PROGRESSIVE EXTERNAL OPHTHALMOPLEGIA(PEO)

POLG2 MTDNA Deletions with autosomal Dominant progressive external opthalmoplegia (ad-PEO)

DESCRIPTION - Nuclear Mitochondrial DNA Analysis

POLG2 sequencing Mitochondrial DNA (mtDNA) replication is a coordinated action of many nuclear-encoded proteins and upon the correct balance of nucleotides within the mitochondrial matrix. MtDNA is replicated by DNA polymerase gamma, which is composed of a 140-kD catalytic subunit (POLG1) and a 55-kD accessory subunit (POLG2). POLG2 gene has 8 coding exons and maps on chromosome 17q. The major role of POLG2 55-kD subunit is for highly processive mtDNA synthesis and enhanced DNA binding by the DNA polymerase G holoenzyme. This disorder ad-PEO arises through haploinsufficiency or heterodimerization of the mutated and wildtype proteins. It promotes mtDNA deletions by stalling the DNA replication fork. The progressive accumulation of mtDNA deletions causes COX deficiency in muscle fibers and results in the clinical phenotype

Test Order Code	POLG2-SEQGX
CPT Codes	83891 x 1, 83898 x 9, 83904 x 18
Indications For Testing	Clinical diagnosis of chronic PEO, Alpers syndrome and no evidence of neoplastic, metabolic, inflammatory and sporadic degenerative neurological disorder. Refractory seizures and developmental delay Confirmation or assistance with a clinical diagnosis Prenatal diagnosis only if a familial mutation is identified Genetic counseling
Turn Around Time	Less than two weeks. Expedited analysis is available upon request for an additional charge.
Specimen Requirements	Peripheral Blood Peripheral blood collection requires a Lavender-top (EDTA) vaccutainer tube available in the DNA Specimen Collection Kit. Keep sample at ambient temperature and ship by overnight courier to arrive at the Molecular Laboratory within 24 hrs after collection of the specimen. If shipment is delayed by one or two days, the specimen should be refrigerated and shipped at room temperature. Adults: 1 tube with 7.0 mL whole blood Children & Infants: 1 tube with 5-6 mL whole blood
Specimen Kits	DNA Specimen Collection Kits can be obtained from Transgenomic Molecular Laboratory.
Shipping and Contact Information	Transgenomic Molecular Laboratory 12325 Emmet Street Omaha, NE 68164 USA Phone: (866) 500-GENE / (866) 500-4363 Fax: (402) 452-5447 E-mail: labservice@transgenomiclabs.com
Test Submission and Patient Consent Forms	Test Requisition and Patient Consent Form Due to the unique nature of genetic testing, patients should receive pre-test and post-test counseling. Informed consent is recommended.
Test Methodology	The exons and flanking intron regions of POLG2 gene are PCR amplified and bidirectional sequencing is performed.
Sensitivity	Accuracy – 99% accuracy reported for mutation detection with bidirectional sequencing analysis. Limitations - The methodology will detect mutations located only within the regions defined by the primers. Some sequence alterations detected by this assay will be of unknown clinical relevance. Interpretation of test results should be in the context of the patient’s clinical and family histories, ethnicity, and other laboratory test results.
References	Carrodeguas, J. A.; Theis, K.; Bogenhagen, D. F.; Kisker, C. : Crystal structure and deletion analysis show that the accessory subunit of mammalian DNA polymerase gamma, Pol-gamma-B, functions as a homodimer. Molec. Cell 7: 43-54, 2001. Longley, M. J.; Clark, S.; Man, C. Y. W.; Hudson, G.; Durham, S. E.; Taylor, R. W.; Nightingale, S.; Turnbull, D. M.; Copeland, W. C.; Chinnery, P. F. : Mutant POLG2 disrupts DNA polymerase gamma subunits and causes progressive external ophthalmoplegia. Am. J. Hum. Genet. 78: 1026-1034, 2006.

OMIM Entries for:

POLG2-Related Disorders

157640	THYMIDINE KINASE, MITOCHONDRIAL; TK2
174763	POLYMERASE, DNA, GAMMA; POLG
203700	ALPERS DIFFUSE DEGENERATION OF CEREBRAL GRAY MATTER WITH HEPATIC CIRRHOSIS
258450	PROGRESSIVE EXTERNAL OPHTHALMOPLEGIA WITH MITOCHONDRIAL DNA DELETIONS, AUTOSOMAL RECESSIVE
607459	SENSORY ATAXIC NEUROPATHY, DYSARTHRIA, AND OPHTHALMOPARESIS; SANDO

Additional References

Mitomap
A human mitochondrial genome database. A compendium of polymorphisms and mutations of the human mitochondrial DNA. http://www.mitomap.org/

Note: The performance characteristics of this test were validated by TRANSGENOMIC Molecular Laboratory. The U.S. Food and Drug Administration (FDA) has not approved this test. However, FDA approval is currently not required for clinical use of this test. The results are not intended to be used as the sole means for clinical diagnosis or patient management decisions. TRANSGENOMIC Molecular Laboratory is authorized under Clinical Laboratory Improvement Amendments (CLIA) to perform high-complexity testing.

TRANSGENOMIC MOLECULAR LABORATORY

Phone: (866) 500-GENE/ (866) 500-4363

FAX: (402) 452-5447