Molecular Genetic Testing for Mitochondrial Disease: From One Generation to the Next
Purchase on Springer.com
$39.95 / €34.95 / £29.95*
Rent the article at a discountRent now
* Final gross prices may vary according to local VAT.
Molecular genetic diagnostic testing for mitochondrial disease has evolved continually since the first genetic basis for a clinical mitochondrial disease syndrome was identified in the late 1980s. Owing to global limitations in both knowledge and technology, few individuals, even among those with strong clinical or biochemical evidence of mitochondrial respiratory chain dysfunction, ever received a definitive molecular diagnosis prior to 2005. Clinically available genetic diagnostic testing options improved by 2006 to include sequencing and deletion analysis of an increasing number of individual nuclear genes linked to mitochondrial disease, genome-wide microarray analysis for chromosomal copy number abnormalities, and mitochondrial DNA whole genome sequence analysis. To assess the collective effect of these tests on the genetic diagnosis of suspected mitochondrial disease, we report here results from a retrospective review of the diagnostic yield in patients evaluated from 2008 to 2011 in the Mitochondrial-Genetics Diagnostic Clinic at The Children’s Hospital of Philadelphia. Among 152 patients aged 6 weeks to 81 years referred for clinical evaluation of multisystem presentations concerning for suspected mitochondrial disease, a genetic etiology was established that confirmed definite mitochondrial disease in 16.4 % and excluded primary mitochondrial disease in 9.2 %. Substantial diagnostic challenges remain owing to the clinical difficulty and frank low yield of a priori selecting individual nuclear genes to sequence based on particular symptomatic or biochemical manifestations of suspected mitochondrial disease. These findings highlight the particular utility of massively parallel nuclear exome sequencing technologies, whose benefits and limitations are explored relative to the clinical genetic diagnostic evaluation of mitochondrial disease.
- Haas RH, Parikh S, Falk MJ, Saneto RP, Wolf NI, Darin N, et al. Mitochondrial disease: a practical approach for primary care physicians. Pediatrics 2007;120:1326–1333. CrossRef
- Haas RH, Parikh S, Falk MJ, Saneto RP, Wolf NI, Darin N, et al. The in-depth evaluation of suspected mitochondrial disease. Mol Genet Metaob 2008;94:16–37. CrossRef
- Tucker EJ, Compton AG, Thorburn DR. Recent advances in the genetics of mitochondrial encephalopathies. Curr Neurol Neurosci Rep 2010;10:277–285. CrossRef
- DiMauro S, Schon EA. Mitochondrial respiratory-chain diseases. N Engl J Med 2003;348:2656–2668. CrossRef
- Naviaux RK. Developing a systematic approach to the diagnosis and classification of mitochondrial disease. Mitochondrion 2004;4:351–361. CrossRef
- Bernier FP, Boneh A, Dennett X, Chow CW, Cleary MA, Thorburn DR. Diagnostic criteria for respiratory chain disorders in adults and children. Neurology 2002;59:1406–1411. CrossRef
- Wolf NI, Smeitink JA. Mitochondrial disorders: a proposal for consensus diagnostic criteria in infants and children. Neurology 2002;59:1402–1405. CrossRef
- Tucker EJ, Compton AG, Calvo SE, Thorburn DR. The molecular basis of human complex I deficiency. IUBMB Life 2011;63:669–677.
- Wallace DC, Singh G, Lott MT, Hodge JA, Schurr TG, Lezza AM, et al. Mitochondrial DNA mutation associated with Leber's hereditary optic neuropathy. Science 1988;242:1427–1430. CrossRef
- Wallace DC, Zheng XX, Lott MT, Shoffner JM, Hodge JA, Kelley RI, et al. Familial mitochondrial encephalomyopathy (MERRF): genetic, pathophysiological, and biochemical characterization of a mitochondrial DNA disease. Cell 1988;55:601–610. CrossRef
- Kogelnik AM, Lott MT, Brown MD, Navathe SB, Wallace DC. MITOMAP: a human mitochondrial genome database. Nucleic Acids Res 1996;24:177–179. CrossRef
- DiMauro S, Garone C. Historical perspective on mitochondrial medicine. Dev Disabil Res Rev 2010;16:106–113. CrossRef
- Wong LJ, Scaglia F, Graham BH, Craigen WJ. Current molecular diagnostic algorithm for mitochondrial disorders. Molecular genetics and metabolism. 2010;100:111–117. CrossRef
- Wong LJ. Molecular genetics of mitochondrial disorders. Dev Disabil Res Rev 2010;16:154–162. CrossRef
- Falk MJ, Robin NH. The primary care physician's approach to congenital anomalies. Primary care. 2004;31:605–619. CrossRef
- Naviaux RK, Nguyen KV. POLG mutations associated with Alpers' syndrome and mitochondrial DNA depletion. Ann Neurol 2004;55:706–712. CrossRef
- Falk MJ. MITO 101 – Genetic Counseling for Mitochondrial Disease: United Mitochondrial Disease Foundation; 2008. Available at: www.umdf.org. Accessed December 19, 2012.
- Calvo SE, Mootha VK. The mitochondrial proteome and human disease. Annu Rev Genomics Hum Genet 2010;11:25–44. CrossRef
- Saneto RP, Naviaux RK. Polymerase gamma disease through the ages. Dev Disabil Res Rev 2010;16:163–174. CrossRef
- Falk MJ. Neurodevelopmental manifestations of mitochondrial disease. J Dev Behav Pediatr 2010;31:610–621. CrossRef
- Trounce IA, Pinkert CA. Cybrid models of mtDNA disease and transmission, from cells to mice. Curr Top Dev Biol 2007;77:157–183. CrossRef
- Zweier M, Rauch A. The MEF2C-Related and 5q14.3q15 Microdeletion Syndrome. Mol Syndromol 2012;2:164–170. CrossRef
- Scaglia F, Towbin JA, Craigen WJ, Belmont JW, Smith EO, Neish SR, et al. Clinical spectrum, morbidity, and mortality in 113 pediatric patients with mitochondrial disease. Pediatrics 2004;114:925–931. CrossRef
- Calvo SE, Tucker EJ, Compton AG, Kirby DM, Crawford G, Burtt NP, et al. High-throughput, pooled sequencing identifies mutations in NUBPL and FOXRED1 in human complex I deficiency. Nat Genet 2010;42:851–858. CrossRef
- Calvo SE, Compton AG, Hershman SG, Lim SC, Lieber DS, Tucker EJ, et al. Molecular diagnosis of infantile mitochondrial disease with targeted next-generation sequencing. Sci Transl Med 2012;4:118ra10. CrossRef
- Stenson PD, Ball EV, Mort M, Phillips AD, Shaw K, Cooper DN. The Human Gene Mutation Database (HGMD) and its exploitation in the fields of personalized genomics and molecular evolution. Curr Protoc Bioinformatics 2012;Chapter 1:Unit1 13.
- Zhang W, Cui H, Wong LJ. Application of next generation sequencing to molecular diagnosis of inherited diseases. Top Curr Chem 2012 May 11 [Epub ahead of print].
- Pagliarini DJ, Calvo SE, Chang B, Sheth SA, Vafai SB, Ong SE, et al. A mitochondrial protein compendium elucidates complex I disease biology. Cell 2008;134:112–123. CrossRef
- Tang S, Huang T. Characterization of mitochondrial DNA heteroplasmy using a parallel sequencing system. Biotechniques 2010;48:287–296. CrossRef
- Li M, Schonberg A, Schaefer M, Schroeder R, Nasidze I, Stoneking M. Detecting heteroplasmy from high-throughput sequencing of complete human mitochondrial DNA genomes. Am J Hum Genet 2010;87:237–249. CrossRef
- Zhang W, Cui H, Wong LJ. Comprehensive one-step molecular analyses of mitochondrial genome by massively parallel sequencing. Clin Chem 2012;58:1322–1331. CrossRef
- Wang J, Venegas V, Li F, Wong LJ. Analysis of mitochondrial DNA point mutation heteroplasmy by ARMS quantitative PCR. Curr Protoc Hum Genet 2011;Chapter 19:Unit 19 6.
- Hadjigeorgiou GM, Kim SH, Fischbeck KH, Andreu AL, Berry GT, Bingham P, et al. A new mitochondrial DNA mutation (A3288G) in the tRNA(Leu(UUR)) gene associated with familial myopathy. J Neurol Sci 1999;164:153–157. CrossRef
- Schrier SA, Wong LJ, Place E, Ji JQ, Pierce EA, Golden J, et al. Mitochondrial tRNA-serine (AGY) m.C12264T mutation causes severe multisystem disease with cataracts. Discov Med 2012;13:143–150.
- Santorelli FM, Tanji K, Sano M, Shanske S, El-Shahawi M, Kranz-Eble P, et al. Maternally inherited encephalopathy associated with a single-base insertion in the mitochondrial tRNATrp gene. Ann Neurol 1997;42:256–260. CrossRef
- Brown MD, Allen JC, Van Stavern GP, Newman NJ, Wallace DC. Clinical, genetic, and biochemical characterization of a Leber hereditary optic neuropathy family containing both the 11778 and 14484 primary mutations. Am J Med Genet 2001;104:331–338.
- Molecular Genetic Testing for Mitochondrial Disease: From One Generation to the Next
Volume 10, Issue 2 , pp 251-261
- Cover Date
- Print ISSN
- Online ISSN
- Additional Links
- Next generation sequencing
- massively parallel sequencing
- whole exome sequencing
- retrospective study
- mitochondrial disease diagnosis
- Author Affiliations
- 1. Divisions of Human Genetics and Child Development and Metabolic Disease, Department of Pediatrics, The Children’s Hospital of Philadelphia and University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, 19104, USA
- 2. Department of Ophthalmology, Ocular Genomics Institute, Massachusetts Eye and Ear Infirmary, Harvard Medical School, Boston, MA, USA