Mitochondrial Disorders Genetic Testing

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1 Mitochondrial Disorders Genetic Testing A Comprehensive Guide

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3 Introduction Mitochondrial disorders are a group of related, clinically diverse, genetic diseases with a prevalence of 1/5,000 to 1/8,500 that result from dysfunction of the mitochondrial respiratory chain. 1 They can be caused by defects in either the mitochondrial DNA (mtdna) or in nuclear genes. The heterogeneous clinical features and genetic causes make diagnosing mitochondrial disorders challenging. An accurate diagnosis is important for patient management and genetic counseling. CLINICAL INFORMATION Clinical Presentation Mitochondrial disorders may affect a single organ, but many involve multiple organ systems, particularly those that are highly dependent on aerobic metabolism, such as the brain, skeletal muscle, heart, kidney, and endocrine system (Figure 1). Patients may present at any age; however, nuclear DNA mutations generally present in childhood and mtdna mutations are more likely to present in late childhood or in adults. Some affected individuals exhibit clinical features that fall into discrete clinical syndromes, such as Leber s Hereditary Optic Neuropathy (LHON) and Kearns-Sayre syndrome (KSS) (Table 1). However, often the clinical features are highly variable and non-specific and many affected persons do not fit into one particular category. Similar clinical features can be caused by different mutations in mtdna or mutations in many different nuclear genes. Common features of mitochondrial disease may include: 1-4 Common Symptoms of Mitochondrial Disorders Ataxia Cardiomyopathy Chorea Chronic diarrhea or constipation Delayed gastric emptying Dementia Developmental delay /Intellectual disability Diabetes mellitus Exercise intolerance Failure to thrive Gastrointestinal reflux Hypotonia Liver failure Migraines Muscle weakness Optic atrophy Pigmentary retinopathy Progressive external ophthalmoplegia Ptosis Recurrent vomiting Seizures Sensorineural deafness Spasticity Stroke-like episodes MITOCHONDRIAL DISORDERS GUIDE 2

4 CLINICAL INFORMATION Table 1. Clinical syndromes of mitochondrial diseases (adapted from Chinnery, PF. 2010) Disorder Primary symptoms CPEO Eye muscle paralysis, droopy eyelids (both eyes) Late childhood- or adult-onset peripheral neuropathy, lack of muscular coordination, pigmentary retinopathy Stroke-like episodes at younger than 40, seizures, dementia, lactic acidosis and/or ragged red fibers NARP MELAS MEMSA Myopathy, seizures, cerebellar ataxia MERRF Muscle twitching, seizures, cerebellar ataxia, myopathy LHON Subacute bilateral painless visual failure Leigh Syndrome (LS) Onset in first year, psychomotor regression, respiratory failure, failure to thrive, hypotonia CPEO, chronic progressive external opthalmoplegia; NARP, neurologic weakness with ataxia and retinitis pigmentosa; MELAS, mitochondria encephalopathy with lactic acidosis and stroke-like episodes; MEMSA, myoclonic epilepsy myopathy sensory ataxia; MERRF, myoclonic epilepsy with ragged red fibers; LHON, Leber's Hereditary Optic Neuropathy Figure 1. Symptoms of Mitochondrial Disorders Heart Conduction disorder Wolff-Parkinson-White syndrome Cardiomyopathy Skeletal muscle Weakness Fatigue Myopathy Neuropathy Brain Seizures Myoclonus Ataxia Stroke Dementia Migraine Nuclear DNA Subunits Oxidative phosphorylation Eye Optic neuropathy Ophthalmoplegia Retinopathy Liver Hepatopathy ATP Kidney Fanconi s syndrome Glomerulopathy Mitochondrial DNA Pancreas Diabetes mellitus Nuclear DNA Colon Pseudo-obstruction 3 Inner ear Sensorineural hearing loss Blood Pearson s syndrome

5 Diagnosis Diagnosing patients with mitochondrial disorders is challenging due to the varied clinical presentation, genetic heterogeneity, and frequent need for invasive testing procedures. The diagnosis is typically considered in patients with progressive disorders involving multiple organ systems and is sometimes obvious if the patient exhibits one of the classic syndromes with stereotypical features such as MELAS, MERRF, LHON, NARP, or KSS. If the diagnosis is not obvious, the following studies can be used to help guide the diagnostic process: Family history: especially if a maternal inheritance pattern is present. Neuroimaging studies: CT and MRI. Functional studies: brain stem dysfunction, abnormal BAERS/ VERS/EEG, increased signal in the basal ganglia, delayed myelination, white matter abnormalities, cerebellar atrophy and lactate elevation on magnetic resonance spectroscopy (MRS). Laboratory investigations: lactate, pyruvate, lactate/pyruvate ratio, alanine, acylcarnitine profile and urine organic acids.* Muscle, liver and/or heart biopsy: assay of electron transport chain activity, light microscopy, and electron microscopy.* Genetic testing *Biochemical test results for mitochondrial disorders may not be reliable or reproducible, and rarely can the underlying etiology be determined without molecular studies. Molecular genetic testing is required to make a definitive diagnosis, provide guidance on management and prognosis, and permit accurate risk counseling. For mitochondrial disorders that result from mutations in nuclear genes, molecular genetic testing can also facilitate prenatal diagnosis. MITOCHONDRIAL DISORDERS GUIDE 4

6 Genetic Heterogeneity The inheritance pattern can be autosomal dominant, autosomal recessive, X-linked or maternal. Similar clinical features can be caused by mitochondrial (mtdna) variants or nuclear gene variants (genetic heterogeneity), and conversely, a variant in a single nuclear or mitochondrial gene may be associated with different clinical features (clinical heterogeneity). Symptoms may present at any age; however, individuals with nuclear DNA variants generally present in childhood and those with mtdna variants generally present in late childhood or in adults. Approximately 1,500 nuclear genes and the mitochondrial genome are involved in maintaining proper mitochondrial respiratory chain function. Each mitochondrion has multiple copies of mtdna and there are hundreds to thousands of mitochondria per cell, dependent on the cell type. The mtdna encodes for ribosomal RNAs (two genes), transfer RNAs (22 genes), and 13 proteins that are part of the respiratory chain. The other genes required for mitochondrial function are encoded in the nuclear genome (Figure 2). MtDNA variants can arise de novo (has arisen new in that individual and was not inherited from the mother) or are maternally inherited. In most cases, mtdna point variants are inherited, whereas large deletions arise de novo. Usually, mtdna pathogenic variants affect only a fraction of the mitochondria; the coexistence of normal and pathogenic mtdna is called heteroplasmy. When the percentage of pathogenic mtdna reaches a certain threshold, which varies by tissue type, age, and specific variant, the function of that tissue may become impaired. The pathogenic load varies within and between tissues, and the manifestation of mitochondrial disease reflects tissuespecific pathogenic load. However, access to the relevant tissues for testing is not always possible. 5

7 Due to the bottle neck effect, the inheritance of mitochondrial DNA disorders within families is difficult to predict: A mother can pass on a small proportion of pathogenic mtdna, or a very high proportion. In certain tissues, like blood, there may be selection against some of these variants, so that cells with normal mtdna are selectively retained. Therefore, results of genetic testing from the blood may not accurately reflect the heteroplasmy in the relevant tissue(s). Pathogenic variants in mtdna may only be identified in specific tissues, particularly those with a lower rate of cell division, such as skeletal muscle, heart, and brain. Disorders that arise from nuclear gene variants that affect mitochondrial function may be inherited in an autosomal dominant, autosomal recessive, or X-linked manner, and genetic testing from blood samples accurately reflects the genetic defect in all tissues. Figure 2. Mitochondrial genome and respiratory chain ND1 ND2 165 rrna 125 rrna Cyt b Complex I Complex III Complex IV Complex V Transfer RNA Ribosomal RNA Control region of DNA ND6 ND5 ND4 COXI COXII ATPase8 COXIII ND3 ND4L ATPase6 Matrix Succinate Fumarate O 2 ADP H 2 O ATP IMM ND1 ND2 ND3 COX I ND6 ND4 Cyt b COX II A8 ND5 ND4L CoQ COX III A6 IMS Complex I Complex II Complex III Cyt c Complex IV Complex V/ATP synthase mtdna-encoded subunits ndna-encoded subunits ~ ~16 The mitochondrial genome and mitochondrial respiratory chain (RC), showing ndna-encoded subunits (blue) and mtdnaencoded subunits (colors corresponding to the genes in the mitochondrial genome above). MITOCHONDRIAL DISORDERS GUIDE 6

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9 Clinical Indications 1. Diagnostic testing in an individual with a mitochondrial disorder a. Confirm a clinical diagnosis of a specific genetic syndrome or type of mitochondrial disorder b. Provide information about prognosis 2. Assistance with selection of optimal treatment options 3. Predictive testing for asymptomatic family members of a proband with a known pathogenic variant associated with a genetic form of mitochondrial disease a. Enable clinical monitoring, follow-up, and optimal treatment when symptoms develop in an individual with a positive result b. Reduce anxiety and forego clinical monitoring if result is negative 4. Prenatal diagnosis in at-risk pregnancies for known, pathogenic variants in nuclear genes TEST INFORMATION 5. Genetic counseling, recurrence risk determination, and family planning MITOCHONDRIAL DISORDERS GUIDE 8

10 TEST INFORMATION Testing Options Testing of the Mitochondrial Genome and Nuclear Genes Test Name Genes / Mutations Included TAT Combined Mito Genome Plus Mito Nuclear Genes (319 Genes) XomeDxPlus Full mitochondrial genome plus AARS, AARS2, ABCB11, ABCB4, ABCB7, ABCD4, ACAD9, ACADM, ACADVL, ACO2, ACSF3, ADCK3 (CABC1; COQ8), ADCK4, AFG3L2, AGK, AGL, AIFM1, ALAS2, ALDOA, ALDOB, ALG1, ALG11, ALG13, ALG2, ALG3, ALG6, ALG9, AMACR, APOPT1, APTX, ARG1, ASL, ASS1, ATP5A1, ATP5E, ATP7B, ATP8B1, ATPAF2 (ATP12), AUH, B4GALT1, BCKDHA, BCKDHB, BCS1L, BOLA3, C10ORF2, C12ORF65, C19ORF12, CA5A, CARS2, CHKB, CISD2, CLPB, COA5 (C2ORF64), COA6, COASY, COG4, COG5, COG6, COG7, COG8, COQ2, COQ4, COQ6, COQ9, COX10, COX14 (C12ORF62), COX15, COX20 (FAM36A), COX4I2, COX6A1, COX6B1, COX7B, CPS1, CPT1A, CPT2, CYC1, DARS, DARS2, DBT, DDHD1, DDHD2, DDOST, DGUOK, DLAT, DLD, DMGDH, DNA2, DNAJC19, DNM1L, DNM2, DOLK, DPAGT1, DPM1, DPM3, EARS2, ECHS1, ELAC2, ENO3, ETFA, ETFB, ETFDH, ETHE1, FAH, FARS2, FASTKD2, FBP1, FBXL4, FDX1L, FH, FLAD1, FOXRED1, G6PC, GAA, GAMT, GARS, GATM, GBE1, GCDH, GFER, GFM1 (EFG1), GFM2, GLRX5, GMPPA, GSS, GTPBP3, GYG1, GYG2, GYS1, GYS2, HADHA, HADHB, HARS2, HCFC1, HIBCH, HLCS, HMGCL, HMGCS2, HSD17B10, HSPD1, IARS2, IBA57, ISCA2, ISCU, IVD, LAMP2, LARS, LARS2, LDHA, LIAS, LIPT1, LMBRD1, LRPPRC, LYRM4, LYRM7, MARS, MARS2, MCCC1, MCCC2, MCEE, MFF, MFN2, MGAT2, MGME1, MICU1, MLYCD, MMAA, MMAB, MMACHC, MMADHC (C2ORF25), MOGS, MPC1 (BRP44L), MPDU1, MPI, MPV17, MRPL12, MRPL3, MRPL44, MRPS16, MRPS22, MRPS7, MTFMT, MTO1, MTPAP, MTR, MTRR, MUT, NADK2, NAGS, NARS2, NDUFA1, NDUFA10, NDUFA11, NDUFA12, NDUFA2, NDUFA4, NDUFA9, NDUFAF1, NDUFAF2, NDUFAF3 (C3ORF60), NDUFAF4 (C6ORF66), NDUFAF5, NDUFAF6, NDUFAF7 (C2ORF56), NDUFB3, NDUFB9, NDUFS1, NDUFS2, NDUFS3, NDUFS4, NDUFS6, NDUFS7, NDUFS8, NDUFV1, NDUFV2, NFS1, NFU1, NGLY1, NR2F1, NUBPL, OPA1, OPA3, OTC, PARS2, PC, PCCA, PCCB, PDHA1, PDHB, PDHX, PDP1, PDSS1, PDSS2, PET100, PFKM, PGAM2, PGM1, PHKA1, PHKA2, PHKB, PHKG2, PMM2, PNPT1, POLG, POLG2, PRKAG2, PRPS1, PTRH2, PUS1, PYGM, QARS, RANBP2, RARS, RARS2, REEP1 (C2ORF23), RFT1, RMND1, RRM2B, SARS2, SCO1, SCO2, SDHA, SDHAF1, SERAC1, SFXN4, SLC19A2, SLC19A3, SLC22A5, SLC25A1, SLC25A13, SLC25A15, SLC25A19, SLC25A20, SLC25A22, SLC25A3 (PHC), SLC25A38, SLC25A4, SLC2A2, SLC35A1, SLC35A2, SLC35C1, SLC37A4, SLC6A8, SLC7A7, SPAST, SPG7, SPTLC1, SRD5A3, SSR4, STT3A, STT3B, STXBP1, SUCLA2, SUCLG1, SURF1, TACO1, TARS2, TAZ, TIMM8A, TK2, TMEM126A, TMEM165, TMEM70, TPK1, TRIT1, TRMU, TRNT1, TSFM, TTC19, TUFM, TYMP, UQCC2, UQCC3, UQCRB, UQCRC2, UQCRQ, VARS2, WDR45, WFS1, YARS2 Whole exome sequencing (WES) plus mitochondrial genome sequencing and deletion testing Testing of the Mitochondrial Genome (mtdna) 6 weeks 8 weeks Test Name Genes / Mutations Included TAT Next-Generation Sequence Analysis and Deletion Testing of the Mitochondrial Genome Full mitochondrial genome (including non-specific phenotypes, and MELAS, MERRF, NARP, LHON, MIDD, MICM, LS, KSS, CPEO, Pearson syndrome etc.) 4 weeks 58 Confirmed Disease- Causing mtdna Point Mutations and Deletion Testing Deletion/Duplication Testing of the Mitochondrial Genome 58 confirmed disease-causing mtdna point mutations (see list in Test Info Sheet) and large scale deletion analysis of the mitochondrial genome (including LHON [18 mutations], MELAS [13 mutations], LS/NARP [22 mutations], MIHL/MIDM [10 mutations)] MERRF [6 mutations], KSS, CPEO, Pearson syndrome, etc.) Large scale deletion/duplication analysis of the mitochondrial genome 3-4 weeks 3-4 weeks 9

11 Testing Options Testing of Nuclear Genes Important for Normal Mitochondrial Function Test Name Genes / Mutations Included TAT Comprehensive Mitochondrial Nuclear Gene Panel (319 Genes) AARS, AARS2, ABCB11, ABCB4, ABCB7, ABCD4, ACAD9, ACADM, ACADVL, ACO2, ACSF3, ADCK3 (CABC1; COQ8), ADCK4, AFG3L2, AGK, AGL, AIFM1, ALAS2, ALDOA, ALDOB, ALG1, ALG11, ALG13, ALG2, ALG3, ALG6, ALG9, AMACR, APOPT1, APTX, ARG1, ASL, ASS1, ATP5A1, ATP5E, ATP7B, ATP8B1, ATPAF2 (ATP12), AUH, B4GALT1, BCKDHA, BCKDHB, BCS1L, BOLA3, C10ORF2, C12ORF65, C19ORF12, CA5A, CARS2, CHKB, CISD2, CLPB, COA5 (C2ORF64), COA6, COASY, COG4, COG5, COG6, COG7, COG8, COQ2, COQ4, COQ6, COQ9, COX10, COX14 (C12ORF62), COX15, COX20 (FAM36A), COX4I2, COX6A1, COX6B1, COX7B, CPS1, CPT1A, CPT2, CYC1, DARS, DARS2, DBT, DDHD1, DDHD2, DDOST, DGUOK, DLAT, DLD, DMGDH, DNA2, DNAJC19, DNM1L, DNM2, DOLK, DPAGT1, DPM1, DPM3, EARS2, ECHS1, ELAC2, ENO3, ETFA, ETFB, ETFDH, ETHE1, FAH, FARS2, FASTKD2, FBP1, FBXL4, FDX1L, FH, FLAD1, FOXRED1, G6PC, GAA, GAMT, GARS, GATM, GBE1, GCDH, GFER, GFM1 (EFG1), GFM2, GLRX5, GMPPA, GSS, GTPBP3, GYG1, GYG2, GYS1, GYS2, HADHA, HADHB, HARS2, HCFC1, HIBCH, HLCS, HMGCL, HMGCS2, HSD17B10, HSPD1, IARS2, IBA57, ISCA2, ISCU, IVD, LAMP2, LARS, LARS2, LDHA, LIAS, LIPT1, LMBRD1, LRP- PRC, LYRM4, LYRM7, MARS, MARS2, MCCC1, MCCC2, MCEE, MFF, MFN2, MGAT2, MGME1, MICU1, MLYCD, MMAA, MMAB, MMACHC, MMADHC (C2ORF25), MOGS, MPC1 (BRP44L), MPDU1, MPI, MPV17, MRPL12, MRPL3, MRPL44, MRPS16, MRPS22, MRPS7, MTFMT, MTO1, MTPAP, MTR, MTRR, MUT, NADK2, NAGS, NARS2, NDUFA1, NDUFA10, NDUFA11, NDUFA12, NDUFA2, NDUFA4, NDUFA9, NDUFAF1, NDUFAF2, NDUFAF3 (C3ORF60), NDUFAF4 (C6ORF66), NDUFAF5, NDUFAF6, NDUFAF7 (C2ORF56), NDUFB3, NDUFB9, NDUFS1, NDUFS2, NDUFS3, NDUFS4, NDUFS6, NDUFS7, NDUFS8, NDUFV1, NDUFV2, NFS1, NFU1, NGLY1, NR2F1, NUBPL, OPA1, OPA3, OTC, PARS2, PC, PCCA, PCCB, PDHA1, PDHB, PDHX, PDP1, PDSS1, PDSS2, PET100, PFKM, PGAM2, PGM1, PHKA1, PHKA2, PHKB, PHKG2, PMM2, PNPT1, POLG, POLG2, PRKAG2, PRPS1, PTRH2, PUS1, PYGM, QARS, RANBP2, RARS, RARS2, REEP1 (C2ORF23), RFT1, RMND1, RRM2B, SARS2, SCO1, SCO2, SDHA, SDHAF1, SERAC1, SFXN4, SLC19A2, SLC19A3, SLC22A5, SLC25A1, SLC25A13, SLC25A15, SLC25A19, SLC25A20, SLC25A22, SLC25A3 (PHC), SLC25A38, SLC25A4, SLC2A2, SLC35A1, SLC35A2, SLC35C1, SLC37A4, SLC6A8, SLC7A7, SPAST, SPG7, SPTLC1, SRD5A3, SSR4, STT3A, STT3B, STXBP1, SUCLA2, SUCLG1, SURF1, TACO1, TARS2, TAZ, TIMM8A, TK2, TMEM126A, TMEM165, TMEM70, TPK1, TRIT1, TRMU, TRNT1, TSFM, TTC19, TUFM, TYMP, UQCC2, UQCC3, UQCRB, UQCRC2, UQCRQ, VARS2, WDR45, WFS1, YARS2 6 weeks Mitochondrial Encephalopathy/Leigh Syndrome Nuclear Gene Panel (146 Genes) AARS2, ACAD9, ACO2, ADCK3 (CABC1; COQ8), AFG3L2, AIFM1, APOPT1, APTX, ATP5A1, ATP5E, ATPAF2 (ATP12), AUH, BCS1L, BOLA3, C10ORF2, C12ORF65, CA5A, COG8, COQ2, COQ4, COQ6, COQ9, COX10, COX14 (C12ORF62), COX15, COX20 (FAM36A), COX6B1, CPT1A, CPT2, CYC1, DARS, DARS2, DGUOK, DLAT, DLD, DNM1L, EARS2, ECHS1, ETFDH, ETHE1, FARS2, FASTKD2, FBP1, FBXL4, FH, FOXRED1, GCDH, GFER, GFM1 (EFG1), GFM2, GTPBP3, GYG2, HIBCH, HLCS, HSPD1, IARS2, IBA57, ISCA2, LARS2, LIAS, LIPT1, LRPPRC, LYRM7, MARS2, MFF, MFN2, MPC1 (BRP44L), MPV17, MRPL44, MRPS22, MTFMT, MTPAP, NADK2, NARS2, NDUFA1, NDUFA10, NDUFA11, NDUFA12, NDUFA2, NDUFA4, NDUFA9, NDUFAF1, NDUFAF2, NDUFAF3 (C3ORF60), NDUFAF4 (C6ORF66), NDUFAF5, NDUFAF6, NDUFAF7 (C2ORF56), NDUFB3, NDUFS1, NDUFS2, NDUFS3, NDUFS4, NDUFS6, NDUFS7, NDUFS8, NDUFV1, NDUFV2, NFU1, NUBPL, PC, PCCA, PCCB, PDHA1, PDHB, PDHX, PDP1, PDSS1, PDSS2, PET100, PNPT1, POLG, RANBP2, RARS2, RMND1, RRM2B, SCO1, SCO2, SDHA, SDHAF1, SERAC1, SLC19A3, SLC22A5, SLC25A1, SLC25A15, SLC25A19, SLC25A22, SLC35A2, STXBP1, SUCLA2, SUCLG1, SURF1, TACO1, TARS2, TK2, TMEM70, TPK1, TRMU, TSFM, TTC19, TUFM, TYMP, UQCC2, UQCC3, UQCRQ, VARS2 6 weeks MITOCHONDRIAL DISORDERS GUIDE 10

12 Testing Options Testing of Nuclear Genes Important for Normal Mitochondrial Function Cont. Test Name Genes / Mutations Included TAT Lactic Acidosis/Pyruvate Metabolism Nuclear Gene Panel (153 Genes) ACAD9, ADCK3 (CABC1; COQ8), AGK, AGL, AIFM1, ALDOB, ATP5E, ATPAF2 (ATP12), B4GALT1, BCKDHA, BCKDHB, BCS1L, BOLA3, C10ORF2, C12ORF65, CA5A, CARS2, COG4, COG8, COQ2, COQ4, COQ9, COX10, COX14 (C12ORF62), COX15, COX6B1, CYC1, DARS2, DBT, DGUOK, DLAT, DLD, DNM1L, EARS2, ECHS1, ELAC2, ETFA, ETFB, ETFDH, ETHE1, FARS2, FBP1, FBXL4, FDX1L, FH, FOXRED1, G6PC, GFER, GFM1 (EFG1), GTPBP3, GYG2, GYS2, HADHA, HADHB, HIBCH, HLCS, HMGCS2, HSD17B10, HSPD1, IBA57, ISCU, LARS, LARS2, LDHA, LIAS, LIPT1, LRPPRC, LYRM4, LYRM7, MARS, MFF, MLYCD, MPC1 (BRP44L), MPV17, MRPL12, MRPL44, MRPS16, MRPS22, MRPS7, MTFMT, MTO1, NADK2, NARS2, NDUFA1, NDUFA10, NDUFA11, NDUFA9, NDUFAF1, NDUFAF3 (C3ORF60), NDUFAF5, NDUFAF6, NDUFB3, NDUFB9, NDUFS1, NDUFS2, NDUFS3, NDUFS4, NDUFS6, NDUFS7, NDUFS8, NDUFV1, NFS1, NFU1, PARS2, PC, PCCA, PCCB, PDHA1, PDHB, PDHX, PDP1, PDSS1, PDSS2, PFKM, PHKG2, PNPT1, POLG, POLG2, PUS1, RARS2, RMND1, RRM2B, SARS2, SCO2, SDHAF1, SERAC1, SFXN4, SLC25A13, SLC25A19, SLC25A3 (PHC), SLC25A4, SLC2A2, SLC35A2, SLC37A4, SLC7A7, SUCLA2, SUCLG1, SURF1, TARS2, TAZ, TK2, TMEM70, TPK1, TRMU, TRNT1, TSFM, TTC19, TUFM, TYMP, UQCC2, UQCC3, UQCRB, UQCRC2, UQCRQ, YARS2 6 weeks Progressive External Ophthalmoplegia (PEO)/ Optic Atrophy Nuclear Gene Panel (55 Genes) Methylglutaconic Aciduria Nuclear Gene Panel (13 Genes) POLG Sequence Analysis Mitochondrial Myopathy, Lactic Acidosis and Sideroblastic Anemia (MLASA) ACO2, ALG13, ALG3, APTX, AUH, C10ORF2, C12ORF65, CISD2, CLPB, COX7B, DARS, DDHD2, DGUOK, DNA2, DNAJC19, DNM1L, DPM1, EARS2, FH, GYG2, ISCA2, MCEE, MFF, MFN2, MGME1, MOGS, MTFMT, MTO1, MTPAP, NARS2, NDUFAF3 (C3ORF60), NR2F1, OPA1, OPA3, PDHX, PDSS1, POLG, POLG2, PRPS1, RRM2B, SLC19A2, SLC19A3, SLC25A4, SPG7, SRD5A3, STT3B, SUCLA2, TACO1, TIMM8A, TK2, TMEM126A, TSFM, TYMP, VARS2, WFS1 AGK, ATP5E, ATPAF2 (ATP12), AUH, CLPB, DNAJC19, HMGCL, OPA3, POLG, SERAC1, SUCLA2, TAZ, TMEM70 POLG PUS1 4 weeks 4 weeks 4-5 weeks 4-5 weeks Mitochondrial Complex II Deficiency (MT-C2D) SDHA 4 weeks Additional testing options are available, including targeted variant testing for a previously identified pathogenic or likely pathogenic variant. Appropriate test selection depends on the specific clinical history of a patient, including family and personal health histories as well as familial test results. Testing for most genes includes sequencing and deletion/duplication analysis via next-generation sequencing and/or exon array testing. 11

13 Sample Submission Genetic testing can be performed on blood, oral rinse or extracted DNA samples. GeneDx test kits are available to ordering providers, and include sample collection items (such as mouthwash for oral rinse and collection tubes), the necessary sample submission paperwork, and a self-addressed return shipping label. Additionally, all test requisition forms are available for download from the GeneDx website: Please note that all testing must be performed under the guidance of a healthcare provider. For more information on the sample submission process, please visit our website: or us at: MITOCHONDRIAL DISORDERS GUIDE 12

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15 Genetic Test Results Nearly all test results fall into one of four categories: 1. Positive (pathogenic variant(s) identified) 2. Likely pathogenic variant(s) identified 3. Variant(s) of uncertain significance (VUS) identified 4. Negative (no variants of clinical significance identified) GeneDx test reports contain detailed information about a specific genetic result and, if available, medical management options. Genetic counseling is recommended prior to genetic testing to understand the benefits and limitations of testing and after genetic testing to discuss the implications of the genetic test results. Genetic counseling services across the country can be found at Positive Result A positive result indicates a pathogenic (disease-causing) genetic variant (change) was identified in a specific disease gene. This finding confirms an underlying genetic cause for the patient's symptoms and provides a diagnosis of a specific genetic disorder or indicates an increased risk for developing a genetic disorder. Knowledge of the specific pathogenic variant(s) provides valuable information to the patients, their healthcare providers and family members because it helps to determine the recurrence risk and to develop an appropriate medical management plan. A medical management plan may include lifestyle modifications, ongoing screening, preventative medications and measures, and/ or surgical/medical device interventions. Furthermore, a positive genetic test result allows targeted testing of at-risk relatives to determine if any of them carry the pathogenic variant(s) as well as to address the recurrence risk of the disorder in future offspring. RESULTS & MANAGEMENT MITOCHONDRIAL DISORDERS GUIDE 14

16 Likely Pathogenic Variant Result A likely pathogenic result indicates the presence of genetic variant(s) in a specific disease gene for which there is significant, but not conclusive, evidence that the variant(s) are diseasecausing. This finding strongly suggests an underlying genetic cause of the patient s disorder or indicates an increased risk for developing a genetic disorder. With this type of result, medical management options and testing of family members are often similar as described above for a positive result. Variant of Uncertain Significance (VUS) A variant of uncertain significance (VUS) result indicates an inconclusive outcome of a genetic test. A VUS is a change in a gene for which the association with disease cannot be clearly established. The available information for the variant is either insufficient or conflicting, and it cannot be determined at this time whether the variant is associated with a specific genetic disorder or if the variant is a unrelated (benign) variant unrelated to the patient s disorder. RESULTS & MANAGEMENT In the case of a VUS test result, all medical management recommendations should be based on clinical symptoms, and past personal and family history. Predictive genetic testing of family members for a VUS is not indicated. Nevertheless, in some circumstances, it can be useful to test other family members through our Variant Testing Program to gain more evidence about the variant itself and its possible association with disease. Over time, additional clinical evidence may be collected about certain VUS, which could ultimately lead to the reclassification of the variant and test result. 15

17 Negative Result A negative result indicates that the genetic test did not identify reportable, medically relevant variant(s) in any of the genes tested. Therefore, the cause for the patient s disorder or family history remains unknown. Although the patient s disorder may be caused by non-genetic factors, a negative genetic test result does not completely rule out an underlying genetic cause. For example, the patient s disorder may be due to unidentified genetic changes in gene regions or genes not included in the initial test. Depending on the patient s personal and family health history, additional genetic testing may be indicated for the patient or another family member. A genetic specialist or other healthcare providers can determine if further genetic testing is appropriate. In case of a negative genetic test result, all medical management recommendations should be based on clinical symptoms in addition to past personal and family history. Predictive genetic testing of family members is not available. When an individual tests negative for a familial pathogenic variant that was previously identified in another affected family member, this is considered a true negative test result. In most cases, this means that the individual has no greater risk for developing the specific genetic disorder that runs in the family than anyone in the general population. Medical Management The treatment of mitochondrial can vary. In most cases, physicians use a combination of vitamins, optimized nutrition, overall general health and prevention of symptom worsening during times of illness. Knowledge of the genetic etiology of a mitochondrial disorder may guide selection of the most appropriate treatment options in some cases. MITOCHONDRIAL DISORDERS GUIDE 16

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19 Implications for Family Members Regardless of the result, patients should share their test report with their blood relatives, who can then discuss the results with their healthcare providers. Sharing a copy of the test result with family members and healthcare providers will help to determine if additional testing is necessary and will ensure that the proper test is ordered for relatives, if indicated. For positive or likely pathogenic test results in autosomal dominant conditions, first-degree relatives (including parents, siblings, and children) have a 50% chance to have the same variant. The risk for other family members to carry the variant depends on how closely related they are to the person with a positive or likely pathogenic test result. It is important to remember that for most of these genes, not all people who inherit a pathogenic or likely pathogenic variant will mitochondrial impairment due to reduced penetrance. In cases where the gene is associated with an autosomal recessive condition, an individual inherits two pathogenic variants, one from each parent. Siblings of the individual with a mitochondrial disorder have a 25% chance to inherit both pathogenic variants and develop a mitochondrial disorder Genetic Counseling Prior to genetic testing, patients should speak with their healthcare provider and/or a genetics specialist about their personal and family health history. Healthcare providers should discuss the benefits and limitations of testing, as well as possible test results. These conversations help to determine if the patient is an appropriate candidate for testing, facilitate the ordering of appropriate test(s) and ensure that the patient has agreed to the proposed genetic testing (written informed consent). If pathogenic variant(s) have already been identified in a family member, testing of the specific variant(s) is appropriate. If no pathogenic variant(s) are known in a family with a specific genetic disorder, an affected family member with the highest likelihood of a positive test outcome (an individual manifesting associated clinical symptoms) is ideally the best person for initial testing within a family. In instances when an affected family member is MITOCHONDRIAL DISORDERS GUIDE 18 KEY INFORMATION

20 not available, testing of an unaffected family member may be considered, although a negative test result will not guarantee that the unaffected individual does not have an increased risk to develop the clinical symptoms that are present in the family. Once a patient makes the decision to undergo genetic testing, post-test genetic counseling is recommended to understand the implications of the results, including a discussion of the appropriate medical management based on both the test results and the patient s medical and family history. Genetic counseling services across the country can be found at Insurance Coverage and Cost for Genetic Testing GeneDx accepts all commercial insurance plans and is a Medicare provider. Additionally, GeneDx is a registered provider with several Medicaid plans. If a patient does not have health insurance coverage or cannot afford to pay the cost of testing, GeneDx offers a financial assistance program to help ensure that all patients have access to medically necessary genetic testing. KEY INFORMATION For more information on the paperwork that is required by some insurance carriers, as well as additional details on patient billing and our financial assistance program, please visit our website: Genetic Information Nondiscrimation Act The Genetic Information Nondiscrimination Act of 2008, also referred to as GINA, is a federal law that protects Americans from discrimination by health insurance companies and employers based on their genetic information. However, this law does not cover life insurance, disability insurance, or long-term care insurance. GINA s employment protections do not extend to individuals in the U.S. military, federal employees, Veterans Health Administration and Indian Health Service. Some of these organizations may have internal policies to address genetic discrimination. For more information, please visit: 19

21 Genetic Testing Process Patient Identification Sample Submission Discussion of personal and family history The patient s sample and necessary paperwork are sent to the laboratory Explanation of genetic testing options Genetic Testing At the laboratory, genetic testing for most genes includes next-generation sequencing and/or exon array analysis Genetic Test Results Genetic Testing Report Neurogenetic Test Report Contains information on the results of the genetic test and available medical management options Patient Name: Date of Birth: Specimen Type: Submitters ID No: Ordered By: No: Not Provided GeneDx Accession Comprehensive Epilepsy Panel Obtained: 12/11/2015 Date Specimen, Not Received: PROVIDED 3/7/2016 Date Specimen Name: Accession No: MockTest015 PatientGeneDx Not Provided Started: Test 3/22/2016 Date Test(s) Birth: Date Specimen Obtained: Not Provided Date of Other: Validation Date of Report: DateType: Specimen Received: 3/9/2012 Specimen None N TESTS ID No: - VALIDATIO Xpanded Panel Submitters GENEDX 3/9/2012 Date Test(s) Started: / Autism/ID By: 2000 Genes seizures. Ordered Analysis of l delay, and Date of Report: 4/11/2012 SAMPLE, Epilepsy Not Provided Blood in EDTA None Dr. Neurology Genetics Diagnostic Test(s) requested: for Testing / Sequence disorder, developmenta also submitted ) were of autism spectrum father (GeneDx# ) and mother (GeneDx# history Requested: Comprehensive Epilepsy Panel / Sequencing Deletion/Duplication Analysis of 53 Genes Test(s)and with reported Female Test Indication(s): Epileptic encephalopathy. Result: POSITIVE Relevant History: Result: Gene Variant STXBP1 Partial gene deletion, exons 6-8 this individual's A sample from analysis. variant segregation POSITIVE Gene Zygosity HeterozygousWDR45 Inherited Classification From DNA Zygosity Variant Coding Variant of De Mode of Heterozygous Novo Uncertain Inheritance C>T Significance p.q16x c.46 with an iron gene is associated gene. This brain iron the WDR45 ration with variant in of neurodegene for a pathogenic diagnosis is heterozygousis consistent with the signal involved in result Disease tion X-linked Classification Neurodegenera with brain Disease-causing accumulation mutation This individual This of the 53 genes complexes pathogenic No other reportable variants were detected by sequencing: and deletion/duplication analysis X-linked disorder. form multi-protein 2012). De novo Interpretation et al.,. proteins, which control (Haack et al., included on this panel. (NBIA) (Haack with accumulation WD repeat Interpretation: STXBP1 partial deletion: The final report is sent to the ordering healthcare provider l delay one of the and cell cycle iron accumulation gene encodes regulation, autophagy tion with brain global developmenta and dementia The WDR45 This individual is heterozygous for a partial deletion of the STXBP1 gene,transcriptional which is consistent cause neurodegenera including early-onset parkinsonism, have transduction, X-linked WDR45 gene in males and females, of dystonia, WDR45 Summary: WDR45 variants et al., with the diagnosis of epileptic encephalopathy. the or adult onset are similar variants in with pathogenic syndrome (Ohba adolescent clinical features followed by y 50% of patients overlap with Rett 2012). The y in childhood may childhood encephalopath Saitsu et al., 2013). Approximatel Intragenic deletion including exons 6-8 of the STXBP1 gene [transcript static NM_ ]. features in of the 2012; The clinical gene, [93.40]% Genomic coordinates: chr9: [hg19/grch37] (Haack et al., et al., 2015)..3). For this epilepsy (Nishioka gene (NM_ al., 2013). Hayflick et 3 in the WDR45 Xpanded Panel. in the This individual is heterozygous for a partial deletion of the STXBP1 gene2014; that includes exons 6-8. C>T in exon Autism/ID c.46both the Q16X variant 10x by the not harbor (CAA>TAA): minimum partial and complete STXBP1 gene deletions have been identified in patients with epilepsy (Boone al., of at a et ) do p.gln16ter was covered father (GeneDx# 2010; Saitsu et al., 2010; Milh et al., 2011; Mignot et al.,p.q16x: 2011). The presence the deletion is consistent codingofregion WDR ) and to cause loss mother (GeneDx# with the diagnosis of epileptic encephalopathy in this individual. variant is predicted not observed This individual's Q16X nonsensemrna decay. It was gene. The iated WDR45 gene. Exome Sequencing the WDR45 in not nonsense-med NHLBI or the Mutations in the STXBP1 gene have been identified in patients with early infantile epileptic has been identified variant has truncation ancestry in pathogenic variant through proteinand African American Although this neurodegeneration with encephalopathy, also called Ohtahara syndrome. Most individuals with STXBP1 mutations exhibiteither clonic A pathogenic of European protein function in these populations.the diagnosis of of normal individuals spasms with a suppression-burst pattern on EEG, intractable seizures, and severe intellectual disability 6,500 benign variant is consistent with in approximately not a common its presence it is reported (Saitsu et al., 2008; Mignot et al., 2011). Some individuals with STXBP1 mutations have been to our knowledge, Project, indicating previously with myoclonic seizures, hypomyelination or delayed myelination, and/or a non-epileptic movement disorder this individual. (NBIA) in been reported characterized by tremor, dystonic posturing, or choreaform movements (Saitsu etiron al., accumulation 2010; Saitsu et al., brain 2008; Milh et al., 2011). More recently, STXBP1 mutations have been identified in patients with isolated intellectual disability or intellectual disability and nonsyndromic epilepsy (Hamdan et al., 2011; Hamdan et al., 2009). Mutations in the STXBP1 gene are inherited in autosomal dominant manner and are typically de novo, although inheritance of a mutation from an unaffected parent with somatic mosaicism has been reported (Saitsu et al., 2011). Recommendation: 1. Testing for the partial deletion in the STXBP1 gene is available to the parents of this child to determine if the deletion was inherited or arose de novo. If desired, molecular prenatal diagnosis is available to at-risk family members to address the recurrence risk. MD Gaithersburg, 2. Genetic counseling is recommended to discuss the implications of this test Parkway report, specifically including 207 Perry the risk of recurrence for this family and testing optionsgenedx for other- at-risk family members. GeneDx Perry Parkway - Gaithersburg, MD Tel (301) Fax (301) Page 1 of Tel (301) Fax (301) Page 1 of 2 Post-Test Discussion Healthcare provider discusses the test results, medical management options, and implications for family members with the patient MITOCHONDRIAL DISORDERS GUIDE 20

22 Resources for Patients 1. United Mitochondrial Disease Foundation, a patient organization that promotes research and education for the diagnosis, treatment, and cure of mitochondrial disorders: 2. American Epilepsy Society: 3. Epilepsy Foundation: 4. GeneDx neurology page: 5. GeneReviews, a database of genetic diseases: 6. National Society of Genetic Counselors, to help you find a counselor near you: References 1. Chinnery, P.F. Mitochondrial disorders overview. NCBI Bookshelf GeneReviews. NIH National Library of Medicine [www.ncbi.nlm.nih.gov/books/nbk1224]. 2. Longo, N. Mitochondrial encephalopathy. Neurol Clin N Am 21: van Adel B.A. and Tarnopolsky, M.A. Metabolic myopathies: Update J Clin Neuromuscular Disease. 10(3): Tarnopolsky, MA and Sandeep, R. Mitochondrial myopathies: Diagnosis, exercise intolerance and treatment options. (2005). Medicine and Science in Sports and Exercise. 37(12):

23 Notes MITOCHONDRIAL DISORDERS GUIDE 22

24 About GeneDx GeneDx was founded in 2000 by two scientists from the National Institutes of Health (NIH) to address the needs of patients diagnosed with rare disorders and the clinicians treating these conditions. Today, GeneDx has grown into a global industry leader in genomics, having provided testing to patients and their families in over 55 countries. Led by its world-renowned whole exome sequencing program, and an unparalleled comprehensive genetic testing menu, GeneDx has a continued expertise in rare and ultra-rare disorders. Additionally, GeneDx also offers a number of other genetic testing services, including: diagnostic testing for hereditary cancers, cardiac, mitochondrial, and neurological disorders, prenatal diagnostics, and targeted variant testing. At GeneDx, our technical services are backed by our unmatched scientific expertise and our superior customer support. Our growing staff includes more than 30 geneticists and 100 genetic counselors specializing in clinical genetics, molecular genetics, metabolic genetics, and cytogenetics who are just a phone call or away to assist you with your questions and testing needs. We invite you to visit our website: to learn more about us. 207 Perry Parkway Gaithersburg, MD T (Toll-free), F E GeneDx. All rights reserved /16 Information current as of 10/16

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