Revisiting Mendelian Disorders Through Exome Sequencing

Overview

Journal Hum Genet

Specialty Genetics

Date 2011 Feb 19

PMID 21331778

Citations 92

Authors

Chee-Seng Ku

Nasheen Naidoo

Yudi Pawitan

Affiliations

Soon will be listed here.

Abstract

Over the past several years, more focus has been placed on dissecting the genetic basis of complex diseases and traits through genome-wide association studies. In contrast, Mendelian disorders have received little attention mainly due to the lack of newer and more powerful methods to study these disorders. Linkage studies have previously been the main tool to elucidate the genetics of Mendelian disorders; however, extremely rare disorders or sporadic cases caused by de novo variants are not amendable to this study design. Exome sequencing has now become technically feasible and more cost-effective due to the recent advances in high-throughput sequence capture methods and next-generation sequencing technologies which have offered new opportunities for Mendelian disorder research. Exome sequencing has been swiftly applied to the discovery of new causal variants and candidate genes for a number of Mendelian disorders such as Kabuki syndrome, Miller syndrome and Fowler syndrome. In addition, de novo variants were also identified for sporadic cases, which would have not been possible without exome sequencing. Although exome sequencing has been proven to be a promising approach to study Mendelian disorders, several shortcomings of this method must be noted, such as the inability to capture regulatory or evolutionary conserved sequences in non-coding regions and the incomplete capturing of all exons.

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References

Bolze A, Byun M, McDonald D, Morgan N, Abhyankar A, Premkumar L . Whole-exome-sequencing-based discovery of human FADD deficiency. Am J Hum Genet. 2010; 87(6):873-81. PMC: 2997374. DOI: 10.1016/j.ajhg.2010.10.028. View

Collin R, Safieh C, Littink K, Shalev S, Garzozi H, Rizel L . Mutations in C2ORF71 cause autosomal-recessive retinitis pigmentosa. Am J Hum Genet. 2010; 86(5):783-8. PMC: 2869006. DOI: 10.1016/j.ajhg.2010.03.016. View

Day I . dbSNP in the detail and copy number complexities. Hum Mutat. 2009; 31(1):2-4. DOI: 10.1002/humu.21149. View

Teslovich T, Musunuru K, Smith A, Edmondson A, Stylianou I, Koseki M . Biological, clinical and population relevance of 95 loci for blood lipids. Nature. 2010; 466(7307):707-13. PMC: 3039276. DOI: 10.1038/nature09270. View

Voight B, Scott L, Steinthorsdottir V, Morris A, Dina C, Welch R . Twelve type 2 diabetes susceptibility loci identified through large-scale association analysis. Nat Genet. 2010; 42(7):579-89. PMC: 3080658. DOI: 10.1038/ng.609. View

Mathew C . New links to the pathogenesis of Crohn disease provided by genome-wide association scans. Nat Rev Genet. 2007; 9(1):9-14. DOI: 10.1038/nrg2203. View

Alexander R, Fang G, Rozowsky J, Snyder M, Gerstein M . Annotating non-coding regions of the genome. Nat Rev Genet. 2010; 11(8):559-71. DOI: 10.1038/nrg2814. View

Sandhu M, Weedon M, Fawcett K, Wasson J, Debenham S, Daly A . Common variants in WFS1 confer risk of type 2 diabetes. Nat Genet. 2007; 39(8):951-3. PMC: 2672152. DOI: 10.1038/ng2067. View

Seng K, Kee Seng C . The success of the genome-wide association approach: a brief story of a long struggle. Eur J Hum Genet. 2008; 16(5):554-64. DOI: 10.1038/ejhg.2008.12. View

10.

Sobreira N, Cirulli E, Avramopoulos D, Wohler E, Oswald G, Stevens E . Whole-genome sequencing of a single proband together with linkage analysis identifies a Mendelian disease gene. PLoS Genet. 2010; 6(6):e1000991. PMC: 2887469. DOI: 10.1371/journal.pgen.1000991. View

11.

Musunuru K, Kathiresan S . Genetics of coronary artery disease. Annu Rev Genomics Hum Genet. 2010; 11:91-108. DOI: 10.1146/annurev-genom-082509-141637. View

12.

Turner E, Ng S, Nickerson D, Shendure J . Methods for genomic partitioning. Annu Rev Genomics Hum Genet. 2009; 10:263-84. DOI: 10.1146/annurev-genom-082908-150112. View

13.

Winckler W, Weedon M, Graham R, McCarroll S, Purcell S, Almgren P . Evaluation of common variants in the six known maturity-onset diabetes of the young (MODY) genes for association with type 2 diabetes. Diabetes. 2007; 56(3):685-93. DOI: 10.2337/db06-0202. View

14.

Ng S, Nickerson D, Bamshad M, Shendure J . Massively parallel sequencing and rare disease. Hum Mol Genet. 2010; 19(R2):R119-24. PMC: 2953741. DOI: 10.1093/hmg/ddq390. View

15.

Johnson J, Gibbs J, Van Maldergem L, Houlden H, Singleton A . Exome sequencing in Brown-Vialetto-van Laere syndrome. Am J Hum Genet. 2010; 87(4):567-9. PMC: 2948797. DOI: 10.1016/j.ajhg.2010.05.021. View

16.

Choi M, Scholl U, Ji W, Liu T, Tikhonova I, Zumbo P . Genetic diagnosis by whole exome capture and massively parallel DNA sequencing. Proc Natl Acad Sci U S A. 2009; 106(45):19096-101. PMC: 2768590. DOI: 10.1073/pnas.0910672106. View

17.

Lesage S, Brice A . Parkinson's disease: from monogenic forms to genetic susceptibility factors. Hum Mol Genet. 2009; 18(R1):R48-59. DOI: 10.1093/hmg/ddp012. View

18.

Klein R, Zeiss C, Chew E, Tsai J, Sackler R, Haynes C . Complement factor H polymorphism in age-related macular degeneration. Science. 2005; 308(5720):385-9. PMC: 1512523. DOI: 10.1126/science.1109557. View

19.

Bonnefond A, Durand E, Sand O, Graeve F, Gallina S, Busiah K . Molecular diagnosis of neonatal diabetes mellitus using next-generation sequencing of the whole exome. PLoS One. 2010; 5(10):e13630. PMC: 2964316. DOI: 10.1371/journal.pone.0013630. View

20.

Wheeler D, Srinivasan M, Egholm M, Shen Y, Chen L, McGuire A . The complete genome of an individual by massively parallel DNA sequencing. Nature. 2008; 452(7189):872-6. DOI: 10.1038/nature06884. View