Coverage Policy Manual
Policy #: 2007016
Category: Laboratory
Initiated: September 2007
Last Review: June 2022
  Genetic Test: Amyotrophic Lateral Sclerosis

Description:
Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder that involves deterioration of both the upper motor neurons (UMNs) and the lower motor neurons (LMNs), and which eventually progresses to fatal paralysis, typically within 3 to 5 years of onset.
 
There are many different types of ALS; these types are distinguished by their signs and symptoms and their genetic cause or lack of clear genetic association. Most people with ALS have a form of the condition that is described as sporadic, which means it occurs in people with no apparent history of the disorder in their family. People with sporadic ALS usually first develop features of the condition in their late fifties or early sixties. A small proportion of people with ALS, estimated at 5 to 10 percent, have a family history of the condition. The signs and symptoms of familial ALS (FALS) typically first appear in one's late forties or early fifties. Rarely, people with familial ALS develop symptoms in childhood or their teenage years. These individuals have a form of the disorder known as juvenile ALS.
Mutations in several genes, including the C9orf72, SOD1, TARDBP, FUS, ANG, ALS2, SETX, and VAPB genes, cause familial ALS and contribute to the development of sporadic ALS. Mutations in the C9orf72 gene are responsible for 30 to 40 percent of familial ALS in the United States and Europe. Worldwide, SOD1 gene mutations cause about 20 percent of familial ALS, TARDBP gene mutations account for about 5 percent, FUS gene mutations cause about 5 percent, and ANG gene mutations account for around 1 percent. The other genes that have been associated with familial ALS each account for a small proportion of cases. It is estimated that 60 percent of individuals with familial ALS have an identified genetic mutation. The cause of the condition in the remaining individuals remains unknown.
 
Various laboratories provide genetic testing for ALS, primarily for SOD1 or angiogenin (ANG) sequence variants using polymerase chain reaction (PCR) amplification and direct sequencing. PCR-based single-strand conformation polymorphism (SSCP) analysis is also used to identify susceptibility variants for ALS.
 
Coding
 
There are CPT codes to more specifically report several of the gene mutations associated with FALS.
 
CPT code 81403 includes:
ANG (angiogenin, ribonuclease, RNase A family, 5) (eg, amyotrophic lateral sclerosis), full gene sequence
 
CPT code 81404 includes:
SOD1 (superoxide dismutase 1, soluble) (eg, amyotrophic lateral sclerosis), full gene sequence
 
CPT code 81405 includes:
TARDBP (TAR DNA binding protein) (eg, amyotrophic lateral sclerosis), full gene sequence
 
CPT code 81406 includes:
FUS (fused in sarcoma) (amyotrophic lateral sclerosis), full gene sequence
SETX (senataxin) (eg, ataxia), full gene sequence
 
CPT 81479 would be used to report testing for ALS2, C90rf72 and VAPB gene mutations.
 
HCPCS S3800 (Genetic testing for amyotrophic lateral sclerosis) was introduced into HCPCS as an active code on 1 Jul 2007.
 
 

Policy/
Coverage:
EFFECTIVE June 2021
 
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
 
Genetic testing for amyotrophic lateral sclerosis does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness.
 
For member with contracts without primary coverage criteria, Genetic testing for amyotrophic lateral sclerosis is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
 
EFFECTIVE PRIOR TO June 2021
Genetic testing for amyotrophic lateral sclerosis does not meet primary coverage criteria and is not covered.
 
Primary Coverage Criteria requires an intervention must be proven to be effective. If there is a lack of scientific evidence regarding a new intervention, or if the available scientific evidence is in conflict or the subject of continuing debate, the new intervention shall be deemed “not effective”.  
 
For contracts without primary coverage criteria, genetic testing for amyotrophic lateral sclerosis is considered investigational and is not covered.  Investigational services are an exclusion in the member benefit certificate.

Rationale:
In this instance the diagnosis of ALS can be made with other findings and does not require genetic testing to confirm the diagnosis or determine treatment.  By Tanaka et al:  "Although more than 130 years have gone by since the first description in 1869 by Jean-Martin Charcot, the mechanism underlying the characteristic selective motor neuron degeneration in amyotrophic lateral sclerosis (ALS) has remained elusive. Modest advances in this research field have been achieved by the identification of copper/zinc superoxide dismutase 1 (SOD1) as one of the causative genes for rare familial ALS (FALS) and by the development and analysis of mutant SOD1 transgenic mouse models. However, in sporadic ALS (SALS) with many more patients, causative or critical genes situated upstream of the disease pathway have not yet been elucidated and no available disease models have been established. To approach genes causative or critical for ALS, gene expression profiling in tissues primarily affected by the disease has represented an attractive research strategy. We have been working on screening these genes employing and combining several new technologies such as cDNA microarray, molecular indexing, and laser capture microdissection. Many of the resultant genes are of intense interest and may provide a powerful tool for determining the molecular mechanisms of ALS. However, we have barely arrived at the starting point and are confronting an enormous number of genes whose roles remain undetermined. Challenging tasks lie ahead of us such as identifying which genes are really causative for ALS and developing a disease model of SALS with due consideration for the expression changes in those genes."
 
The prevalence of ALS is relatively low and more than 90% of ALS patients show no familial trait. Up to 3% of ALS patients with no family history of the disease have SOD1 mutations.  Of the 5%-10% of ALS patients with a familial trait only 20%-30% of the cases are associated with a mutation in the copper/zinc superoxide dismutase 1 gene (SOD1).  Failure to detect a SOD1 mutation does not rule out familial ALS.
 
2011 Update
 
Clinical Utility:
The clinical utility of a direct diagnostic test for the detection of a mutation of the  SOD1 gene to confirm a diagnosis of Amyotrophic Lateral Sclerosis does not rise to the level of usefulness required at this time.
 
New York State Validation Program:
Currently there is no evidence that testing for a mutation of the SOD1 gene in Amyotrophic Lateral Sclerosis has been validated by the New York State Validation program.
 
Clinical Appropriateness:
The SOD1 mutation genetic testing is not deemed appropriate for patients in which a clinical diagnosis of Amyotrophic Lateral Sclerosis has been made, except for the purposes of genetic counseling for family members and sub typing of the mutation.
 
EGAPP:
SOD1 mutation testing has not been evaluated by EGAPP. It has not been identified as a topic of interest, and it is not currently on the list of tests to be evaluated in the future.
 
Gene Reviews:
Gene mutation testing has been evaluated by Gene Reviews and is recognized as a legitimate testing modality for confirmation of the diagnosis of ALS. It is currently on the Gene Reviews website with a full explanation of the testing process and the current laboratories that perform these molecular diagnostic tests. Tests for several different gene mutations are available; however, the SOD1 mutation is, by far the most common mutation found. The information gained from testing for these mutations is used purely for defining a subtype of the mutation and for genetic counseling.
 
American College of Medical Genetics:
Gene mutation testing for the SOD1 gene is not currently listed on the website for the American College of Medical Genetics.
 
BCBSA MPRM Policy:
BCBSA MPRM currently has no policy on SOD1 gene mutation testing for Amyotrophic Lateral Sclerosis.
 
Hayes Inc Assessment:
Hayes Inc Assessment states that gene mutation testing for Amyotrophic Lateral Sclerosis has a C rating for the SOD1 gene and a D rating for other, less common gene mutations known to be associated with ALS.
 
2012 Update
A literature review was conducted using the MEDLINE database through May 2012.  There was no new literature identified that would prompt a change in the coverage statement.
 
2013 Update
A literature search was conducted through May 2013.  There was no new information identified that would prompt a change in the coverage statement.  There remains a lack of scientific evidence regarding the clinical utility of genetic testing in the diagnosis and treatment of ALS.
 
No specific therapy for patients with SOD1 gene mutations have been approved (Anderson, 2012). Clinical trials on drugs targeting SOD1 are currently underway and are discussed below. Miller and colleagues recently published results of a first-in-man, phase 1, placebo-controlled trial assessing the safety, tolerability and pharmacokinetics of an intrathecal administration of ISIS 333611 in patients with SOD1-related familial ALS (Miller, 2013).
 
The EFNS Task Force published an update of the 2005 EFNS guidelines on the clinical management of ALS (Andersen, 2012). The task force gives recommendations which result in either an A, B or C recommendation depending on the level of evidence.  No recommendations were given based on A, B, or C level of evidence. Recommendations where there is a lack of evidence but a consensus of opinion, are noted as “Good Clinical Practice Points (GCPP)”. The following recommendations were stated as GCPP.
 
    • “Clinical DNA analysis for gene mutation should only be performed in cases with a known family history of ALS, and in sporadic ALS cases with the characteristic phenotype of the recessive D90A mutation (GCPP)”.
    • Clinical DNA analysis for gene mutations should not be performed in cases with sporadic ALS with a typical classical ALS phenotype (GCPP).
 
The following ongoing clinical trials were identified on the clinicaltrials.gov website:
 
NCT00706147- Phase 2/3 randomized, placebo-controlled trial to assess the efficacy, safety and tolerability of arimoclomol in SOD1 positive familial ALS.  This study is sponsored by the University of Miami in collaboration with the ALS Association, FDA Office of Orphan Products Development and Massachusetts General Hospital. The study is currently recruiting and has an estimated completion date of December 2013.
 
NCT01083667- Phase 1/2 open-label study to assess the safety, tolerability and effect on SOD1 levels by pyrimethamine in patients with familial ALS. The study is sponsored by Weill Medical College of Cornell Univeristy in collaboration with the Muscular Dystrophy Association. The study has an estimated completion date of May 2013.
 
The results of the literature search do not prompt a change in the coverage statement. Further evidence is needed regarding the clinical utility of genetic testing in the diagnosis and management of ALS.
 
2014 Update
A literature search was conducted through May 2014.  There was no new information identified that would prompt a change in the coverage statement.
 
2015 Update
A literature search was conducted through May 2015. There was no new information that would prompt a change in the coverage statement. At present, there is no published scientific evidence supporting the clinical utility of genetic testing for amyotrophic lateral sclerosis.  There is no FDA approved medications for patients with SOD1 or other gene mutations. Clinical trials are ongoing on the use of arimoclomol and pyrimethamine in patients with SOD1 mutations (Clinicaltrials.gov, 2015).
 
Other gene mutations identified with familial amyotrophic lateral sclerosis include C9orf72, SOD1, TARDBP, FUS, ANG, ALS2, SETX, and VAPB. The literature search did not identify any specific therapy for patients with these gene mutations.
  
2017 Update
A literature search conducted through May 2017 did not reveal any new information that would prompt a change in the coverage statement.
 
2018 Update
A literature search conducted through May 2018 did not reveal any new information that would prompt a change in the coverage statement.
 
2019 Update
A literature search was conducted through May 2019.  There was no new information identified that would prompt a change in the coverage statement.  
 
2020 Update
A literature search was conducted through May 2020.  There was no new information identified that would prompt a change in the coverage statement.  
 
2021 Update
Annual policy review completed with a literature search using the MEDLINE database through May 2021. No new literature was identified that would prompt a change in the coverage statement.
 
2022 Update
Annual policy review completed with a literature search using the MEDLINE database through May 2022. No new literature was identified that would prompt a change in the coverage statement.

CPT/HCPCS:
81403Molecular pathology procedure, Level 4 (eg, analysis of single exon by DNA sequence analysis, analysis of >10 amplicons using multiplex PCR in 2 or more independent reactions, mutation scanning or duplication/deletion variants of 2-5 exons) ANG (angiogenin, ribonuclease, RNase A family, 5) (eg, amyotrophic lateral sclerosis), full gene sequence ARX (aristaless-related homeobox) (eg, X-linked lissencephaly with ambiguous genitalia, X-linked mental retardation), duplication/deletion analysis CEL (carboxyl ester lipase [bile salt-stimulated lipase]) (eg, maturity-onset diabetes of the young [MODY]), targeted sequence analysis of exon 11 (eg, c.1785delC, c.1686delT) CTNNB1 (catenin [cadherin-associated protein], beta 1, 88kDa) (eg, desmoid tumors), targeted sequence analysis (eg, exon 3) DAZ/SRY (deleted in azoospermia and sex determining region Y) (eg, male infertility), common deletions (eg, AZFa, AZFb, AZFc, AZFd) DNMT3A (DNA [cytosine-5-]-methyltransferase 3 alpha) (eg, acute myeloid leukemia), targeted sequence analysis (eg, exon 23) EPCAM (epithelial cell adhesion molecule) (eg, Lynch syndrome), duplication/deletion analysis F8 (coagulation factor VIII) (eg, hemophilia A), inversion analysis, intron 1 and intron 22A F12 (coagulation factor XII [Hageman factor]) (eg, angioedema, hereditary, type III; factor XII deficiency), targeted sequence analysis of exon 9 FGFR3 (fibroblast growth factor receptor 3) (eg, isolated craniosynostosis), targeted sequence analysis (eg, exon 7) (For targeted sequence analysis of multiple FGFR3 exons, use 81404) GJB1 (gap junction protein, beta 1) (eg, Charcot-Marie-Tooth X-linked), full gene sequence GNAQ (guanine nucleotide-binding protein G[q] subunit alpha) (eg, uveal melanoma), common variants (eg, R183, Q209) Human erythrocyte antigen gene analyses (eg, SLC14A1 [Kidd blood group], BCAM [Lutheran blood group], ICAM4 [Landsteiner-Wiener blood group], SLC4A1 [Diego blood group], AQP1 [Colton blood group], ERMAP [Scianna blood group], RHCE [Rh blood group, CcEe antigens], KEL [Kell blood group], DARC [Duffy blood group], GYPA, GYPB, GYPE [MNS blood group], ART4 [Dombrock blood group]) (eg, sickle-cell disease, thalassemia, hemolytic transfusion reactions, hemolytic disease of the fetus or newborn), common variants HRAS (v-Ha-ras Harvey rat sarcoma viral oncogene homolog) (eg, Costello syndrome), exon 2 sequence KCNC3 (potassium voltage-gated channel, Shaw-related subfamily, member 3) (eg, spinocerebellar ataxia), targeted sequence analysis (eg, exon 2) KCNJ2 (potassium inwardly-rectifying channel, subfamily J, member 2) (eg, Andersen-Tawil syndrome), full gene sequence KCNJ11 (potassium inwardly-rectifying channel, subfamily J, member 11) (eg, familial hyperinsulinism), full gene sequence Killer cell immunoglobulin-like receptor (KIR) gene family (eg, hematopoietic stem cell transplantation), genotyping of KIR family genes Known familial variant not otherwise specified, for gene listed in Tier 1 or Tier 2, or identified during a genomic sequencing procedure, DNA sequence analysis, each variant exon (For a known familial variant that is considered a common variant, use specific common variant Tier 1 or Tier 2 code) MC4R (melanocortin 4 receptor) (eg, obesity), full gene sequence MICA (MHC class I polypeptide-related sequence A) (eg, solid organ transplantation), common variants (eg, *001, *002) MT-RNR1 (mitochondrially encoded 12S RNA) (eg, nonsyndromic hearing loss), full gene sequence MT-TS1 (mitochondrially encoded tRNA serine 1) (eg, nonsyndromic hearing loss), full gene sequence NDP (Norrie disease [pseudoglioma]) (eg, Norrie disease), duplication/deletion analysis NHLRC1 (NHL repeat containing 1) (eg, progressive myoclonus epilepsy), full gene sequence PHOX2B (paired-like homeobox 2b) (eg, congenital central hypoventilation syndrome), duplication/deletion analysis PLN (phospholamban) (eg, dilated cardiomyopathy, hypertrophic cardiomyopathy), full gene sequence RHD (Rh blood group, D antigen) (eg, hemolytic disease of the fetus and newborn, Rh maternal/fetal compatibility), deletion analysis (eg, exons 4, 5, and 7, pseudogene) RHD (Rh blood group, D antigen) (eg, hemolytic disease of the fetus and newborn, Rh maternal/fetal compatibility), deletion analysis (eg, exons 4, 5, and 7, pseudogene), performed on cell-free fetal DNA in maternal blood (For human erythrocyte gene analysis of RHD, use a separate unit of 81403) SH2D1A (SH2 domain containing 1A) (eg, X-linked lymphoproliferative syndrome), duplication/deletion analysis TWIST1 (twist homolog 1 [Drosophila]) (eg, Saethre-Chotzen syndrome), duplication/deletion analysis UBA1 (ubiquitin-like modifier activating enzyme 1) (eg, spinal muscular atrophy, X-linked), targeted sequence analysis (eg, exon 15) VHL (von Hippel-Lindau tumor suppressor) (eg, von Hippel-Lindau familial cancer syndrome), deletion/duplication analysis VWF (von Willebrand factor) (eg, von Willebrand disease types 2A, 2B, 2M), targeted sequence analysis (eg, exon 28)
81404Molecular pathology procedure, Level 5 (eg, analysis of 2-5 exons by DNA sequence analysis, mutation scanning or duplication/deletion variants of 6-10 exons, or characterization of a dynamic mutation disorder/triplet repeat by Southern blot analysis) ACADS (acyl-CoA dehydrogenase, C-2 to C-3 short chain) (eg, short chain acyl-CoA dehydrogenase deficiency), targeted sequence analysis (eg, exons 5 and 6) AQP2 (aquaporin 2 [collecting duct]) (eg, nephrogenic diabetes insipidus), full gene sequence ARX (aristaless related homeobox) (eg, X-linked lissencephaly with ambiguous genitalia, X-linked mental retardation), full gene sequence AVPR2 (arginine vasopressin receptor 2) (eg, nephrogenic diabetes insipidus), full gene sequence BBS10 (Bardet-Biedl syndrome 10) (eg, Bardet-Biedl syndrome), full gene sequence BTD (biotinidase) (eg, biotinidase deficiency), full gene sequence C10orf2 (chromosome 10 open reading frame 2) (eg, mitochondrial DNA depletion syndrome), full gene sequence CAV3 (caveolin 3) (eg, CAV3-related distal myopathy, limb-girdle muscular dystrophy type 1C), full gene sequence CD40LG (CD40 ligand) (eg, X-linked hyper IgM syndrome), full gene sequence CDKN2A (cyclin-dependent kinase inhibitor 2A) (eg, CDKN2A-related cutaneous malignant melanoma, familial atypical mole-malignant melanoma syndrome), full gene sequence CLRN1 (clarin 1) (eg, Usher syndrome, type 3), full gene sequence COX6B1 (cytochrome c oxidase subunit VIb polypeptide 1) (eg, mitochondrial respiratory chain complex IV deficiency), full gene sequence CPT2 (carnitine palmitoyltransferase 2) (eg, carnitine palmitoyltransferase II deficiency), full gene sequence CRX (cone-rod homeobox) (eg, cone-rod dystrophy 2, Leber congenital amaurosis), full gene sequence CYP1B1 (cytochrome P450, family 1, subfamily B, polypeptide 1) (eg, primary congenital glaucoma), full gene sequence EGR2 (early growth response 2) (eg, Charcot-Marie-Tooth), full gene sequence EMD (emerin) (eg, Emery-Dreifuss muscular dystrophy), duplication/deletion analysis EPM2A (epilepsy, progressive myoclonus type 2A, Lafora disease [laforin]) (eg, progressive myoclonus epilepsy), full gene sequence FGF23 (fibroblast growth factor 23) (eg, hypophosphatemic rickets), full gene sequence FGFR2 (fibroblast growth factor receptor 2) (eg, craniosynostosis, Apert syndrome, Crouzon syndrome), targeted sequence analysis (eg, exons 8, 10) FGFR3 (fibroblast growth factor receptor 3) (eg, achondroplasia, hypochondroplasia), targeted sequence analysis (eg, exons 8, 11, 12, 13) FHL1 (four and a half LIM domains 1) (eg, Emery-Dreifuss muscular dystrophy), full gene sequence FKRP (fukutin related protein) (eg, congenital muscular dystrophy type 1C [MDC1C], limb-girdle muscular dystrophy [LGMD] type 2I), full gene sequence FOXG1 (forkhead box G1) (eg, Rett syndrome), full gene sequence FSHMD1A (facioscapulohumeral muscular dystrophy 1A) (eg, facioscapulohumeral muscular dystrophy), evaluation to detect abnormal (eg, deleted) alleles FSHMD1A (facioscapulohumeral muscular dystrophy 1A) (eg, facioscapulohumeral muscular dystrophy), characterization of haplotype(s) (ie, chromosome 4A and 4B haplotypes) GH1 (growth hormone 1) (eg, growth hormone deficiency), full gene sequence GP1BB (glycoprotein Ib [platelet], beta polypeptide) (eg, Bernard-Soulier syndrome type B), full gene sequence (For common deletion variants of alpha globin 1 and alpha globin 2 genes, use 81257) HNF1B (HNF1 homeobox B) (eg, maturity-onset diabetes of the young [MODY]), duplication/deletion analysis HRAS (v-Ha-ras Harvey rat sarcoma viral oncogene homolog) (eg, Costello syndrome), full gene sequence HSD3B2 (hydroxy-delta-5-steroid dehydrogenase, 3 beta- and steroid delta-isomerase 2) (eg, 3-beta-hydroxysteroid dehydrogenase type II deficiency), full gene sequence HSD11B2 (hydroxysteroid [11-beta] dehydrogenase 2) (eg, mineralocorticoid excess syndrome), full gene sequence HSPB1 (heat shock 27kDa protein 1) (eg, Charcot-Marie-Tooth disease), full gene sequence INS (insulin) (eg, diabetes mellitus), full gene sequence KCNJ1 (potassium inwardly-rectifying channel, subfamily J, member 1) (eg, Bartter syndrome), full gene sequence KCNJ10 (potassium inwardly-rectifying channel, subfamily J, member 10) (eg, SeSAME syndrome, EAST syndrome, sensorineural hearing loss), full gene sequence LITAF (lipopolysaccharide-induced TNF factor) (eg, Charcot-Marie-Tooth), full gene sequence MEFV (Mediterranean fever) (eg, familial Mediterranean fever), full gene sequence MEN1 (multiple endocrine neoplasia I) (eg, multiple endocrine neoplasia type 1, Wermer syndrome), duplication/deletion analysis MMACHC (methylmalonic aciduria [cobalamin deficiency] cblC type, with homocystinuria) (eg, methylmalonic acidemia and homocystinuria), full gene sequence MPV17 (MpV17 mitochondrial inner membrane protein) (eg, mitochondrial DNA depletion syndrome), duplication/deletion analysis NDP (Norrie disease [pseudoglioma]) (eg, Norrie disease), full gene sequence NDUFA1 (NADH dehydrogenase [ubiquinone] 1 alpha subcomplex, 1, 7.5kDa) (eg, Leigh syndrome, mitochondrial complex I deficiency), full gene sequence NDUFAF2 (NADH dehydrogenase [ubiquinone] 1 alpha subcomplex, assembly factor 2) (eg, Leigh syndrome, mitochondrial complex I deficiency), full gene sequence NDUFS4 (NADH dehydrogenase [ubiquinone] Fe-S protein 4, 18kDa [NADH-coenzyme Q reductase]) (eg, Leigh syndrome, mitochondrial complex I deficiency), full gene sequence NIPA1 (non-imprinted in Prader-Willi/Angelman syndrome 1) (eg, spastic paraplegia), full gene sequence NLGN4X (neuroligin 4, X-linked) (eg, autism spectrum disorders), duplication/deletion analysis NPC2 (Niemann-Pick disease, type C2 [epididymal secretory protein E1]) (eg, Niemann-Pick disease type C2), full gene sequence NR0B1 (nuclear receptor subfamily 0, group B, member 1) (eg, congenital adrenal hypoplasia), full gene sequence PDX1 (pancreatic and duodenal homeobox 1) (eg, maturity-onset diabetes of the young [MODY]), full gene sequence PHOX2B (paired-like homeobox 2b) (eg, congenital central hypoventilation syndrome), full gene sequence PLP1 (proteolipid protein 1) (eg, Pelizaeus-Merzbacher disease, spastic paraplegia), duplication/deletion analysis PQBP1 (polyglutamine binding protein 1) (eg, Renpenning syndrome), duplication/deletion analysis PRNP (prion protein) (eg, genetic prion disease), full gene sequence PROP1 (PROP paired-like homeobox 1) (eg, combined pituitary hormone deficiency), full gene sequence PRPH2 (peripherin 2 [retinal degeneration, slow]) (eg, retinitis pigmentosa), full gene sequence PRSS1 (protease, serine, 1 [trypsin 1]) (eg, hereditary pancreatitis), full gene sequence RAF1 (v-raf-1 murine leukemia viral oncogene homolog 1) (eg, LEOPARD syndrome), targeted sequence analysis (eg, exons 7, 12, 14, 17) RET (ret proto-oncogene) (eg, multiple endocrine neoplasia, type 2B and familial medullary thyroid carcinoma), common variants (eg, M918T, 2647_2648delinsTT, A883F) RHO (rhodopsin) (eg, retinitis pigmentosa), full gene sequence RP1 (retinitis pigmentosa 1) (eg, retinitis pigmentosa), full gene sequence SCN1B (sodium channel, voltage-gated, type I, beta) (eg, Brugada syndrome), full gene sequence SCO2 (SCO cytochrome oxidase deficient homolog 2 [SCO1L]) (eg, mitochondrial respiratory chain complex IV deficiency), full gene sequence SDHC (succinate dehydrogenase complex, subunit C, integral membrane protein, 15kDa) (eg, hereditary paraganglioma-pheochromocytoma syndrome), duplication/deletion analysis SDHD (succinate dehydrogenase complex, subunit D, integral membrane protein) (eg, hereditary paraganglioma), full gene sequence SGCG (sarcoglycan, gamma [35kDa dystrophin-associated glycoprotein]) (eg, limb-girdle muscular dystrophy), duplication/deletion analysis SH2D1A (SH2 domain containing 1A) (eg, X-linked lymphoproliferative syndrome), full gene sequence SLC16A2 (solute carrier family 16, member 2 [thyroid hormone transporter]) (eg, specific thyroid hormone
81405Molecular pathology procedure, Level 6 (eg, analysis of 6-10 exons by DNA sequence analysis, mutation scanning or duplication/deletion variants of 11-25 exons, regionally targeted cytogenomic array analysis) Cytogenomic constitutional targeted microarray analysis of chromosome 22q13 by interrogation of genomic regions for copy number and single nucleotide polymorphism (SNP) variants for chromosomal abnormalities (When performing cytogenomic [genome-wide] analysis, for constitutional chromosomal abnormalities. See 81228, 81229, 81349)
81406Molecular pathology procedure, Level 7 (eg, analysis of 11-25 exons by DNA sequence analysis, mutation scanning or duplication/deletion variants of 26-50 exons) ACADVL (acyl-CoA dehydrogenase, very long chain) (eg, very long chain acyl-coenzyme A dehydrogenase deficiency), full gene sequence ACTN4 (actinin, alpha 4) (eg, focal segmental glomerulosclerosis), full gene sequence AFG3L2 (AFG3 ATPase family gene 3-like 2 [S. cerevisiae]) (eg, spinocerebellar ataxia), full gene sequence AIRE (autoimmune regulator) (eg, autoimmune polyendocrinopathy syndrome type 1), full gene sequence ALDH7A1 (aldehyde dehydrogenase 7 family, member A1) (eg, pyridoxine-dependent epilepsy), full gene sequence ANO5 (anoctamin 5) (eg, limb-girdle muscular dystrophy), full gene sequence ANOS1 (anosmin-1) (eg, Kallmann syndrome 1), full gene sequence APP (amyloid beta [A4] precursor protein) (eg, Alzheimer disease), full gene sequence ASS1 (argininosuccinate synthase 1) (eg, citrullinemia type I), full gene sequence ATL1 (atlastin GTPase 1) (eg, spastic paraplegia), full gene sequence ATP1A2 (ATPase, Na+/K+ transporting, alpha 2 polypeptide) (eg, familial hemiplegic migraine), full gene sequence ATP7B (ATPase, Cu++ transporting, beta polypeptide) (eg, Wilson disease), full gene sequence BBS1 (Bardet-Biedl syndrome 1) (eg, Bardet-Biedl syndrome), full gene sequence BBS2 (Bardet-Biedl syndrome 2) (eg, Bardet-Biedl syndrome), full gene sequence BCKDHB (branched-chain keto acid dehydrogenase E1, beta polypeptide) (eg, maple syrup urine disease, type 1B), full gene sequence BEST1 (bestrophin 1) (eg, vitelliform macular dystrophy), full gene sequence BMPR2 (bone morphogenetic protein receptor, type II [serine/threonine kinase]) (eg, heritable pulmonary arterial hypertension), full gene sequence BRAF (B-Raf proto-oncogene, serine/threonine kinase) (eg, Noonan syndrome), full gene sequence BSCL2 (Berardinelli-Seip congenital lipodystrophy 2 [seipin]) (eg, Berardinelli-Seip congenital lipodystrophy), full gene sequence BTK (Bruton agammaglobulinemia tyrosine kinase) (eg, X-linked agammaglobulinemia), full gene sequence CACNB2 (calcium channel, voltage-dependent, beta 2 subunit) (eg, Brugada syndrome), full gene sequence CAPN3 (calpain 3) (eg, limb-girdle muscular dystrophy [LGMD] type 2A, calpainopathy), full gene sequence CBS (cystathionine-beta-synthase) (eg, homocystinuria, cystathionine beta-synthase deficiency), full gene sequence CDH1 (cadherin 1, type 1, E-cadherin [epithelial]) (eg, hereditary diffuse gastric cancer), full gene sequence CDKL5 (cyclin-dependent kinase-like 5) (eg, early infantile epileptic encephalopathy), full gene sequence CLCN1 (chloride channel 1, skeletal muscle) (eg, myotonia congenita), full gene sequence CLCNKB (chloride channel, voltage-sensitive Kb) (eg, Bartter syndrome 3 and 4b), full gene sequence CNTNAP2 (contactin-associated protein-like 2) (eg, Pitt-Hopkins-like syndrome 1), full gene sequence COL6A2 (collagen, type VI, alpha 2) (eg, collagen type VI-related disorders), duplication/deletion analysis CPT1A (carnitine palmitoyltransferase 1A [liver]) (eg, carnitine palmitoyltransferase 1A [CPT1A] deficiency), full gene sequence CRB1 (crumbs homolog 1 [Drosophila]) (eg, Leber congenital amaurosis), full gene sequence CREBBP (CREB binding protein) (eg, Rubinstein-Taybi syndrome), duplication/deletion analysis DBT (dihydrolipoamide branched chain transacylase E2) (eg, maple syrup urine disease, type 2), full gene sequence DLAT (dihydrolipoamide S-acetyltransferase) (eg, pyruvate dehydrogenase E2 deficiency), full gene sequence DLD (dihydrolipoamide dehydrogenase) (eg, maple syrup urine disease, type III), full gene sequence DSC2 (desmocollin) (eg, arrhythmogenic right ventricular dysplasia/cardiomyopathy 11), full gene sequence DSG2 (desmoglein 2) (eg, arrhythmogenic right ventricular dysplasia/cardiomyopathy 10), full gene sequence DSP (desmoplakin) (eg, arrhythmogenic right ventricular dysplasia/cardiomyopathy 8), full gene sequence EFHC1 (EF-hand domain [C-terminal] containing 1) (eg, juvenile myoclonic epilepsy), full gene sequence EIF2B3 (eukaryotic translation initiation factor 2B, subunit 3 gamma, 58kDa) (eg, leukoencephalopathy with vanishing white matter), full gene sequence EIF2B4 (eukaryotic translation initiation factor 2B, subunit 4 delta, 67kDa) (eg, leukoencephalopathy with vanishing white matter), full gene sequence EIF2B5 (eukaryotic translation initiation factor 2B, subunit 5 epsilon, 82kDa) (eg, childhood ataxia with central nervous system hypomyelination/vanishing white matter), full gene sequence ENG (endoglin) (eg, hereditary hemorrhagic telangiectasia, type 1), full gene sequence EYA1 (eyes absent homolog 1 [Drosophila]) (eg, branchio-oto-renal [BOR] spectrum disorders), full gene sequence F8 (coagulation factor VIII) (eg, hemophilia A), duplication/deletion analysis FAH (fumarylacetoacetate hydrolase [fumarylacetoacetase]) (eg, tyrosinemia, type 1), full gene sequence FASTKD2 (FAST kinase domains 2) (eg, mitochondrial respiratory chain complex IV deficiency), full gene sequence FIG4 (FIG4 homolog, SAC1 lipid phosphatase domain containing [S. cerevisiae]) (eg, Charcot-Marie-Tooth disease), full gene sequence FTSJ1 (FtsJ RNA methyltransferase homolog 1 [E. coli]) (eg, X-linked mental retardation 9), full gene sequence FUS (fused in sarcoma) (eg, amyotrophic lateral sclerosis), full gene sequence GAA (glucosidase, alpha; acid) (eg, glycogen storage disease type II [Pompe disease]), full gene sequence GALC (galactosylceramidase) (eg, Krabbe disease), full gene sequence GALT (galactose-1-phosphate uridylyltransferase) (eg, galactosemia), full gene sequence GARS (glycyl-tRNA synthetase) (eg, Charcot-Marie-Tooth disease), full gene sequence GCDH (glutaryl-CoA dehydrogenase) (eg, glutaricacidemia type 1), full gene sequence GCK (glucokinase [hexokinase 4]) (eg, maturity-onset diabetes of the young [MODY]), full gene sequence GLUD1 (glutamate dehydrogenase 1) (eg, familial hyperinsulinism), full gene sequence GNE (glucosamine [UDP-N-acetyl]-2-epimerase/N-acetylmannosamine kinase) (eg, inclusion body myopathy 2 [IBM2], Nonaka myopathy), full gene sequence GRN (granulin) (eg, frontotemporal dementia), full gene sequence HADHA (hydroxyacyl-CoA dehydrogenase/3-ketoacyl-CoA thiolase/enoyl-CoA hydratase [trifunctional protein] alpha subunit) (eg, long chain acyl-coenzyme A dehydrogenase deficiency), full gene sequence HADHB (hydroxyacyl-CoA dehydrogenase/3-ketoacyl-CoA thiolase/enoyl-CoA hydratase [trifunctional protein], beta subunit) (eg, trifunctional protein deficiency), full gene sequence HEXA (hexosaminidase A, alpha polypeptide) (eg, Tay-Sachs disease), full gene sequence HLCS (HLCS holocarboxylase synthetase) (eg, holocarboxylase synthetase deficiency), full gene sequence HMBS (hydroxymethylbilane synthase) (eg, acute intermittent porphyria), full gene sequence HNF4A (hepatocyte nuclear factor 4, alpha) (eg, maturity-onset diabetes of the young [MODY]), full gene sequence IDUA (iduronidase, alpha-L-) (eg, mucopolysaccharidosis type I), full gene sequence INF2 (inverted formin, FH2 and WH2 domain containing) (eg, focal segmental glomerulosclerosis), full gene sequence IVD (isovaleryl-CoA dehydrogenase) (eg, isovaleric acidemia), full gene sequence JAG1 (jagged 1) (eg, Alagille syndrome), duplication/deletion analysis JUP (junction plakoglobin) (eg, arrhythmogenic right ventricular dysplasia/cardiomyopathy 11), full gene sequence KCNH2 (potassium voltage-gated channel, subfamily H [eag-related], member 2) (eg, short QT syndrome, long QT syndrome), full gene sequence KCNQ1 (potassium voltage-gated channel, KQT-like subfamily, member 1) (eg, short QT syndrome, long QT syndrome), full gene sequence KCNQ2 (potassium voltage-gated channel, KQT-like subfamily, member 2) (eg, epileptic encephalopathy), full gene sequence LDB3 (LIM domain binding 3) (eg, familial dilated cardiomyopathy, myofibrillar myopathy), full gene sequence LDLR (low den
81479Unlisted molecular pathology procedure
S3800Genetic testing for amyotrophic lateral sclerosis (als)

References: Andersen PM, Abrahams S, Borasio GD, et al.(2012) EFNS guidelines on the clinical management of amyotrophic lateral sclerosis (MALS)-revised report of an EFNS task force. European Journal of Neurology 2012, 19:360-375.

Battistini S, Giannini F, et al.(2005) SOD1 mutations in amyotrophic lateral sclerosis. Results from a multicenter Italian study. J Neurol, 2005; 252:782-8.

Clinicaltrials.gov. Accessed at www.clinicaltrials.gov. Last accessed June 15, 2015.

Clinicaltrials.gov. Accessed at www.clinicaltrials.gov. Last accessed June 17, 2013.

Dellefave L, Siddique T.(2007) Amyotrophic lateral sclerosis overview. http://www.geneclinics.org/profiles.

Genetics Home Reference.(2015) Amyotrophic Lateral Sclerosis. http://ghr.nlm.nih.gov/condition/amyotrophic-lateral-sclerosis. Last accessed June 2015.

Gonzalez de Aguilar JL, Echaniz-Laguna A, et al.(2007) Amyotrophic lateral sclerosis: all roads lead to Rome. J Neurochem, 2007; 101:1153-60.

Gros-Louis F, Gaspar C, Rouleau GA.(2006) Genetics of familial and sporadic amyotrhophic lateral sclerosis. Biochimica Biophysica Acta, 2006; 1762:956-72.

Miller TM, Pestronk A, David W, et al.(2013) An antisense oligonucleotide against SOD1 delivered intrathecally for patients with SOD1 familial amyotrophic lateral sclerosis: a phase 1, randomized, first-in-man study. Lancet neurol. 2013 My;12(5):435-42.

Tanaka F, Niwa JI, et al.(2006) Gene expression profiling toward understanding of ALS pathogenesis. Ann N Y Acad Sci, 2006; 1086:1-10.


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