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Rare Diseases: How Genomics has Transformed Thinking, Diagnoses and Hope for Affected Families

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Rare Diseases in the Age of Health 2.0

Part of the book series: Communications in Medical and Care Compunetics ((CMCC,volume 4))

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Abstract

The latest methods for sequencing DNA have already revolutionized our approach to the management of very rare diseases. It is now possible—using whole genome sequencing and whole exome sequencing of genomes—to diagnose phenotypically complex monogenic diseases in a significant number of cases. A pan-Canadian initiative launched in 2011 (FORGE) has developed a highly sophisticated and productive pipeline that has identified the causative genes for 67 % of cases studied. This has obvious impacts that are immediately actionable for families and their caring physicians as well as implications for implementing models of personalized medicine. It also promises to impact profoundly on our understanding of pathway biology and could accelerate the speed at which we develop medicines for both rare and common diseases.

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References

  • Beaulieu CL, Samuels ME, Ekins S, McMaster C, Edwards A, Krainer A, Hicks GG, Frey BJ, Boycott KM, MacKenzie AE. A generalizable pre-clinical research approach for orphan disease therapy. Orphanet J Rare Dis. 2012;7:39.

    Article  Google Scholar 

  • Bentley DR, Balasubramanian S, et al. Accurate whole genome sequencing using reversible terminator chemistry. Nature. 2008;456:53–9.

    Article  Google Scholar 

  • Bernier FP, Caluseriu O, Ng S, Schwartzentruber J, Buckingham KJ, Innes AM, Jabs EW, Innis JW, Schuette JL, Gorski JL, Byers PH, Andelfinger G, Siu V, Lauzon J, Fernandez BA, McMillin M, Scott RH, Racher H, FORGE Canada Consortium, Majewski J, Nickerson DA, Shendure J, Bamshad MJ, Parboosingh JS. Haploinsufficiency of SF3B4, a component of the pre-mRNA spliceosomal complex, causes Nager syndrome. Am J Hum Genet. 2012;90:925–33.

    Article  Google Scholar 

  • Carter MT, Boycott KM. A new syndrome with multiple capillary malformations, intractable seizures, and brain and limb anomalies. Am J Med Genet A. 2011;155:301–6.

    Article  Google Scholar 

  • Doherty D, Chudley AE, Coghlan G, Innes AM, Lemire EG, Rogers RC, Mhanni A, Ishak GE, Jones SJM, Zhan SH, Fejes AP, FORGE Canada Consortium, Triggs-Raine B, Zelinski T. Mutations in the G protein signaling modulator 2 gene, GPSM2, cause the brain malformations and hearing loss in Chudley-McCullough syndrome. Am J Hum Genet. 2012;90:1088–93.

    Article  Google Scholar 

  • Fernandez BA, Green JS, Barrett B, Macmillan A, McColl S, Fernandez S, Rahman P, Mahoney K, Pereira SL, Scherer SW, Boycott KM, Woods MO, FORGE Canada Consortium. Adult siblings with homozygous G6PC3 mutations expand our understanding of the severe congenital neutropenia type 4 (SCN4) phenotype. BMC Med Genet. 2012;13:111.

    Article  Google Scholar 

  • Feuk L, Carson AR, Scherer SW. Structural variation in the human genome. Nature Rev Genet. 2006;7:85–97.

    Article  Google Scholar 

  • Gibson WT, Hood RL, Zhan SH, Bulman DE, Fejes AP, Moore R, Mungall AJ, Eydoux P, Babul-Hirji R, An J, Marra MA, FORGE Canada Consortium, Chitayat D, Boycott KM, Weaver DD, Jones SJM. Mutations in EZH2 cause weaver syndrome. Am J Hum Genet. 2012;90:110–8.

    Article  Google Scholar 

  • Hood R, Lines MA, Nikkel S, Schwartzentruber J, Beaulieu C, Nowaczyk MJM, Allanson J, Kim CA, Wieczorek D, Moilanen JS, Lacombe D, Gillessen-Kaesbach G, Whiteford ML, Robledo C, Quaio DC, Gomy I, Bertola DR, Albrecht B, Platzer K, McGillivray G, Zou R, McLeod DR, Chudley AE, Chodirker BN, Marcadier J, FORGE Canada Consortium, Majewski J, Bulman DE, White SM, Boycott KM. Mutations in SRCAP, SNF2-related CREBBP activator protein, cause floating-Harbor syndrome. Am J Hum Genet. 2012;90:308–13.

    Article  Google Scholar 

  • International Human Genome Sequencing Consortium. Initial sequencing and analysis of the human genome. Nature. 2001;409:860–921.

    Article  Google Scholar 

  • International Human Genome Sequencing Consortium. Finishing the euchromatic sequence of the human genome. Nature. 2004;431:931–45.

    Article  Google Scholar 

  • Koenekoop RK, Wang H, Majewski J, Wang X, Lopez I, Chen Y, Li Y, Fishman G, Ren H, Schwartzentruber J, Solanki N, Traboulsi E, Cheng J, Nageeb M, FORGE Canada Consortium, Keser V, Mardon G, Fu Q, Chen R. Mutations in NMNAT1 cause Leber congenital amaurosis and identify a new disease pathway for retinal degeneration. Nature Genet. 2012;44(9):1035–40.

    Article  Google Scholar 

  • Lines MA, Huang L, Schwartzentruber J, Douglas S; Lynch DC, Beaulieu C, Almeida MLG, Zechi-Ceide RM, Gener B, Gillessen-Kaesbach G, Nava C, Baujat G, Horn D, Kini U, Caliebe A, Alanay Y, Utine GE, Lev D, Kohlhase J, Grix AW, Lohmann DR, Hehr U, Böhm D, FORGE Canada Consortium, Majewski J, Bulman DE, Wieczorek D, Boycott KM. Haploinsufficiency of a spliceosomal GTPase encoded by EFTUD2 causes mandibulofacial dysostosis with microcephaly. Am J Hum Genet. 2012;90:369–377.

    Google Scholar 

  • Lynch DC, Dyment DA, Huang L, Nikkel SM, Lacombe D, Campeau PM, Lee B, Bacino CA, Michaud JL, Bernier FP, FORGE Canada Consortium, Parboosingh JS, Innes AM. Identification of novel mutations confirms PDE4D as a major gene causing acrodysostosis. Hum Mutat (Epub). 2012;31(1):97–102.

    Google Scholar 

  • Majewski J, Schwartzentruber JA, Caqueret A, Patry L, Marcadier J, Fryns JP, Boycott KM, Ste-Marie LG, McKiernan FE, Marik I, Esch HV, FORGE Canada Consortium, Michaud JL, Samuels ME. Mutations in NOTCH2 in families with Hadju-Cheney syndrome. Hum Mutat. 2011;32:1114–7.

    Article  Google Scholar 

  • McDonell LM, Mirzaa GM, et al. Mutations in STAMBP, encoding a deubiquitinating enzyme, cause microcephaly–capillary malformation syndrome. Nature Genet. 2013; 45(5):556–562.

    Google Scholar 

  • McKernan KJ, Peckam HE, et al. Sequence and structural variation in a human genome uncovered by short read, massively parallel ligation sequencing using two-base encoding. Genome Res. 2009;19:1527–41.

    Article  Google Scholar 

  • McMillan HJ, Worthylake T, Schwartzentruber J, Gottlieb CC, Lawrence SE, Mackenzie A, Beaulieu CL, Mooyer PA; FORGE Canada Consortium, Wanders RJ, Majewski J, Bulman DE, Geraghty MT, Ferdinandusse S, Boycott KM. Specific combination of compound heterozygous mutations in 17β-hydroxysteroid dehydrogenase type 4 (HSD17B4) defines a new subtype of D-bifunctional protein deficiency. Orphanet J Rare Dis. 2012;7(1):1–9.

    Article  Google Scholar 

  • Mendel G. Experiments in plant hybridisation. 1865. http://www.mendelweb.org.

  • Moffatt P, Ben Amor M, Roschger P, Klaushofer K, Schwartzentruber JA, Paterson AD, Hu P, Marshall C, FORGE Canada Consortium, Fahiminiya S, Majewski J, Beaulieu CL, Boycott KM, Rauch F. Metaphyseal dysplasia with maxillary hypoplasia and brachydactyly is caused by a duplication in RUNX2. Am J Hum Genet 2013;92(2):252–258.

    Google Scholar 

  • Moore AF, Florez JC. Genetic susceptibility to type 2 diabetes and implications for anti-diabetic therapy. Annu Rev Med. 2008;59:95–111.

    Article  Google Scholar 

  • Pelletier G, Feingold M. Case report 1. In: Bergsma D, editor. Syndrome identification. White Plains: National Foundation-March of Dimes; 1973. p. 8–9.

    Google Scholar 

  • Rivière JB, Mirzaa GM, O’Roak BJ, Beddaoui M, Alcantara D, Conway RL, St-Onge J, Schwartzentruber JA, Gripp KW, Nikkel SM, Worthylake T, Sullivan CT, Ward TR, Butler HE, Kramer NA, Albrecht B, Armour CM, Armstrong L, Caluseriu O, Cytrynbaum C, Drolet BA, Innes AM, Lauzon JL, Lin AE, Mancini GM, Meschino WS, Reggin JD, Saggar AK, Lerman-Sagie T, Uyanik G, Weksberg R, Zirn B, Beaulieu CL, FORGE Canada Consortium, Majewski J, Bulman DE, O’Driscoll M, Shendure J, Graham JM Jr, Boycott KM, Dobyns WB. De novo germline and postzygotic mutations in AKT3, PIK3R2 and PIK3CA cause a spectrum of related megalencephaly syndromes. Nat Genet. 2012;44:934–40.

    Article  Google Scholar 

  • Samuels ME, Gallo-Payet N, Hasselmann C, Magne F, Patry L, Chouinard L, Schwartzentruber J, Rene P, Sawyer N, Bouvier M, Djemli A, Delvin E, Huot C, Eugene D, Deal CL, van Vliet G, Majewski J, Deladoey J, FORGE Canada Consortium. Bioinactive ACTH causing glucocorticoid deficiency. J Clin Endocrinol Metab 2013a;98(2):736–742.

    Google Scholar 

  • Samuels ME, Majewski J, Alirezaie N, Fernandez I, Casals F, Patey N, Decaluwe H, Gosselin I, Haddad E, Hodgkinson A, Idaghdour A, Marchand V, Michaud JL, Rodrigue MA, Desjardins S, Dubois S, Deist FL, Awadalla P, Raymond V, Maranda B. Exome sequencing identifies mutations in the gene TTC7A in French-Canadian cases with hereditary multiple intestinal atresia. J Med Genet 2013b;50(5):324–329.

    Google Scholar 

  • Schuurs-Hoeijmakers JH, Geraghty MT, Ben-Salem S, de Bot ST, Nijhof B, van de Vondervoort II, van der Graaf M, Nobau AC, Otte-Heller I, Vermeer S, Smith AC, Humphreys P, Schwartzentruber J, FORGE Canada Consortium, Ali BR, Al-Yahyaee SA, Tariq S, Pramathan T, Bayoumi R, Kremer HP, van de Warrenburg BP, van den Akker WM, Gilissen C, Veltman JA, Janssen IM, Vulto-van Silfhout AT, van der Velde-Visser S, Lefeber DJ, Diekstra A, Erasmus CE, Willemsen MA, Vissers LE, Lammens M, van Bokhoven H, Brunner HG, Wevers RA, Schenck A, Al-Gazali L, de Vries BB, de Brouwer AP. Mutations in DDHD2, encoding an intracellular phospholipase A1, cause a recessive form of complex hereditary spastic paraplegia. Am J Hum Genet. 2012;91:1073–1081.

    Google Scholar 

  • Srour M, Hamdan FF, Schwartzentruber JA, Patry L, Ospina LH, Shevell MI, Désilets V, Dobrzeniecka S, Mathonnet G, Lemyre E, Massicotte C, Labuda D, Amrom V, Andermann E, Sébire G, Maranda B, Rouleau GA, FORGE Canada Consortium, Majewski J, Michaud JL. Mutations in TMEM231 cause Joubert syndrome in French Canadians. J Med Genet. 2012a;49:1–6.

    Article  Google Scholar 

  • Srour M, Schwartzentruber J, Hamdan FF, Ospina LH, Patry L, Labuda D, Massicotte C, Dobrzeniecka S, Capo-Chichi JM, Papillon-Cavanagh S, Samuels ME, Boycott KM, Shevell MI, Laframboise R, Désilets V, FORGE Canada Consortium, Maranda B, Rouleau GA, Majewski J, Michaud JL. Mutations in C5ORF42 cause Joubert syndrome in the French Canadian Population. Am J Hum Genet. 2012b;90:693–700.

    Article  Google Scholar 

  • Venter JC, et al. The sequence of the human genome. Science. 2001;291:1304–51.

    Article  Google Scholar 

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Acknowledgments

We would like to thank Alain Beaudet, President of CIHR and Thomas Caskey, who served as Chairman of the Board of Genome Canada for several years, both of whom were key players in the conceptualization of the rare disease initiative in Canada. We would like to thank the Government of Canada for their continued support of the Canadian Institutes of Health Research and Genome Canada.

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Authors and Affiliations

  1. Genome Canada, 2100-150, Metcalfe Street, Ottawa, ON, K2P 1P, Canada

    Pierre Meulien & Cindy Bell

  2. CIHR Institute of Genetics, McGill University, 3649 Promenade Sir William Osler, Montreal, QC, H3G 0B1, Canada

    Paul Lasko

  3. Children’s Hospital of Eastern Ontario Research Institute, University of Ottawa, Ottawa, ON, K1H 8L1, Canada

    Alex MacKenzie & Kym Boycott

Authors
  1. Pierre Meulien
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  2. Paul Lasko
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  3. Alex MacKenzie
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  4. Cindy Bell
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  5. Kym Boycott
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Corresponding author

Correspondence to Pierre Meulien .

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Editors and Affiliations

  1. Health Design and Technology Institute, Coventry University, Coventry, United Kingdom

    Rajeev K. Bali

  2. International Council on Medical & Care Compunetics (ICMCC), Utrecht, The Netherlands

    Lodewijk Bos

  3. Johns Hopkins Urban Health Institute, Baltimore, Maryland, USA

    Michael Christopher Gibbons

  4. iBellieve Foundation, Toronto, Canada

    Simon Ibell

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Meulien, P., Lasko, P., MacKenzie, A., Bell, C., Boycott, K. (2014). Rare Diseases: How Genomics has Transformed Thinking, Diagnoses and Hope for Affected Families. In: Bali, R., Bos, L., Gibbons, M., Ibell, S. (eds) Rare Diseases in the Age of Health 2.0. Communications in Medical and Care Compunetics, vol 4. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-38643-5_3

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  • DOI: https://doi.org/10.1007/978-3-642-38643-5_3

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