The Genetics Laboratory 1111 Laboratory Avenue Nowhere, State 00839 (555) 920-3333

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Patient Name: ID number: DOB: Gender:

Soledad Raskin 021201234 01/28/2010 Female

Personal and Family Information

Race/Ethnicity: Argentine Hispanic Family health history: brother deceased at age 5, hx of severe headaches Personal health history: developmental delay, hypotonia, seizures, encephalopathy

Ordering Physician: Dr. Parker Date of Report: May 15, 2012

Test Performed:
Indication for testing: Specimen Type: Date of Collection:

POLG1 Sequence Analysis

Diagnostic testing for a symptomatic individual Blood April 20, 2012

Result: Interpretation:

A heterozygous c.1399G>A (p.A467T) mutation was detected.

Test results should be interpreted in the context of the patient's clinical and family history. It is our understanding that this individual has clinical symptoms consistent with a possible mitochondrial disorder. For the purpose of this analysis, we assume that this information is accurate. A heterozygous c.1399G>A (p.A467T) mutation was detected in this individual's POLG1 gene. The A467T mutation in exon 6 is the most common mutation reported in POLG1. The A467T mutant enzyme possesses only 4% of wild type DNA gamma polymerase activity due to the failure to interact with the accessory subunit which is required for the processive DNA synthesis and tight binding of the polymerase gamma complex to DNA. This result indicates that this individual is at least a carrier. This analysis will not detect large heterozygous deletions or duplications, or mutations within the promoter or deep intronic regions. If intragenic deletions/duplications are suspected, then we would recommend oligonucleotide array CGH analysis of the POLG locus. Clinical correlation and genetic counseling are recommended. Genetic testing is available for at-risk relatives.

Guidance:

Genetic consultation for the individual is useful for clarifying carrier risk and implications for other family members - (see supplemental information) For additional questions about the test or result, please contact the laboratory Additional information regarding this test is available at GeneTests (http://www.genetests.org) Information for the individual tested and their family is available at Genetics Home Reference (http://ghr.nlm.nih.gov/)

This report (which includes the supplemental information on the following page) was approved by:

Name: Soledad Raskin

ID Number: 021201234

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_____________________ John Doe, M.D., Ph.D. Director, The Genetics Laboratory

__________ Date

General disclaimer: This test is used for clinical purposes. It should not be regarded as investigational or for research. The laboratory is regulated under CLIA of 1988.

Supplemental Information:
DNA polymerase gamma is the only DNA polymerase found in animal cell mitochondria. It bears sole responsibility for mitochondrial DNA biosynthesis. Mutations in POLG1, the catalytic subunit of polymerase gamma, cause a variety of mitochondrial diseases, including dominant and recessive forms of progressive external ophthalmoplegia (PEO), Alpers syndrome, Parkinsonism, juvenile spinocerebellar ataxia-epilepsy syndrome (SCAE), as well as sensory ataxia, neuropathy, dysarthria and ophthalmoparesis (SANDO). Alpers syndrome is an early-onset fatal disease characterized by hepatic failure, intractable seizures and global neurological deterioration (OMIM#203700). SANDO is a juvenile-onset mixed sensory and cerebellar atactic syndrome complicated by epileptic seizures and myoclonus. Accumulation of multiple mtDNA deletions in post-mitotic tissues such as muscle and brain is noted in adPEO and arPEO. Much lesser amounts of mtDNA deletion molecules are detected in the muscle tissue of patients affected with SANDO or SCAE. In contrast, depletion of liver mtDNA rather than mtDNA deletion is associated with Alpers syndrome in patients bearing mutations in POLG1. Genetic consultation is a process that includes 1) confirming, diagnosing, or ruling out a genetic condition, 2) identifying medical management issues, and/or 3) counseling to educate and help people understand, adapt, and make informed choices with regard to the medical, psychological and familial implications of genetic contributions to disease, and the risk for disease occurrence or recurrence. A genetic consultation can be provided by a clinical geneticist, genetic counselor or other health care professional, as relevant to the medical or counseling services sought. A directory of board-certified MD and PhD geneticists can be found at http://www.abmg.org and a directory of genetic counselors can be found at http://www.nsgc.org. Test method: The coding exons and immediately flanking intronic regions of POLG1 gene located at 15q25 were PCR amplified. The corresponding PCR products were sequenced in the forward and reverse directions using automated fluorescent dideoxy sequencing method. This analysis will not detect large heterozygous deletions or duplications, inversions, or mutations within the promoter or deep intronic regions. Nucleotide numbering is based on GenBank accession number NM_002693.1; nucleotide 1 corresponds to the A of the start codon ATG. The interpretation of nucleotide changes is based on our current understanding of the specific gene. This interpretation may change over time as more information about this gene becomes available. Possible diagnostic errors include sample mix-ups, genetic variants that interfere with analysis, incorrect assignment of biological parentage, and other sources. Please contact a genetic counselor at the Medical Genetics Laboratories if there is reason to suspect one of these sources of error.

References:
1. Naviaux RK, et al. (2004) POLG mutations associated with Alpers' syndrome and mitochondrial DNA depletion. Ann Neurol 55:706-12 2. Van Goethem G, et al. (2005) Infantile hepatocerebral syndromes associated with mutations in the mitochondrial DNA polymerasegammaA. Brain 128:723-31 3. Wong L-JC, et al. (2008) Molecular and clinical genetics of mitochondrial diseases due to POLG mutations. Hum Mutat. 29:E15072. 4. Milone M, et al. (2008) Sensory ataxic neuropathy with ophthalmoparesis caused by POLG mutations. Neuromuscul Disord. 18:626-32 5. Tang S, Wong LJ, et al. (2011) Mitochondrial DNA polymerase gamma mutations: an ever expanding molecular and clinical spectrum. J Med Genet. 48(10):669-81.