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 30, 2012

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

POLG OligoArray Analysis (deletion/duplication analysis)

Diagnostic testing for a symptomatic individual Blood April 20, 2012

Result:

A loss in copy number encompassing at least 5.7 Kb (nucleotide positions 89878439 to 89872739 involving exons 1 through 3 of the POLG gene 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. Previous analysis in this laboratory had identified a heterozygous c.1399G>A (p.A467T) mutation in this individual's POLG1 gene, indicating that this individual is at least a carrier for POLG deficiency. We were requested to evaluate this individual for possible dosage changes in the POLG locus by OligoArray hybridization. A loss in copy number encompassing at least 5.7 Kb (nucleotide positions 89878439 to 89872739 involving exons 1 through 3 of the POLG gene was detected. Dosage could not be evaluated in the 5 flanking region due to limited coverage in this region. This result is consistent with a heterozygous deletion of POLG exons 1 3. Targeted analyses are recommended for this individuals biological parents in order to establish the phase of this deletion mutation and the p.A467T mutation. Clinical correlation and genetic counseling are recommended. Genetic testing is available for at-risk relatives.

Interpretation:

Name: Soledad Raskin

ID Number: 021201234

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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: _____________________ 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. 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. Clinical correlation and genetic counseling are recommended. Genetic testing is available for at-risk relatives. 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: Comparative genomic hybridization is performed on a custom oligonucleotide microarray to assess for copy number changes in the nuclear gene(s) of interest based upon the indication for testing. Findings are reported according to genome build hg19. While this analysis can detect most relevant deletions or duplications in the nuclear locus of interest, it is possible that some copy number changes resulting in intragenic deletions and/or duplications may not be detectable if they occur in regions lacking corresponding probes. Small scale gene mutations, such as point mutations, will not be detected by this assay. Therefore, sequencing of the relevant gene(s) may also be appropriate depending on additional biochemical evidence or clinical suspicion. In addition, the detection of a heterozygous deletion would generally warrant direct DNA sequencing of the other allele in autosomal recessive disorders. In some circumstances, testing of additional family members may be necessary in order to clarify the clinical significance of findings.

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 polymerase-

Name: Soledad Raskin

ID Number: 021201234

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gammaA. 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.