Mitochondrial Disease

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Use the power of our genetic testing to identify Mitochondrial Diseases and related disorders

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Challenges in the Diagnosis of Mitochondrial Diseases 1-4

• Mitochondrial disease is thought to be the most common type of metabolic disease occurring in childhood, with an estimated frequency of 1 in 5,000 live births. • Mitochondrial disease can be caused by mutations in either the mitochondrial or nuclear genome. • The diagnostic spectrum of mitochondrial disorders is much broader than previously thought which could potentially lead to misdiagnosis and/or inappropriate treatment. • Because of phenotypic and locus heterogeneity, traditional sequential genetic testing results in molecular diagnoses for only a fraction of patients.

Mitochondrial Disorder “Red-Flags”5 Physicians should have a high index of suspicion for mitochondrial disorders, and should consider such a diagnosis in any child presenting with multisystem involvement or with single-system involvement without a clear explanation. • Short Stature

• Diabetes mellitus

• Neurosensory hearing loss

• Hypertrophic cardiomyopathy

• Progressive external ophthalmoplegia

• Renal tubular acidosis

• Axonal neuropathy

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Mitochondrial Phenotypes A hallmark of mitochondrial disease is that patients can present with any symptom, in any organ, at any age and with any mode of inheritance.1

Eyes & Ears

• Visual Loss/Blindness • External Ophthalmoplegia • Pigmentary Retinopathy • Optic Atrophy • Ptosis • Hearing Loss/ Deafness

Systemic

• Failure to Gain Weight • Fatigue

Brain

• Stroke-Like Episodes • Developmental Delays • Dementia • Migraines • Seizures • Spasticity • Ataxia

Heart

• Cardiomyopathy • Cardiac Conduction Defects

Lungs

• Respiratory Problems • Exercise Intolerance

Pancreas and Thyroid

Liver

• Liver Failure

• Parathyroid Failure • Hypothyroidism • Diabetes

Kidney

Gastrointestinal Problems

• Renal Tubular Acidosis or Wasting • Renal Glomerular Disease

• Diarrhea/Constipation • Irritable Bowel Syndrome • Cramping

Muscles

• Proximal Myopathy • Exercise Intolerance • Muscle Pain • Hypotonia

Nerves

• Absent Reflexes • Neuropathic Pain • Fainting

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Complete Mitochondrial Evaluation This reflex test provides the coverage you need to make a confident diagnosis. If Tier 1 (mtDNA) is negative we will automatically reflex to Tier 2 (Nuclear Mitome) testing. This approach can provide a diagnosis with efficiency, economy, and certainty.

Tier 1: Mitochondrial Whole Genome Analysis This test includes sequence analysis of the entire 16,559 base pairs and the 37 genes included in the mitochondrial genome. Large deletion testing is also included and will identify deletions over 500 base pairs. This test will also report a patient’s haplogroup. Genes Analyzed by the mtDNA MT-ATP6, MT-ND1, MT-ND4, MT-ND4L, MT-ND5, MT-ND6, MT-RNR1, MT-TE, MT-TH, MT-TK, MT-TL1, MT-TS1, MT-TV. Two ribosomal RNA’s and 22 transfer RNA’s

Tier 2: 448 Nuclear Mitochondrial Genes Analyzed The Nuclear Mitome test is a comprehensive next-generation sequencing (NGS) panel that includes 448 nuclear genes encoding mitochondrial respiratory chain complexes, as well as other genes inducing secondary mitochondrial dysfunction or that cause diseases which mimic mitochondrial disorders. Our application of innovative custom capture technology with NGS enables high sensitivity for mutation detection and unparalleled coverage of the targeted 448 nuclear mitochondrial genes. Our Nuclear Mitome test has a mean depth of 1500X and 98% coverage of the targeted regions.

Genes Analyzed by the Nuclear Mitome Test Secondary Inhibitors of the Respiratory Chain Complex and Phenocopies Oxidative Phosphorylation Subunits Mitochondrial Transcription and Translation Factors Mitochondrial Carrier Protein Genes Oxidative Phosphorylation Assembly Factors Genes with Purported Mitochondrial Regulatory Function Mitochondrial DNA Synthesis and Mitochondrial Biogenesis Genes 0

50

100 Number of Genes

150

200

Indications For Testing • Individuals with multiple complex neurologic features or a single neurological symptom with other system involvement • Children presenting with lactic acidosis • Individuals with clinical symptoms characteristic of a specific mitochondrial disorder • Individuals with any progressive multisystem disorder of unknown etiology Each of these tests can be ordered individually

Partnering to Provide Diagnostic Answers

Transgenomic is a leader in the medical community and a proud partner of research projects striving toward medical advances in patient care.

MSeqDR Project Transgenomic is partnering with the scientific community by sharing mitochondrial variants with the MSeqDR Project, a global mitochondrial variant database, in an effort to reclassify variants of unknown significance. This will enhance diagnostic capabilities.

United Mitochondrial Disease Foundation Transgenomic provides funding for “Grand Rounds” meetings to help educate health care professionals on the diagnosis and treatment of mitochondrial disease.

TSC Variant Database Transgenomic has partnered with the Tuberous Sclerosis Alliance (TS Alliance) by sharing anonymized data on TSC genetic variants to the TSC Variant Database. This effort supports advances in the understanding and treatment of TSC.

ALD Connect Transgenomic is providing ABCD1 variants to the X-ALD Variant Database to strengthen the knowledge of this condition.

Dravet Syndrome Foundation The “Consider Dravet” campaign was developed to inform neurologists and pediatricians of the hallmark signs of Dravet syndrome and to promote early diagnosis in young patients who have this syndrome. Transgenomic is the exclusive sponsor that supports this campaign.

RESOURCES TO ADVANCE YOUR CLINICAL PRACTICE

Timely Diagnostic Answers Transgenomic is continually introducing new tests to provide diagnostic answers to complicated genetic conditions. The scientists are always investigating ways to shorten our turnaround-times as we recognize a patient and their family is waiting for an answer. To ensure no delays in the turnaround-time, please include within the kit: • The requisition form completed entirely

• Clinical notes

• Signatures from the doctor and patient/parents

• Labeled specimen

• A copy of both sides of the patient’s insurance card

Test

Description

TurnaroundTime

Comprehensive Evaluations Complete Mitochondrial Evaluation

Mitochondrial Whole Genome Analysis (mtDNA) reflex to comprehensive sequence analysis of 448 nuclear mitochondrial genes

12 weeks

Mitochondrial Whole Genome Analysis

Sequence analysis of the mitochondrial genome and large deletion analysis

4 weeks

Nuclear Mitome

Comprehensive sequence analysis of 448 nuclear mitochondrial genes

12 weeks

Targeted Panels AD-PEO Panel

Autosomal Dominant Progressive External Opthalmoplegia Panel (Sequence analysis of C10orf2, OPA1, POLG, POLG2, SLC25A4)

4 weeks

Mitochondrial Point Mutation Deletion Assay

The mitochondrial genome is assayed to detect 46 select point mutations within the mitochondrial genome that have been confirmed as disease-causing as well as large deletions.

4 weeks

Mitochondrial DNA Deletion Assay

Mitochondrial genome assayed to detect large deletions

4 weeks

Mitochondrial Depletion Panel

mtDNA Depletion Syndrome (Sequence analysis of POLG, DGUOK, MPV17)

4 weeks

Mitochondrial Depletion/ Deletion Panel

mtDNA Depletion Syndrome and Multiple Deletion Panel (Sequence analysis of POLG, DGUOK, MPV17, C10orf2, OPA1, POLG2, SLC25A4, TK2, TYMP)

4 weeks

Complex I Panel

Complex 1 Deficiency Panel (Sequence analysis of NDUFA1, NDUFA2, NDUFA7, NDUFAF2, NDUFAF3, NDUFS4, NDUFS5, NDUFS6, NDUFS7, NDUFS8, NDUFV1, NDUFV2)

4 weeks

Complex IV Panel

Complex IV Deficiency Panel (Sequence analysis of COX10, SCO1, 4 weeks SCO2, SURF1)

Single Genes and Phenotype-specific Testing BCS1L, POLG, POLG2, MELAS, NARP, LHON, RCD, CYTB, DFNS, MERRF, ACADVL (VLCAD), C10orf2, OPA1, SLC25A4, TYMP

4 weeks

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Result Report: Simple and Concise Transgenomic provides reports that are clear and concise, including clinical interpretations and recommendations. Our reports also discuss our comprehensive methodology and any test-related limitations.

DNA Change

 ll reported variants are A confirmed with Sanger sequencing to ensure a high level of analytical specificity.

Gene

Protein Change

% Heteroplasmy

Classification++

DISCOVER THE POWER OF OUR GENETIC TESTING

We are committed to advancing your clinical practice Transgenomic offers:

Genetic testing panels We provide comprehensive genetic testing panels available for mitochondrial disease and associated disorders.

Professional support and resources Our scientific and genetic counseling team is here to support you with everything from test selection to outcomes research, analysis, and interpretation.

Test reports Clear and comprehensive genetic testing reports assist you in making effective and timely patient management decisions.

References: 1. Hahn, S.H. Targeted next-generation sequencing expands the spectrum of mitochondrial disorders. Genome Med, 2012. 4(3): p. 22. 2. Vonchi, D. et al. Next-generation sequencing reveals DGUOK mutations in adult patients with mitochondrial DNA multiple deletions. Brain, 2012. 135(11): p. 3404-15. 3. Graham, B.H. Diagnostic challenges of mitochondrial disorders: complexities of two genomes. Methods Mol Biol, 2012. 837: p. 35-46. 4. Lieber, D.S., et al. Targeted exome sequencing of suspected mitochondrial disorders. Neurology, 2013. 80(19): p. 1762-70. 5. Koenig, M.K. Presentation and diagnosis of mitochondrial disorders in children. Pediatr Neurol, 2008. 38(5): p. 305-13. TO LEARN MORE, VISIT LABS.TRANSGENOMIC.COM TODAY OR CALL 1-877-274-9432 TO REQUEST A VISIT FROM ONE OF OUR MOLECULAR DIAGNOSTIC SPECIALISTS.

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Document No. 602426 04/15