities and research councils).



Data sharing rules within UCL-ex

UCL-ex is a collaboration between clinical groups and analysts to facilitate the analysis of the large amount of exome sequence data being generated. The difficulty is to strike a balance between data confidentiality, data ownership but also the advantages associated with sharing data across multiple groups to facilitate variant calling, case control analysis and generally speaking the dissection of both complex and Mendelian disorders.

Clinical PIs are typically the “owners” of a exome sequence data and analysts at UCL provide calls/association tests back to the clinical groups. The general rules of engagement are listed below:

1- Vincent Plagnol will keep a list of PIs up to date (see below), and if others want to join I will approve it provided that it creates no conflict with other PIs. If there is a conflict, I will check that the relevant PIs are happy with any addition to UCL-ex.

2- If any conflict came up (ie related diseases) I will make sure that data are properly separated and no conflict comes up (note that I am not aware of any such issue as of now). Collaborations down the road are obviously welcome.

3- all the data will remain on the UCL Genetics Institute server and they will only be analyzed within this collaboration. No raw data will be shared without explicit approval.

4- within that set of analysts, it is appropriate to use the data in any way that is useful for case control type analysis (gene based, single variant based...).

5- It is acceptable, if a variant of interest to PI X comes up in another collection (with PI Y in charge), to have PI X ask PI Y whether the individuals in question share a related phenotype to what is of interest to PI X.




Publications using samples from UCL-ex:

Primary immune deficiencies:

LRBA gene deletion in a patient presenting with autoimmunity without hypogammaglobulinemia. Burns SO, Zenner HL, Plagnol V, Curtis J, Mok K, Eisenhut M, Kumararatne D, Doffinger R, Thrasher AJ, Nejentsev S.
J Allergy Clin Immunol. 2012



Ophthalmology
Mutations in ARL2BP, Encoding ADP-Ribosylation-Factor-Like 2 Binding Protein, Cause Autosomal-Recessive Retinitis Pigmentosa, Davidson AE, Schwarz N, Zelinger L, Stern-Schneider G, Shoemark A, Spitzbarth B, Gross M, Laxer U, Sosna J, Sergouniotis PI, Waseem NH, Wilson R, Kahn RA, Plagnol V, Wolfrum U, Banin E, Hardcastle AJ, Cheetham ME, Sharon D, Webster AR, Am J Hum Genet. 2013

RP1L1 variants are associated with a spectrum of inherited retinal diseases including retinitis pigmentosa and occult macular dystrophy., Davidson AE, Sergouniotis PI, Mackay DS, Wright GA, Waseem NH, Michaelides M, Holder GE, Robson AG, Moore AT, Plagnol V, Webster AR. Hum Mutat. 2013

Recessive mutations in KCNJ13, encoding an inwardly rectifying potassium channel subunit, cause leber congenital amaurosis. Sergouniotis PI, Davidson AE, Mackay DS, Li Z, Yang X, Plagnol V, Moore AT, Webster AR. Am J Hum Genet. 2011

Biallelic mutations in PLA2G5, encoding group V phospholipase A2, cause
benign fleck retina
., Sergouniotis PI, Davidson AE, Mackay DS, Lenassi E, Li Z, Robson AG, Yang X, Kam JH, Isaacs TW, Holder GE, Jeffery G, Beck JA, Moore AT, Plagnol V, Webster AR. Am J Hum Genet. 2011

Dermatology
Mutations in AQP5, Encoding a Water-Channel Protein, Cause Autosomal-Dominant Diffuse Nonepidermolytic Palmoplantar Keratoderma.
Blaydon DC, Lind LK, Plagnol V, Linton KJ, Smith FJ, Wilson NJ, McLean WH, Munro CS, South AP, Leigh IM, O'Toole EA, Lundström A, Kelsell DP., Am J Hum Genet. 2013

A missense mutation in the MBTPS2 gene underlies the X-linked form of Olmsted syndrome. Haghighi A, Scott CA, Poon DS, Yaghoobi R, Saleh-Gohari N, Plagnol V, Kelsell DP. J Invest Dermatol. 2013

RHBDF2 mutations are associated with tylosis, a familial esophageal cancer syndrome.
Blaydon DC, Etheridge SL, Risk JM, Hennies HC, Gay LJ, Carroll R, Plagnol V, McRonald FE, Stevens HP, Spurr NK, Bishop DT, Ellis A, Jankowski J, Field JK, Leigh IM, South AP, Kelsell DP. Am J Hum Genet. 2012

Inflammatory skin and bowel disease linked to ADAM17 deletion.
Blaydon DC, Biancheri P, Di WL, Plagnol V, Cabral RM, Brooke MA, van Heel DA, Ruschendorf F, Toynbee M, Walne A, O'Toole EA, Martin JE, Lindley K, Vulliamy T, Abrams DJ, MacDonald TT, Harper JI, Kelsell DP. N Engl J Med. 2011

Bone marrow failure
Constitutional mutations in RTEL1 cause severe dyskeratosis congenita.
Walne AJ, Vulliamy T, Kirwan M, Plagnol V, Dokal I. Am J Hum Genet. 2013

Exome sequencing identifies autosomal-dominant SRP72 mutations associated with familial aplasia and myelodysplasia. Kirwan M, Walne AJ, Plagnol V, Velangi M, Ho A, Hossain U, Vulliamy T, Dokal I. Am J Hum Genet. 2012

Exome sequencing identifies MPL as a causative gene in familial aplastic anemia.
Walne AJ, Dokal A, Plagnol V, Beswick R, Kirwan M, de la Fuente J, Vulliamy T, Dokal I.
Haematologica. 2012

Cardiovascular disorders
Genetic complexity in hypertrophic cardiomyopathy revealed by high-throughput sequencing. Lopes LR, Zekavati A, Syrris P, Hubank M, Giambartolomei C, Dalageorgou C, Jenkins S, McKenna W; Uk10k Consortium, Plagnol V, Elliott PM. J Med Genet. 2013

Neurology
Mutations in ANO3 cause dominant craniocervical dystonia: ion channel implicated in pathogenesis. Charlesworth G, Plagnol V, Holmström KM, Bras J, Sheerin UM, Preza E, Rubio-Agusti I, Ryten M, Schneider SA, Stamelou M, Trabzuni D, Abramov AY, Bhatia KP, Wood NW.
Am J Hum Genet. 2012

Kohlschütter-Tönz syndrome: mutations in ROGDI and evidence of genetic heterogeneity. Tucci A, Kara E, Schossig A, Wolf NI, Plagnol V, Fawcett K, Paisán-Ruiz C, Moore M, Hernandez D, Musumeci S, Tennison M, Hennekam R, Palmeri S, Malandrini A, Raskin S, Donnai D, Hennig C, Tzschach A, Hordijk R, Bast T, Wimmer K, Lo CN, Shorvon S, Mefford H, Eichler EE, Hall R, Hayes I, Hardy J, Singleton A, Zschocke J, Houlden H.
Hum Mutat. 2013

Other disease fields
Recessive oligodontia linked to a homozygous loss-of-function mutation in the SMOC2 gene, Alfawaz S, Fong F, Plagnol V, Wong FS, Fearne J, Kelsell DP. Arch Oral Biol. 2013 May;58(5):462-6. doi: 10.1016/j.archoralbio.2012.12.008. Epub 2013 Jan 11.

Cryptogenic multifocal ulcerating stenosing enteritis associated with homozygous deletion mutations in cytosolic phospholipase A2-α Brooke MA, Longhurst HJ, Plagnol V, Kirkby NS, Mitchell JA, Rüschendorf F, Warner TD, Kelsell DP, Macdonald TT.
Gut. 2012






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