Genome sequencing and implications for rare disorders
Open Access
- 24 June 2019
- journal article
- review article
- Published by Springer Science and Business Media LLC in Orphanet Journal of Rare Diseases
- Vol. 14 (1), 1-10
- https://doi.org/10.1186/s13023-019-1127-0
Abstract
The practice of genomic medicine stands to revolutionize our approach to medical care, and to realize this goal will require discovery of the relationship between rare variation at each of the ~ 20,000 protein-coding genes and their consequent impact on individual health and expression of Mendelian disease. The step-wise evolution of broad-based, genome-wide cytogenetic and molecular genomic testing approaches (karyotyping, chromosomal microarray [CMA], exome sequencing [ES]) has driven much of the rare disease discovery to this point, with genome sequencing representing the newest member of this team. Each step has brought increased sensitivity to interrogate individual genomic variation in an unbiased method that does not require clinical prediction of the locus or loci involved. Notably, each step has also brought unique limitations in variant detection, for example, the low sensitivity of ES for detection of triploidy, and of CMA for detection of copy neutral structural variants. The utility of genome sequencing (GS) as a clinical molecular diagnostic test, and the increased sensitivity afforded by addition of long-read sequencing or other -omics technologies such as RNAseq or metabolomics, are not yet fully explored, though recent work supports improved sensitivity of variant detection, at least in a subset of cases. The utility of GS will also rely upon further elucidation of the complexities of genetic and allelic heterogeneity, multilocus rare variation, and the impact of rare and common variation at a locus, as well as advances in functional annotation of identified variants. Much discovery remains to be done before the potential utility of GS is fully appreciated.Keywords
Funding Information
- National Human Genome Research Institute (K08 HG008986)
This publication has 108 references indexed in Scilit:
- Detection of Clinically Relevant Copy Number Variants with Whole-Exome SequencingHuman Mutation, 2013
- The Role and Challenges of Exome Sequencing in Studies of Human DiseasesFrontiers in Genetics, 2013
- Chromosomal Microarray versus Karyotyping for Prenatal DiagnosisThe New England Journal of Medicine, 2012
- Digenic inheritance of an SMCHD1 mutation and an FSHD-permissive D4Z4 allele causes facioscapulohumeral muscular dystrophy type 2Nature Genetics, 2012
- Discovery and Statistical Genotyping of Copy-Number Variation from Whole-Exome Sequencing DepthAmerican Journal of Human Genetics, 2012
- Fidelity of capture-enrichment for mtDNA genome sequencing: influence of NUMTsNucleic Acids Research, 2012
- Copy number variation detection and genotyping from exome sequence dataGenome Research, 2012
- Compound inheritance of a low-frequency regulatory SNP and a rare null mutation in exon-junction complex subunit RBM8A causes TAR syndromeNature Genetics, 2012
- Low and High Expressing Alleles of the LMNA Gene: Implications for Laminopathy Disease DevelopmentPLOS ONE, 2011
- Mendelian Inheritance in Man and Its Online Version, OMIMAmerican Journal of Human Genetics, 2007