Supplement-Direct DNA Testing for Neurogenetic Diseases
By Nancy B. Hanson, MS, Roberta A. Pagon, MD, and Thomas D. Bird, MD
The molecular genetic revolution is having a major impact on the practice of neurology. This phenomenon is especially evident in the area of genetic testing for inherited diseases of the nervous system. The accompanying table lists more than 100 neurological disorders for which a direct DNA test is now commercially available. This table should be of considerable benefit to the busy practicing neurologist who needs quick information concerning the availability of genetic diagnostic testing for the differential diagnosis of specific patients. Metabolic and other non-DNA tests are not listed in this table, but further information about all types of genetic tests can be found at www.genetests.org. This website provides names and phone numbers of laboratories performing genetic testing as well as research laboratories that may be performing additional tests on a noncommercial (research) basis. A complementary website (www. geneclinics.org) provides clinical information and guidelines for interpreting and using DNA tests for many of the disorders listed in the table.
| Table-Neurologic Diseases with Clinically Available DNA Based Genetic Testing | ||||
| Disease Name | Gene Symbol | Gene Locus | Gene Product | Pattern of Inheritance |
| Acid Phosphatase Deficiency | ACP2 | 11p12-p11 | Lysosomal Acid Phosphatase | Autosomal Recessive |
| ACP3 | Chromosome 11 | |||
| Adenosine Monophosphate Deaminase 1 | AMPD1 | 1p21-p13 | AMP Deaminase 1 | Autosomal Dominant |
| Adrenoleukodystrophy, Recessive | PEX 10 | Autosomal Recessive | ||
| PXR1 | 12p13 | Peroxisomal Targeting | ||
| Signal 1 Receptor | ||||
| Adrenoleukodystrophy, X-linked | ALD | Xq28 | Adrenoleukodystrophy protein | X-linked |
| Alpha-Mannosidosis | MANB | 19cen-q12 | Lysosomal Alpha-Mannosidase | Autosomal Recessive |
| Alzheimer Disease, Early Onset Familial | PSEN1 | 14q24 | Presenillin 1 | Autosomal Dominant |
| (Presenillin 1) | ||||
| Amyloidosis Type 1 | TTR | 18q11-q12 | Transthyretin | Autosomal Dominant |
| Amyotrophic Lateral Sclerosis, Familial | SOD1 | 21q22 | Superoxide Dismutase (Cu-Zn) | Autosomal Dominant |
| Angelman Syndrome | ANCR | 15q11-q13 | Imprinting | |
| UBE3A | 15q11-q13 | Ubiquitin-protein ligase E3A | Microdeletion | |
| Apert Sydrome | FGFR2 | 10q26 | Fibroblast growth factor receptor 2 | Autosomal Dominant |
| Apolipoprotein E Genotyping | APOE | 19q13 | Apolipoprotein E | Autosomal Recessive |
| Ataxias—See | ||||
| Ataxia Telangiectasia | ||||
| Friedreich Ataxia | ||||
| Spinocerebellar Ataxia Type 1 | ||||
| Spinocerebellar Ataxia Type II | ||||
| Spinocerebellar Ataxia Type III | ||||
| Spinocerebellar Ataxia Type VI | ||||
| Spinocerebellar Ataxia Type VII | ||||
| Ataxia Telangiectasia | ATM | 11q22-q23 | Autosomal Recessive | |
| Barth Syndrome | TAZ | Xq28 | Tafazzin | X-linked |
| Becker Muscular Dystrophy | DMD | Xp21 | Dystrophin | X-linked |
| Canavan Disease | ASPA | 17pter-p13 | Aspartoacylase | Autosomal Recessive |
| Camitine Deficiency, Systemic | SLC22A5 | 5q31 | Autosomal Recessive | |
| Camitine Palmitoyltransferase Deficiency | CPT1A | 11q | Mitochondrial Camitine | |
| Palmitoyltransferase I | Autosomal Recessive | |||
| CPT2 | 1p32 | Mitochondrial Camitine | ||
| Palmitoyltransferase II | ||||
| Cerebral Autosomal Dominant Arteriopathy with | NOTCH3 | 19p13.2-p13.1 | Notch (Drosophila) homolog 3 | Autosomal Dominant |
| Subcortical Infarcts and Leukoencephalopathy | ||||
| (CADASIL) | ||||
| Charcot-Marie-Tooth Disease, Dominant | EGR2 (KROX20) | 10q21-q22 | Early growth response protein 2 | Autosomal Dominant |
| (Type 1) | MPZ (CMT1B) | 1q22 | Myelin PO protein | |
| PMP22 | 17p11 | Peripheral myelin protein 22 | ||
| (CMT1A/HNPP) | ||||
| Charcot-Marie-Tooth Disease, X-linked | GJB1(CX32) | Xq13 | Gap junction beta-1 protein | |
| (Connexin 32) | X-linked | |||
| Coffin-Lowry Syndrome | RPS6KA3 | Xp22 | Ribosomal Protein S6 | |
| Kinase II Alpha 3 | X-linked Dominant | |||
| Congenital Hypomyelination Neuropathy (CHN) | MPZ | 1q22 | Myelin PO protein | |
| Congenital Muscular Dystrophy | LAMA2 | 6q22-q23 | Laminin Alpha-2 Chain | Autosomal Recessive |
| (Laminin/Merosin type) | ||||
| Cri du Chat Syndrome | 5p deletion | Chromosome Deletion | ||
| Dentatorubral-Pallidoluysian Atrophy | DRPLA | 12p13 | Atrophin-1 | Autosomal Dominant |
| DiGeorge Syndrome | DGCR | 22q11 | Autosomal Dominant | |
| DGS2 | 10p14-p13 | Microdeletion | ||
| Dihydropterin Reductase Deficiency | QDPR | 4p15 | Dihydropteridine Reductase | Autosomal Recessive |
| Duchenne Muscular Dystrophy | DMD | Xp21 | Dystrophin | X-linked Recessive |
| Dystonia Type 1 | DYT1 | 9q34 | TorsinA | Autosomal Dominant |
| Dystonia, Dopa Responsive | ||||
| See GTP Cyclohydrolase Deficiency, Dominant | ||||
| Emery-Dreifuss Muscular Dystrophy | EMD | Xq28 | Emerin | X-linked Recessive |
| LMNA | 1q21 | Lamin A | Autosomal Dominant | |
| Epidermolysis Bullosa with Muscular Dystrophy | PLEC1 | 8q24 | Plectin 1 | Autosomal Recessive |
| Fabry Disease | GLA | Xq22 | Alpha-Galactosidase A | X-linked Recessive |
| Facioscapulohumeral Muscular Dystrophy | FSHMD1A | 4q35 | Autosomal Dominant | |
| Fragile X Syndrome | FMR1 | Xq27 | Fragile X mental | |
| retardation 1 protein | X-linked | |||
| FRAXE Syndrome | FMR2 | Xq28 | Fragile X mental | |
| retardation 2 protein | X-linked Recessive | |||
| Friedreich Ataxia | FRDA1 | 9q13 | Frataxin | Autosomal Recessive |
| Fructose 1,6 Bisphosphatase Deficiency | FBP1 | 9q22 | Fructose-1,6-Bisphosphatase | Autosomal Recessive |
| Fumarate Hydratase | Deficiency | FH | 1q42 | Fumarate Hydratase |
| GTP Cyclohydrolase Deficiency, Dominant | GCH1 | 14q22 | GTP Cyclohydrolase I | Autosomal Dominant |
| Gaucher Disease | GBA | 1q21 | Glucosylceramidase | Autosomal Recessive |
| Glycogen Storage Disease Type V (McArdie) | PYGM | 11q13 | Glycogen Phosphorylase, | |
| Muscle Form | Autosomal Recessive | |||
| Hereditary Fructose Intolerance | ALDOB | 9q22 | Fructose-Bisphosphate | |
| Aldolase B (Liver) | Autosomal Recessive | |||
| Hereditary Neuropathy with Liability to Pressure | PMP22 | 17p11 | Peripheral myelin protein 22 | Autosomal Dominant |
| Palsies (HNPP) | ||||
| Homocystinuria | CBS | 21q22 | Cystathionine Beta-Synthase | Autosomal Recessive |
| Huntington Disease | HD | 4p16 | Huntington | Autosomal Dominant |
| Hurler Syndrome | ||||
| See Mucopolysaccaridosis Type I | ||||
| Hunter Syndrome | ||||
| See Mucopolysaccaridosis Type II | ||||
| Hyperkalemic Periodic Paralysis | SCN4A | 17q23-q25 | Sodium Channel Protein, | |
| Skeletal Muscle | Autosomal Dominant | |||
| Alpha-Subunit | ||||
| Hypokalemic Periodic Paralysis | CACNA1S | 1q32 | Voltage dependent L-type | |
| calcium channel, | Autosomal Dominant | |||
| alpha-1S subunit | ||||
| Kallmann Syndrome, X-linked | KAL1 | Xp22 | Kallmann Syndrome Protein | X-linked |
| Kennedy Disease (Spinobulbular | AR | Xq11-q12 | Androgen receptor | X-linked |
| Muscular Atrophy) | ||||
| KeamsSayre—See Mitochondrial | ||||
| Krabbe Disease | GALC | 14q24-q32 | Galactocerebrosidase | Autosomal Recessive |
| Langer-Giedion Syndrome | LGCR | 8q24 | Autosomal Dominant | |
| Microdeletion | ||||
| Leber Hereditary Optic Neuropathy | ||||
| See Mitochondrial | ||||
| Lesch-Nyhan Syndrome | HPRT1 | Xq26-q27 | Hypoxanthine-Guanine | |
| Phosphoribosyl | X-linked | |||
| Transferase | ||||
| Leigh Disease—See Mitochondrial | ||||
| Limb-Girdle Muscular Dystrophy | ||||
| Autosomal Recessive | ||||
| LGMD 2A | CAPN3 | 15q15-q21 | Calpain P94, Large | |
| (Catalytic) Subunit | ||||
| LGMD 2D | SGCA | 17q12-q21 | Alpha Sarcoglycan | |
| LGMD 2E | SGCB | 4q12 | Beta Sarcoglycan | |
| LGMD 2F | SGCD | 5q33 | Delta Sarcoglycan | |
| Lissencephaly | PAFAH1B1 | 17p13 | Platelet-Activating | Microdeletion |
| Factor Acetylhydrolase 1B | ||||
| Alpha subunit | ||||
| Long Chain 3-Hydroxyacyl-CoA | HADHA | 2p23 | Mitochondrial Trifunctional | |
| Dehydrogenase Deficiency | Enzyme Alpha Subunit | Autosomal Recessive | ||
| HADHB | 2p23 | Mitochondrial Trifunctional | ||
| Enzyme Beta Subunit | ||||
| Malignant Hyperthermia Susceptibility | CACNA1S | 1q32 | Autosomal Dominant | |
| MHS2 | 17q11-q24 | |||
| MHS2 | 7q21-q22 | |||
| MHS4 | 3q13 | |||
| MHS6 | 5p | |||
| RYR1 | 19q13 | Ryanodine Receptor, | ||
| Skeletal Muscle | ||||
| McArdie Syndrome | ||||
| See Glycogen Storage Disease Type V | ||||
| Medium Chain Acyl-CoA | ACADM | 1p31 | Acyl-CoA Dehydrogenase, | |
| Dehydrogenase Deficiency | Medium-Chain Specific | Autosomal Recessive | ||
| Menkes Disease | ATP7A | Xq12-q13 | Copper-Transporting | |
| ATPase 1 | X-linked Recessive | |||
| Methylenetetrahydro Folate Reductase | MTHFR | 1p36 | Methylenetetrahydro | |
| Deficiency | Folate Reductase | Autosomal Recessive | ||
| Miller-Dieker Syndrome | 17p13 | Autosomal Recessive | ||
| Microdeletion | ||||
| Mitochondrial Diseases | Mitochondrial | |||
| Keams-Sayre | mitochondrial | |||
| Leber Optic Atrophy (LHON) | MTND1 | mitochondrial | NADH-Ubiquinone | |
| Oxidoreductase Chain 1 | ||||
| MTND4 | mitochondrial | NADH-Ubiquinone | ||
| Oxidoreductase Chain 4 | ||||
| MTND6 | mitochondrial | NADH-Ubiquinone | ||
| Oxidoreductase Chain 6 | ||||
| MTCYB | mitochondrial | Cytochrome B | ||
| Leigh Disease | MTATP6 | mitochondrial | ATP Synthase 6 | |
| Mitochondrial Myopathy Encephalopathy, | MTTL1 | mitochondrial | Mitochondrial tRNA Leucine 1 | |
| Lactic Acidosis and Strokelike Episodes | ||||
| (MELAS) | ||||
| Myoclonic Epilepsy Associated with Ragged- | MTTK | mitochondrial | Mitochondrial tRNA Lysine | |
| Red Fibers (MERF) | MTTL1 | mitochondrial | Mitochondrial tRNA Leucine 1 | |
| Neuropathy, Ataxia, and Retinitis Pigmentosa | MTATP6 | mitochondrial | ATP Synthase 6 | |
| (NARP) | ||||
| Lethal Infantile Mitochondrial Myopathy | MTTT | mitochondrial | Mitochondrial tRNA | |
| Threonine | ||||
| Mucopolysaccharidosis Type I (Hurler) | IDUA | 4p16 | Alpha-L-Iduronidase | Autosomal Recessive |
| Mucopolysaccharidosis Type II (Hunter) | IDS | Xq28 | Iduronate 2-Sulfatase | X-linked Recessive |
| Mucopolysaccharidosis Type IIIB (San Filippo) | NAGLU | 17q21 | Alpha-N- | |
| Acetylglucosaminidase | Autosomal Recessive | |||
| Muscular Dystrophy, see | ||||
| Becker Muscular Dystrophy | ||||
| Duchenne Muscular Dystrophy | ||||
| Limb-Girdle Muscular Dystrophy | ||||
| Myotonic Dystrophy | ||||
| Oculopharylgeal Muscular Dystrophy | ||||
| Myotonia Congenita, Dominant | CLCN1 | 7q35 | Chloride Channel Protein, | |
| Skeletal Muscle | Autosomal Dominant | |||
| SCN4A | 17q23-q25 | Sodium Channel Protein, | ||
| Skeletal Muscle | ||||
| Alpha-Subunit | ||||
| Myotonia Congenita, Recessive | CLCN1 | 7q35 | Chloride Channel Protein, | |
| Skeletal Muscle | Autosomal Recessive | |||
| Myotonic Dystrophy | DMPK | 19q13 | Myotonin-Protein Kinase | Autosomal Dominant |
| Neurofibromatosis Type 1 | NF1 | 17q11 | Neurofibromin | Autosomal Dominant |
| Neurofibromatosis Type II | NF2 | 22q12 | Merlin | Autosomal Dominant |
| Neuronal Ceroid Lipofuscinosis, Infantile | PPT | 1p32 | Palmitoyl-Protein Thioesterase | Autosomal Recessive |
| Neuronal Ceroid Lipofuscinosis, Juvenile | CLN3 | 16p12 | CLN3 Protein | Autosomal Recessive |
| Neuropathy, Hereditary with Liability to Pressure | ||||
| Palsies, See HNPP | ||||
| Niemann-Pick Disease, Type A and B | SMPD1 | 11p15 | Sphingomyelin Phosphodiesterase | Autosomal Recessive |
| Niemann-Pick Disease, Type C | NPC1 | 18q11-q12 | unknown | |
| Norrie Disease | NDP | Xp11 | Norrie disease protein | X-linked |
| Oculopharyngeal Muscular Dystrophy | PABP2 | 14q11-q13 | Polyadenylate-Binding Protein 2 | Autosomal Dominant |
| Omithine Transcarbamylase Deficiency | OTC | Xp21 | Omithine Carbamoyltransferase | X-linked Dominant |
| Pelizaeus-Merzbacher Disease | PLP | Xq22 | Myelin proteolipid protein | X-linked |
| Periodic Paralysis, | ||||
| See Hyperkalemic and Hypokalemic | ||||
| Phenylketonuria (PAH Deficiency) | PAH | 12q24 | Phenylalanine-4-Hydroxylase | Autosomal Recessive |
| Prader-Willi Syndrome | PWCR | 15q11-q13 | Imprinting Microdeletion | |
| Pyruvoyl Tetrahydropterin Synthase | PTS | 11q22-q23 | 6-Pyruvoyl Tetrahydrobiopterin | |
| Deficiency | Synthase | Autosomal Recessive | ||
| Refsum Syndrome, Adult | PHYH | 10pter-p11.2 | Phytamoyl-CoA Hydroxylase | Autosomal Recessive |
| Rubinstein-Taybi Syndrome | CREBBP | 16p13 | CREB-Binding Protein | Autosomal Dominant |
| San Filippo Syndrome | ||||
| See Mucopolysaccharidosis Type III | ||||
| Sandhoff Disease | HEXB | 5q13 | Beta-hexosaminidase beta chain | Autosomal Recessive |
| Smith-Magenis Syndrome | SMCR | 17p11 | Microdeletion | |
| Spinal Muscular Atrophy Types I/II/III | NAIP | 5q12-q13 | Neuronal Apoptosis | |
| Inhibitory Protein | Autosomal Recessive | |||
| SMN1 | 5q12-q13 | Survival Motor Neuron Protein 1 | ||
| Spinobulbar Muscular Atrophy | ||||
| See Kennedy Disease | ||||
| Spinocerebellar Ataxia Type I | SCA1 | 6p23 | Ataxin-1 | Autosomal Dominant |
| Spinocerebellar Ataxia Type II | SCA2 | 12q24 | Ataxin-2 | Autosomal Dominant |
| Spinocerebellar Ataxia Type III | MJD | 14q24-q31 | Machado-Joseph Disease Protein 1 | Autosomal Dominant |
| Spinocerebellar Ataxia Type VI | CACNA1A | 19p13 | Autosomal Dominant | |
| Spinocerebellar Ataxia Type VII | SCA7 | 3p21-p12 | Autosomal Dominant | |
| Spinocerebellar Ataxia Type VIII | SCA8 | 13q21 | Autosomal Dominant | |
| Tay-Sachs Disease | HEXA | 15q23-q24 | Beta-hexosaminidase alpha chain | Autosomal Recessive |
| Tuberous Sclerosis | TSC1 | 9q34 | Hamartin | Autosomal Dominant |
| TSC2 | 16p13 | Tuberin | ||
| Velocardiofacial Syndrome | DGS2 | 10p14-p13 | Autosomal Dominant | |
| VCF | 22q11 | Microdeletion | ||
| Williams Syndrome | WBSCR | 7q11 | Autosomal Dominant | |
| Microdeletion | ||||
| Wolf-Hirschhorn Syndrome | WHCR | 4p16 | Chromosome Deletion | |
| von Hippel-Lindau Syndrome | VHL | 3p26-p25 | von Hippel-Lindau Disease | |
| Tumor Suppressor | Autosomal Dominant | |||
| Source: GeneTests. www.genetests.org. January 2000. | ||||
Direct DNA testing is a powerful clinical tool that has both risks and benefits.1 DNA-based testing directly analyzes disease-causing genes. Therefore, this testing can establish a highly specific diagnosis that may have important prognostic and treatment implications. Test results may also have an important bearing on genetic counseling and estimates of risks to other family members. One example is DNA testing that is now available for many forms of inherited ataxia. It is critical to differentiate Fredreich's ataxia (FA) from the dominant spinocerebellar ataxias, and this can usually be accomplished by DNA testing.2 The FA phenotype may overlap that of other ataxias and DNA testing can be highly valuable in establishing the correct diagnosis. This distinction is important because FA typically has an earlier age of onset, an earlier age at death, and increased risk for heart disease and diabetes, and is autosomal recessive compared with the autosomal dominant ataxias.
DNA testing is relatively cost effective compared with other diagnostic laboratory tests. DNA tests typically cost $250-$800. Such tests may also someday be useful in identifying carriers of disease mutations early enough for initiation of therapeutic drugs and treatments. This largely remains a hope for the future, because most neurogenetic disorders have no specific treatments at the present time.
It is worth noting that some DNA-based tests do not identify all possible mutations in a disease gene and other diagnostic tests may also be required. For example, the available DNA test for Duchenne Muscular Dystrophy (DMD) identifies only about 70% of the potential mutations in the DMD gene and a muscle biopsy with straining for dystrophin (the gene product) may be necessary to confirm the diagnosis in some cases.
It is also important to recognize that genetic testing has serious potential risks. A frequent concern is increased stress, anxiety, and depression in individuals receiving a positive test result. This is of particular concern with diseases causing severe progressive disability and reduced lifespan, such as Huntington's disease, familial ALS, and early onset familial Alzheimer's disease.3 Patients need genetic counseling prior to obtaining DNA tests and this is especially true for asymptomatic persons trying to determine if they have inherited a disease mutation.4,5 Patients may have very real concerns regarding possible loss of employment or insurance and most legislatures have not yet come to grips with regulating these issues. The website www.genetests.org also has a directory of genetic clinics to help the clinician locate appropriate genetic counseling resources.
Other areas of concern in the use of DNA tests include the testing of children, testing during adoption proceedings, prenatal diagnosis and termination of pregnancy, and use of testing in legal proceedings, such as criminal cases, child custody, and divorce. Guidelines for such situations and the experience of genetic testing centers have been reported and additional experiences will continue to be published.1,4-6
The genetic diagnosis field is moving rapidly and new DNA tests will continue to become available on a regular basis. The table attached to this report and the www. genetests.org website will be regularly updated. Direct DNA genetic testing provides a remarkable valuable and useful technology that must be combined with caution and good clinical judgment in order to provide the greatest benefit for our patients and their families. —tdb, nbh, rap (Thomas D. Bird, MD, Nancy B. Hanson, MS, and Roberta A. Pagon, MD, Departments of Pediatrics, Medicine, and Neurology, University of Washington, Children's Hospital and Regional Medical Center, and VA Puget Sound Medical Center, Seattle, WA.)
References
1. Bird TD, et al. Why do DNA testing? Practical and ethical implications of new neurogenetic tests. Ann Neurol 1995; 38:141-146.
2. Mosely ML, et al. Incidence of dominant spinocerebellar and Friedreich triplet repeats among 361 ataxia families. Neurology 1998;51:1666-1671.
3. Almqvist EW, et al. A worldwide assessment of the frequency of suicide, suicide attempts, or psychiatric hospitalization after predictive testing for Huntington Disease. Am J Hum Genet 1999;64:1293-1304.
4. Ragon RA. Genetic diagnosis and counseling in D.C. In: Federman D, Federman E, eds. Scientific American Medicine. Vol VIII. New York, NY: Scientific American Inc; 1999:1-9.
5. Mahowald MB, et al. Genetic counseling: Clinical and ethical challenges. Ann Rev Genet 1998;32:547-559.
6. McKinnon WC, et al. Predisposition genetic testing for late-onset disorders in adults. JAMA 1997;278:1217-1220.
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