Abstract
With the increasing amount of molecular genetic testing offered for clinical diagnosis in recent years, there is a rapid growth in the detection of novel or unclassified variants of unknown clinical significance. To determine whether a sequence change is a disease-causing pathogenic mutation or a non-causative variant becomes increasingly important in translational medicine. Interpretation of the clinical significance of an unclassified variant in the mitochondrial genome is even more complicated due to the highly polymorphic feature of the mitochondrial DNA and the unique characteristics of heteroplasmy. The degree of mutant mitochondrial DNA heteroplasmy varies among different tissues; in general, it correlates with the disease severity in affected tissues. In this chapter, we provide updated procedures of evaluating unclassified variants in both the nuclear and mitochondrial genomes by using various databases, computational tools, and structural analysis methods to assist in clinical interpretation.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
References
Ingman M, Gyllensten U (2006) mtDB: Human Mitochondrial Genome Database, a resource for population genetics and medical sciences. Nucleic Acids Res 34:D749–D751
Ruiz-Pesini E, Lott MT, Procaccio V, Poole JC, Brandon MC, Mishmar D, Yi C, Kreuziger J, Baldi P, Wallace DC (2007) An enhanced MITOMAP with a global mtDNA mutational phylogeny. Nucleic Acids Res 35:D823–D828
Richards CS, Bale S, Bellissimo DB, Das S, Grody WW, Hegde MR, Lyon E, Ward BE (2008) ACMG recommendations for standards for interpretation and reporting of sequence variations: revisions 2007. Genet Med 10:294–300
Cotton RG, Auerbach AD, Beckmann JS, Blumenfeld OO, Brookes AJ, Brown AF, Carrera P, Cox DW, Gottlieb B, Greenblatt MS, Hilbert P, Lehvaslaiho H, Liang P, Marsh S, Nebert DW, Povey S, Rossetti S, Scriver CR, Summar M, Tolan DR, Verma IC, Vihinen M, den Dunnen JT (2008) Recommendations for locus-specific databases and their curation. Hum Mutat 29:2–5
Fokkema IF, Taschner PE, Schaafsma GC, Celli J, Laros JF, den Dunnen JT (2011) LOVD v. 2.0: the next generation in gene variant databases. Hum Mutat 32:557–563
Bandelt HJ, Salas A, Taylor RW, Yao YG (2009) Exaggerated status of “novel” and “pathogenic” mtDNA sequence variants due to inadequate database searches. Hum Mutat 30:191–196
Kumar P, Henikoff S, Ng PC (2009) Predicting the effects of coding non-synonymous variants on protein function using the SIFT algorithm. Nat Protoc 4:1073–1081
Adzhubei IA, Schmidt S, Peshkin L, Ramensky VE, Gerasimova A, Bork P, Kondrashov AS, Sunyaev SR (2010) A method and server for predicting damaging missense mutations. Nat Methods 7:248–249
Mathe E, Olivier M, Kato S, Ishioka C, Hainaut P, Tavtigian SV (2006) Computational approaches for predicting the biological effect of p53 missense mutations: a comparison of three sequence analysis based methods. Nucleic Acids Res 34:1317–1325
Tavtigian SV, Deffenbaugh AM, Yin L, Judkins T, Scholl T, Samollow PB, de Silva D, Zharkikh A, Thomas A (2006) Comprehensive statistical study of 452 BRCA1 missense substitutions with classification of eight recurrent substitutions as neutral. J Med Genet 43:295–305
Tchernitchko D, Goossens M, Wajcman H (2004) In silico prediction of the deleterious effect of a mutation: proceed with caution in clinical genetics. Clin Chem 50:1974–1978
Hon LS, Zhang Y, Kaminker JS, Zhang Z (2009) Computational prediction of the functional effects of amino acid substitutions in signal peptides using a model-based approach. Hum Mutat 30:99–106
Brunak S, Engelbrecht J, Knudsen S (1991) Prediction of human mRNA donor and acceptor sites from the DNA sequence. J Mol Biol 220:49–65
Reese MG, Eeckman FH, Kulp D, Haussler D (1997) Improved splice site detection in Genie. J Comput Biol 4:311–323
Houdayer C (2011) In silico prediction of splice-affecting nucleotide variants. Methods Mol Biol 760:269–281
Cartegni L, Wang J, Zhu Z, Zhang MQ, Krainer AR (2003) ESEfinder: a web resource to identify exonic splicing enhancers. Nucleic Acids Res 31:3568–3571
Cartegni L, Chew SL, Krainer AR (2002) Listening to silence and understanding nonsense: exonic mutations that affect splicing. Nat Rev Genet 3:285–298
Mohammadi L, Vreeswijk MP, Oldenburg R, van den Ouweland A, Oosterwijk JC, van der Hout AH, Hoogerbrugge N, Ligtenberg M, Ausems MG, van der Luijt RB, Dommering CJ, Gille JJ, Verhoef S, Hogervorst FB, van Os TA, Gomez Garcia E, Blok MJ, Wijnen JT, Helmer Q, Devilee P, van Asperen CJ, van Houwelingen HC (2009) A simple method for co-segregation analysis to evaluate the pathogenicity of unclassified variants; BRCA1 and BRCA2 as an example. BMC Cancer 9:211
Helm M, Brule H, Friede D, Giege R, Putz D, Florentz C (2000) Search for characteristic structural features of mammalian mitochondrial tRNAs. RNA 6:1356–1379
Wang J, Schmitt ES, Landsverk ML, Zhang VW, Li FY, Graham BH, Craigen WJ, Wong LJ (2012) An integrated approach for classifying mitochondrial DNA variants: one clinical diagnostic laboratory’s experience. Genet Med 14:620–626
Guan MX, Fischel-Ghodsian N, Attardi G (1996) Biochemical evidence for nuclear gene involvement in phenotype of non-syndromic deafness associated with mitochondrial 12S rRNA mutation. Hum Mol Genet 5:963–971
Davidson MM, Walker WF, Hernandez-Rosa E, Nesti C (2009) Evidence for nuclear modifier gene in mitochondrial cardiomyopathy. J Mol Cell Cardiol 46:936–942
Man PY, Griffiths PG, Brown DT, Howell N, Turnbull DM, Chinnery PF (2003) The epidemiology of Leber hereditary optic neuropathy in the North East of England. Am J Hum Genet 72:333–339
DiMauro S, Hirano M (2011) Mitochondrial DNA deletion syndromes, GeneReviews™ [Internet]
Zhang W, Cui H, Wong LJ (2012) Comprehensive one-step molecular analyses of mitochondrial genome by massively parallel sequencing. Clin Chem 58:1322–1331
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2013 Springer Science+Business Media New York
About this chapter
Cite this chapter
Wang, J., Landsverk, M. (2013). Algorithms and Guidelines for Interpretation of DNA Variants. In: Wong, LJ. (eds) Next Generation Sequencing. Springer, New York, NY. https://doi.org/10.1007/978-1-4614-7001-4_6
Download citation
DOI: https://doi.org/10.1007/978-1-4614-7001-4_6
Published:
Publisher Name: Springer, New York, NY
Print ISBN: 978-1-4614-7000-7
Online ISBN: 978-1-4614-7001-4
eBook Packages: Biomedical and Life SciencesBiomedical and Life Sciences (R0)