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Applications of nucleic acid testing in diagnosis and therapy.

Nucleic acid testing or nucleic acid amplification testing, often abbreviated as NAT or NAAT, is a technique that involves amplification and detection of genetic material--the nucleic acids, DNA or RNA--for diagnosis or to provide guidance on therapy. Though the genetic material of every living being is composed of DNA or RNA, variations exist in genome sequences. This genetic variation makes NAT an ideal technique for identification of infectious diseases, cancer, genetic disorders, and mitochondrial disorders and as an aid to personalized and precision medicine based on the knowledge of pharmacogenomics.

NAT can be performed on various types of clinical specimens depending on the disease being diagnosed. Blood, plasma, serum, cerebrospinal fluid, sterile body fluids, sputum, urine, stool, and tissues are some specimens commonly used for NAT. The nucleic acids are first extracted from the cell and other cellular components either by manual or automated methods. The extracted nucleic acids can then be amplified and detected or sequences read using different methods--polymerase chain reaction (PCR), real-time PCR, microarrays, sequencing (Sanger and next-generation), etc. With the advancement in the technology for amplification and detection or sequencing, there has been a great transformation in the applications of NAT. The major applications are discussed below.

NAT for blood screening

NAT has been associated with blood screening for some time. It was first introduced by the German Red Cross in 1997 for blood screening to reduce the risk of transfusion-transmitted viral infections due to the failure of serologic screening tests to detect recently infected donors in the pre-seroconversion "window" phase of infection. (1) With serology tests, it takes about two months after infection for hepatitis C virus (HCV) antibodies to be detected, while NAT can detect HCV RNA about five days after infection. To reduce the window period for detection, European Union regulators began to require in 1999 that all plasma be tested by NAT techniques for HCV if derivatives made from such plasma were to be sold in Europe.

This announcement was a major impetus for the development and implementation of NAT of blood and plasma from donors in the United States and other developed countries. In the U.S., NAT was initially used to screen HCV and human immunodeficiency viruses types 1 and 2 (HIV 1, 2) in blood and blood products, and subsequently extended to hepatitis B virus (HBV) and West Nile virus (WNV). Screening for human T-lymph tropic virus types I and II (HTLV-I, II) and Treponema pallidum (causing syphilis) are also routinely performed using the serological method only. NAT has been adopted in several other countries around the world, including Canada, France, Australia, New Zealand, South Africa, and other countries in Europe and Asia. (2-3) In addition to screening for the organisms mentioned above, blood screening for other organisms, including Plasmodium vivax and Plasmodium falciparum (causing malaria), and Trypanosoma cruzi (causing Chagas disease) are also recommended, depending on the local epidemiological evidence of the disease. (4)

NAT in detecting infectious diseases

NAT is extensively used to detect and identify organisms for proper diagnosis, prognosis, and treatment of diseases. Diagnosing infectious diseases by detecting the nucleic acid of the causative agent in clinical specimens has been found to be more rapid, sensitive, and specific compared to the traditional method of diagnosis using culture or immunological methods. Table 1 provides some examples of organisms that have been detected by NAT in clinical laboratories. (5)

In virology, in addition to detecting the viruses, NAT further aids in identifying genotypes and subtypes, determining resistance to particular antibiotics, and measuring viral load. These applications help to provide guidance on treatment. In bacteriology, NAT has also been applied to resistance testing, the detection of infection due to fastidious bacteria, and the detection of bacterial infection after antibiotics have been administered.

NAT also helps in epidemiological studies and infection control. Table 2 provides some examples of applications of NAT other than detection. (5)

NAT in predicting cancer and guiding cancer treatment

Cancer is a disease caused by an uncontrolled division of abnormal cells in a part of the body. With improved sequencing capability and knowledge of the human genome (DNA), traditional descriptions of cancer--for example, by the organ of primary occurrence--are being superseded by a new classification framework that focuses on the genetic abnormalities and molecular derangements of malignant tumors. The genetic-level changes may consist of single or multiple sequence changes in cell DNA (mutations), addition or deletion of DNA, or changes in the number of copies of particular DNA sequences in cancer cells. Nucleic acid testing helps to identify genetic variations and predicts predisposition to cancer, alters diagnostic categories, enhances treatment strategies, enables early detection and prevention, and improves outcomes for cancer patients. Nucleic acid testing has led to the emergence of precision and personalized medicine--that is, the tailoring of treatment based on the individual's genetic make-up.

Table 3 provides a partial list of predisposition to certain type of cancer based on gene mutations. NAT helps in detection of the mutations in the genes. (6)

Table 4 provides a partial list of cancer drugs that are indicated for cancer patients with particular genetic variants. NAT helps in detection of the patient's genetic mutations. (7)

NAT for personalized and precision medicine

With today's increased knowledge of pharmacogenomics, nucleic acid testing is being increasingly used to provide personalized and precision medicine and avoid adverse reactions from drugs in individuals.

To define the terms: pharmacogenetics studies the effect of a single gene on drug response, while pharmacogenomics deals with the effects of multiple genes on drug response. The term pharmacogenetics was coined by Vogel in 1959, (8) but most of the progress in pharmacogenetics has been made in recent years. Researchers and clinicians have come to understand that every individual metabolizes drugs according to his or her genetic variants and therefore responds to drugs variably. This has enabled advancements in personalized and precision medicine.

Over the last decade, the U.S. Food and Drug Administration (FDA) has been aggressive in providing genetic labeling on new drugs, and also updating product labels for a number of existing therapies, such as warfarin and 6-mercaptopurine. At present, some 120 drugs (9) have pharmacogenetics information in their FDA product label. A current listing of all drugs with such information in the product label can be found in U.S. FDA Table of Pharmacogenomics Biomarkers in Drug Labels. (10) Pharmacogenetics information in product labels ranges from boxed warnings, the highest level of warning in the product label, to information in the clinical pharmacology section.

The Clinical Pharmacogenetics Implementation Consortium (CPIC), formed in 2009, sets guidelines on drug therapy based on pharmacogenetics information. (11) By early 2013, eight CPIC guidelines had been published, which include TPMT and thiopurines, (12) CYP2C19 and clopidogrel, (13) VKORC1/CYP2C9 and warfarin, (14) CYP2D6 and codeine, (15) HLA-B and abacavir, (16) SLCOIBI and simvastatin, (17) HLA-B and allopurinol, (18) and CYP2D6/CYP2C19 and tricyclic antidepressants. (19) These guidelines are summarized in Table 5. Production of a number of other guidelines is ongoing and a listing of in-progress guidelines can be found at The Pharmacogenomics Knowledgebase. (20)

NAT in screening for genetic disorders

NAT is being extensively used for prenatal screening and carrier screening for genetic disorders. Congenital anomalies account for 276,000 perinatal deaths by pregnancy Week 4 annually on a global basis. (21) The aim of prenatal screening is to detect birth defects, such as neural tube defects; chromosome abnormalities (e.g., Down syndrome, fragile X syndrome); and genetic disorders and other conditions (e.g., spina bifida, cleft palate, Tay Sachs disease, sickle cell anemia, thalassemia, cystic fibrosis, and muscular dystrophy). (21)

Carrier screening, the testing of parents in preparation for pregnancy, is used to identify genetic mutations that could cause serious inherited disorders. Some of the more common disorders for which such screening is done are cystic fibrosis, sickle cell disease, thalassemia, and Tay-Sachs disease. (21)

In the Ashkenazi (Eastern European descent) Jewish population, a number of genetic disorders occur more frequently than in the general population. It has been estimated that one in four individuals is a carrier of one of several genetic conditions. These diseases include Tay-Sachs disease, Canavan, Niemann-Pick, Gaucher, familial dysautonomia, Bloom syndrome, Fanconi anemia, cystic fibrosis, and mucolipidosis IV. Table 6 provides a list of common genetic disorders.

NAT in diagnosis of mitochondrial diseases

Mitochondrial diseases are a group of disorders caused by dysfunctional mitochondria--the cellular organelle in which respiration and energy formation occur. Mitochondrial diseases can be caused by genetic mutation in the mitochondrial DNA (mtDNA) or in the nuclear DNA. Mtochondrial diseases may affect a single organ--for example, the eye in Leber hereditary optic neuropathy (LHON)--or may involve many organs, and they often result in major neurologic and myopathic symptoms. Table 7 lists a few disorders caused due to mutations in mitochondrial DNA. (22)

The genetic basis of mitochondrial disease was first discovered in the late 1980s. Since then, mitochondrial disease diagnosis has continued to evolve with improvement in NAT technology. Now, with NAT technologies such as 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 have greatly helped in understanding and diagnosing mitochondrial diseases. (23)

Conclusion

Nucleic acid testing is growing very rapidly in laboratory medicine. With the emergence of newer technology and easy-to-use sample-to-result systems, NAT can be applied in more areas of testing. In the future, NAT will play an important role in making personalized and predictive medicine the standard of care for better healthcare.

REFERENCES

(1.) Hourfar MK, Jork C, Schottstedt V, et al. Experience of German Red Cross blood donor services with nucleic acid testing: Results of screening more than 30 million blood donations for human immunodeficiency virus-1, hepatitis C virus, and hepatitis B virus. Transfusion. 2008;48:1558-1566.

(2.) Busch MP, Glynn SA, Stramer SL, et al. A new safety strategy for estimating risks of transfusion-transmitted viral infections based on rates of detection of recently infected donors. Transfusion. 2005;45:254-264.

(3.) Chamberland ME, Alter HJ, Busch MP, Nemo G, Ricketts M. Emerging infectious disease issues in blood safety. Emerging Infectious Diseases. Vol. 7, No. 3 Supplement, June 2001.

(4.) World Health Organization. Screening donated blood for transfusion-transmissible infections, http:// www.who.int/bloodsafety/ScreeningDonatedBloodforTransfusion.pdf.

(5.) Speers DJ. Clinical applications of molecular biology for infectious diseases. Clin Biochem Rev. 2006 27(1): 39-51.

(6.) National Cancer Institute. Genetic testing for hereditary cancer syndromes, http://www.cancer.gov/ about-cancer/causes-prevention/genetics/genetictesting-fact-sheet.

(7.) Personalized Medicine Coalition. The case for personalized medicine. 4th edition. 2014. httpj/www.personalizedmedicinecoalition.org/Userfiles/PMC-Corporate/ file/pmc_the_case_for_personatized_medicine.pdf.

(8.) Vogel F. [Modern problems of human genetics.] Ergeb Inn Med Kinderheilkd. 1959;12:52-125. In German.

(9.) Singer DE, Albers GW, Dalen JE et al. Antithrombotic therapy in atrial fibrillation: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest. 2004;126(3, suppl):429S-456S.

(10.) US FDA Table of Pharmacogenomic Biomarkers in Drug Labels. www.fda.gov/Drugs/ScienceResearch/ ResearchAreas/Pharmacogenetics/ucm083378.htm.

(11.) Relling MV, Klein TE. CPIC: Clinical Pharmacogenetics Implementation Consortium of the Pharmacogenomics Research Network. Clin Pharmacol Ther. 2011 ;89(3):464-467.

(12.) Relling MV, Gardner EE, Sandborn WJ, et al., Clinical Pharmacogenetics Implementation Consortium guidelines for thiopurine methyltransferase genotype and thiopurine dosing. Clin Pharmacol Ther. 2011;89(3):387391.

(13.) Scott SA, Sangkuhl K, Gardner EE, et al. Clinical Pharmacogenetics Implementation Consortium guidelines for cytochrome P450-2C19 (CYP2C19) genotype and clopidogrel therapy. Clin Pharmacol Ther. 2011;90(2):328-332.

(14.) Johnson JA, Gong L, Whirl-Carrillo M, et al. Clinical Pharmacogenetics Implementation Consortium Guidelines for CYP2C9 and VK0RC1 genotypes and warfarin dosing. Clin Pharmacol Ther. 2011 ;90(4):625-629.

(15.) Crews KR, Gaedigk A, Dunnenberger HM, et al. Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines for codeine therapy in the context of cytochrome P450 2D6 (CYP2D6) genotype. Clin Pharmacol Ther. 2012;91 (2):321-326.

(16.) Martin MA, Klein TE, Dong BJ, Pirmohamed M, Haas DW, Kroetz DL, Clinical pharmacogenetics implementation consortium guidelines for HLA-B genotype and abacavir dosing. Clin Pharmacol Ther. 2012;91 (4):734-738.

(17.) Wilke RA, Ramsey LB, Johnson SG, et al. The Clinical Pharmacogenomics Implementation Consortium: CPIC guideline for SLC01B1 and simvastatin-induced myopathy. Clin Pharmacol Ther. 2012;92(1):112-117.

(18.) Hershfield MS, Callaghan JT, Tassaneeyakul W, et al. Clinical Pharmacogenetics Implementation Consortium guidelines for human leukocyte antigen-B genotype and allopurinol dosing. Clin Pharmacol Ther. 2013;93(2):153-158.

(19.) Hicks JK, Swen JJ, Thorn CF, et al. Clinical Pharmacogenetics Implementation Consortium guideline for CYP2D6 and CYP2C19 genotypes and dosing of tricyclic antidepressants. Clin Pharmacol Ther. 2013;93(5):402408.

(20.) The Pharmacogenomics Knowledgebase, www. PharmBKB.org.

(21.) Gabrielle Gabrielle Heilek. Nucleic Acids: The Use of Nucleic Acid Testing in Molecular Diagnostics Chapter 5. http://www.intechopen.com/books/howtoreference/nucleic-acids-from-basic-aspects-to-laborato- ry-tools/nucleic-acids-the-use-of-nucleic-acid-testingin-molecular-diagnostics.

(22.) Robert W. Taylor and Doug M. Turnbull Mitochondrial DNA Mutations In Human Disease Nat Rev Genet. 2005 May;6(5):389-402.

(23.) McCormick E1, Place E, Falk MJ. Molecular genetic testing for mitochondrial disease: from one generation to the next. Neurotherapeutics. 2013 Apr;10(2):251-61.

Rajasri Chandra, MS, MBA, serves as Product Manager for molecular diagnostics provider AutoGenomics, Inc., based in Vista, CA.
Table 1. Examples of organisms detected by NAT in clinical laboratories

Organisms   Examples

Viruses     Herpes simplex virus (HSV), Cytomegalovirus (CMV),
            Epstein-Barr virus (EBV), Varicella Zoster virus (VZV),
            Human herpes virus type 6,7,8 (HHV), Respiratory
            viruses--Adenovirus, Influenza virus, Parainfluenza
            virus, Human Respiratory Syncytial virus (hRSV),
            Coronavirus, Enterovirus, Human Metapneumovirus (hMPV),
            Rhinovirus, Human Papillomavirus (HPV), Rotavirus,
            Norovirus HIV, HCV, HBV, WNV Dengue, Chikungunya etc.

Bacteria    Sexually transmitted: Chlamydia trachomatis, Neisseria
            gonnorhoea, Trichomonas vaginalis, Mycoplasma hominis,
            Mycoplasma genitalium, Gardnerella vaginalis, Atopobium
            vagiane, Bacteroides fragilis, Prevotella bivia,
            Mobiluncus mulieris, Molbiluncus curtisii, Ureaplasma
            urealyticum, Ureaplasma parvum etc. Acinetabacter
            baumanii, Bordetellea purtusis. Staphylococcus aureaus,
            MRSA, Streptococcus, Enterococcus, Enterobacteriaceae,
            Clostridium difficile, Campylobacter jejuni,
            Plesiomonas shigelloides, Salmonella, E.coli, Listeria
            monocytogenes, Legionella, Haemophilus influenza,
            Neisseria meningitides, Pseudomonas aeruginosa,
            Mycobacterium tuberculosis complex, Nontuberculosis
            Mycobacterium, etc.

Yeast       Candida albicans, Candida glabrata, Candida tropicalis,
            Candida parapsilosis, Candida krusei, Candida
            dubliniensis, etc.

Fungi       Aspergillus spp., Pneumocystis jiroveci

Parasites   Entamoeba histolytica, Giardia lamblia, Plasmodium
            vivax and Plasmodium falciparum, Trichomonas vaginalis,
            etc.

Table 2. Examples of NAT applications other than detection of organisms

Test                                           Example

Viral load monitoring             HIV, HCV, HBV, CMV, EBV

Viral genotyping                  HIV, HBV, HCV, HPV

Bacterial resistance detection    MRSA, VRE, ESBL containing E.coli,
                                  K. pneumoniae, MDR-Tb

Bacterial genotyping              M.tuberculosis, N.meningitidis

Broad-range PCR                   Infective endocarditis, bacterial
                                  meningitis

Table 3. Predisposition to type of cancer based on gene mutation

Disease           Gene(s)         Predisposition to Type of Cancer
Syndrome            with
                  mutation

Hereditary        BRCA1,     Female breast, ovarian, and other cancers,
breast cancer     BRCA2      including prostate, pancreatic, and male
and ovarian                  breast cancer
cancer syndrome

Li-Fraumeni       TP53       Breast cancer, soft tissue sarcoma,
syndrome                     osteosarcoma (bone cancer), leukemia,
                             brain tumors, adrenocortical carcinoma
                             (cancer of the adrenal glands), and other
                             cancers

Cowden syndrome   PTEN       Breast, thyroid, endometrial (uterine
(PTEN hamartoma              lining), and other cancers
tumor syndrome)

Lynch syndrome    MSH2,      Colorectal, endometrial, ovarian, renal
(hereditary       MLH1,      pelvis, pancreatic, small intestine, liver
nonpolyposis      MSH6,      and biliary tract, stomach, brain, and
colorectal        PMS2,      breast cancers
cancer)           EPCAM

Familial          APC        Colorectal cancer, multiple non-malignant
adenomatous                  colon polyps, and both non-cancerous
polyposis                    (benign) and cancerous tumors in the small
                             intestine, brain, stomach, bone, skin, and
                             other tissues

Retinoblastoma    RB1        Eye cancer (cancer of the retina),
                             pinealoma (cancer of the pineal gland),
                             osteosarcoma, melanoma, and soft tissue
                             sarcoma

Multiple          MEN1       Pancreatic endocrine tumors and (usually
endocrine                    benign) parathyroid and pituitary gland
neoplasia type               tumors
1 (Wermer
syndromel

Multiple          RET        Medullary thyroid cancer and
endocrine                    pheochromocytoma (benign adrenal gland
neoplasia type               tumor)
2

Von               VHL        Kidney cancer and multiple noncancerous
Hippel-Lindau                tumors, including pheochromocytoma
syndrome

Table 4. Cancer drugs indicated for patients with particular mutations

Drug Name         Gene                Indication Based on Patient
(Brand)                               Genetic Variants

Ado-trastuzumab   ERBB2 (HER2)        Indicated, as a single agent,
emtansine                             for the treatment of
(Kadcyla)                             metastatic breast cancer
                                      patients with HER2-positive,
                                      who previously received
                                      trastuzumab and a taxane,
                                      separately or in combination

Afatinib          EGFR                Indicated for the first-line
(Gilotrif)                            treatment of patients with
                                      metastatic non-small cell lung
                                      cancer (NSCLC) whose tumors
                                      have epidermal growth factor
                                      receptor (EGFR) exon 19
                                      deletions or exon 21 (L858R)
                                      substitution mutations

Arsenic           PML/RARa            For induction of remission and
trioxide                              consolidation in patients with
(Trisenox)                            acute promyelocytic leukemia
                                      (APL) whose APL is
                                      characterized by the presence
                                      of the t (15;17) translocation
                                      or PML/RAR-alpha gene
                                      expression

Busulfan          Philadelphia        Less effective in chronic
(Busulfex &       Chromosome/         myelogenous leukemia patients
Myleran)          BCR-ABL             who lack the Philadelphia
                                      (Ph1) chromosome

Capecitabine      Dihydropyrimidine   Multiple cancers;
(Xeloda)          dehydrogenase       contraindicated in patients
                  (DPD) deficiency    having DPD deficiency

Cetuximab         EGFR, KRAS          Indicated for treatment of
(Erbitux)                             metastatic colorectal cancer
                                      patients having K-Ras
                                      mutation-negative (wild-type)
                                      and EGFR-expressing

                  BRAF                Indicated for metastatic
                                      colorectal cancer patients who
                                      fail to respond to TKIs and
                                      have non-mutated forms of BRAF
                                      and KRAS genes

Dabrafenib        BRAF                Indicated for the treatment of
(Tafinlar)                            patients with unresectable or
                                      metastatic melanoma with BRAF
                                      V600E mutation

Dasatinib         Philadelphia        Indicated for the treatment of
(Sprycel)         Chromosome/         adults with acute
                  BCR-ABL             lymphoblastic leukemia and
                                      Philadelphia
                                      chromosome-positive (Ph+ ALL)
                                      with resistance or intolerance
                                      to priortherapy

Irinotecan        UGT1A1              Colon cancer patients who are
(Camptosar)                           homozygous for the UGT1A1*28
                                      allele are at increased risk
                                      for neutropenia following
                                      initiation of irinotecan
                                      treatment A reduction in the
                                      starting dose by at least one
                                      level of the drug should be
                                      considered for patients known
                                      to be homozygous for the
                                      UGT1AR28 allele

                  ERCC1               High expression of ERCC1 is
                                      associated with response to
                                      irinotecan therapy in colon
                                      cancer patients

Table 5. Summary of Clinical Pharmacogenetics
Implementation Consortium guidelines

Drug(s)               Gene(s)            CPIC Recommendations

Azathioprine,           TPMT        Dosing recommendations based
6-mercaptopurine                    on TPMT genotype
and thioguanine

Clopidogrel           CYP2C19       Recommendations for
                                    alternative treatment based on
                                    CYP2C19 genotype in
                                    post-percutaneous

Warfarin           VK0RC1/CYP2C9    Recommendations for use of
                                    pharmacogenetics algorithms
                                    that incorporate VK0RC1 and
                                    CYP2C9 genotype with clinical
                                    factors for warfarin dose
                                    prediction

Codeine                CYP2D6       Recommendation to avoid
                                    codeine in individuals with
                                    ultra rapid or poor
                                    metabo-lizer phenotype
                                    predicted based on CYP2D6
                                    genotype

Abacavir               HLA-B        Recommendation to avoid
                                    abacavir in individuals
                                    positive for HLA-B*57:01
                                    genotype

Simvastatin           SLC01B1       Guidance for simvastatin use
                                    or dosing based on SLC01B1
                                    genotype

Allopurinol            HLA-B        Recommendation to avoid
                                    allopurinol in individuals
                                    positive for HLA-B*58:01
                                    genotype

Tricyclic          CYP2D6/CYP2C19   Dosing recommendations for
antidepressants                     tricyclic antidepressants
                                    based on CYP2D6 and CYP2C19
                                    genotype

Table 6. List of common genetic disorders

Syndrome                          Mutation Type          Chromosome

DiGeorge syndrome or        Deletion                        22q
22q11.2 deletion syndrome

Angelman syndrome           Point mutation,                  15
                            Chromosome abnormality,
                            Deletion

Canavan disease             Defective ASPA gene             17p

Charcot--Marie--Tooth       Chromosome abnormality           17
disease

Color blindness             Point mutation                   X

Cri du chat syndrome,       Deletion                         5
chromosome 5p deletion
syndrome

Cystic fibrosis             Point mutation                   7q

Down syndrome               Chromosome abnormality           21

Duchenne muscular           Deletion                         Xp
dystrophy

Haemochromatosis            Point mutation                   6

Haemophilia                 Point mutation                   X

Klinefelter syndrome        Chromosome abnormality           X

Neurofibromatosis           Point mutation                  NF1

Phenylketonuria             Point mutation                  12q

Polycystic kidney disease   Point mutation              16 (PKD1) or
                                                          4 (PKD2)

Prader-Willi syndrome       Chromosome abnormality           15
                            deletion

Sickle-cell disease         Point mutation                   Up

Spinal muscular atrophy     Deletion, Point mutation         5q

Tay-Sachs disease           Point mutation                   15

Turner syndrome             Chromosome abnormality           X

Table 7. Clinical disorders caused by mutations in mitochondrial DNA

Mitochondrial        Clinical       mtDNA Genotype         Gene
DNA Disorder         Phenotype

Kearns-Sayre      Progressive       A single,         Several deleted
syndrome          myopathy,         large-scale       genes
                  ophthalmoplegia,  deletion
                  cardiomyopathy

CPEO              Ophthalmoplegia   A single,         Several deleted
                                    large-scale       genes
                                    deletion

Pearson           Pancytopoenia,    A single,         Several deleted
syndrome          lactic acidosis   large-scale       genes
                                    deletion

MELAS             Myopathy,         3243A>G;3271T>C   TRNL1 ND1 and
                  encephalopathy    Individual        ND5
                  lactic            mutations
                  acidosis,
                  stroke-like
                  episodes

MERRF             Myoclonic         8344A>G;          TRNK
                  epilepsy,         8356T>C
                  myopathy

NARP              Neuropathy,       8993T>G           ATP6
                  ataxia,
                  retinitis
                  pigmentosa

MILS              Progressive       8993T>C           ATP6
                  brain-stem
                  disorder

MIDD              Diabetes,         3243A>G           TRNL1
                  deafness          3460G>A           ND1

LHON              Optic             11778G>A          ND4
                  neuropathy        14484T>C          ND6

Myopathy and      Myopathy,         14709T>C          TRNE
diabetes          weakness,
                  diabetes

Sensorineural     Deafness          1555A>G           RNR1 TRNS1
hearing loss                        Individual
                                    mutations

Exercise          Fatigue, muscle   Individual        CYB
intolerance       weakness          mutations

Fatal,            Encephalopathy,   10158T>C;         ND3
infantile         lactic acidosis   10191T>C
encephalopathy;
Leigh/
Leigh-like
syndrome
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Title Annotation:SPECIAL FEATURE: NUCLEIC ACID TESTING
Author:Chandra, Rajasri
Publication:Medical Laboratory Observer
Article Type:Technical report
Geographic Code:1USA
Date:Jun 1, 2016
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