Coverage Policy Manual
Policy #: 2015017
Category: Laboratory
Initiated: June 2015
Last Review: August 2023
  Genetic Test: Limb-Girdle Muscular Dystrophies
Description:
Muscular Dystrophies
MDs are a group of inherited disorders characterized by progressive weakness and degeneration of skeletal muscle, cardiac muscle, or both, which may be association with respiratory muscle involvement or dysphagia and dysarthria. MDs are associated with a wide spectrum of phenotypes, which may range from rapidly progressive weakness leading to death in the second or third decade of life to clinically asymptomatic disease with elevated CK levels. MDs have been classified on the basis of clinical presentation and genetic etiology. The most common MDs are the dystrophinopathies, Duchenne (DMD) and Becker (BMD) muscular dystrophies, which are characterized by mutations in the dystrophin gene. Other MDs are characterized by the location of onset of clinical weakness and include the LGMDs, facioscapulohumeral MD, oculopharyngeal MD, distal MD, and humeroperoneal MD (also known as Emery-Dreifuss muscular dystrophy). The congenital MDs are a genetically heterogeneous group of disorders, which historically included infants with hypotonia and weakness at birth and findings of MD on biopsy. Finally, myotonic dystrophy is a multisystem disorder characterized by skeletal muscle weakness and myotonia in association with cardiac abnormalities, cognitive impairment, endocrinopathies, and dysphagia.
 
Limb-Girdle Muscular Dystrophies
The term limb-girdle muscular dystrophy is a clinical descriptor for a group of MDs characterized by predominantly proximal muscle weakness (pelvic and shoulder girdles) which may be included in the differential diagnosis of DMD and BMD (Nigro, 2014). Onset can be in childhood or adulthood. The degree of disability depends on the location and degree of weakness. Some LGMD subtypes are characterized by only mild, slowly progressive weakness, while others are associated with early-onset, severe disease with loss of ambulation. LGMDs may be associated with cardiac dysfunction, cardiomyopathy (dilated or hypertrophic), respiratory depression, and dysphagia or dysarthria. Of particular note is the risk of cardiac complications, which is a feature of many but not all LGMDs. Most patients have an elevated CK.
 
LGMDs have an estimated prevalence ranging from 2.27 to 4 per 100,000 in the general population, constituting the fourth most prevalent MD type after the dystrophinopathies (DMD and BMD), facioscapulohumeral MD, and myotonic dystrophy. The prevalence of specific types increases in populations with founder mutations (eg, Finland, Brazil).
 
Genetic Basis and Clinical Correlation
As the genetic basis of the LGMDs has been elucidated, it has been recognized that there is tremendous heterogeneity in genetic mutations that cause the LGMD phenotype. LGMDs were initially classified based on a clinical and locus-based system. As of 2015, at least 9 autosomal dominant types (designated LGMD1A through LGMD1H) and at least 23 autosomal recessive types (designated LGMD2A through LGMD2W) have been identified (Nigro, 2014). Subtypes vary in inheritance, pathophysiology, age of onset, and severity.
 
The prevalence of various mutations and LGMD subtypes can differ widely by country, but the autosomal recessive forms are generally more common. Calpain 3 mutations represent 20% to 40% of LGMD cases, and LGMD2A is the most frequent LGMD in most countries (Nigro, 2011). DYSF mutations leading to LGMD2B are the second most common LGMD in many, but not all, areas (15-25%). Sarcoglycanopathies constitute about 10% to 15% of all LGMDs, but 68% of the severe forms.
 
In an evaluation of 370 patients with suspected LGMD enrolled in a registry from 6 U.S. university centers, 312 of whom muscle biopsy test results were available, Moore et al reported the distribution of LGMD subtypes based on muscle biopsy results as follows: 12% LGMD2A; 18% LGMD2B; 15% LGMD2C-2F; and 1.5% LGMD1C.7
 
Clinical Variability
Other than presentation with proximal muscle weakness, the LGMD subtypes can have considerable clinical variability in terms of weakness severity and associated clinical conditions. The sarcoglycanopathies (LGMD2C-2F) cause a clinical picture similar to that of the intermediate forms of DMD and BMD, with risk of cardiomyopathy in all forms of the disease.
 
Of particular clinical importance is that fact that while most, but not all, LGMD subtypes are associated with an increased risk of cardiomyopathy, arrhythmia, or both, the risk of cardiac disorders is variable across subtypes. LGMD1A, LGMD1B, LGMB2C-K, and LGMD2M-P have all been associated with cardiac involvement. Sarcoglycan mutations tend to be associated with severe cardiomyopathy. Similarly, the LGMD subtypes of LGMD2I and 2C-2F are at higher risk of respiratory failure.
 
Many of the genes associated with LGMD subtypes have allelic disorders, both with neuromuscular disorder phenotypes and clinically unrelated phenotypes. Mutations in the lamin A/C proteins, which are caused by splice-site mutations in the LMNA gene, are associated with several different neuromuscular disorder phenotypes, including Emery-Dreifuss muscular dystrophy, a clinical syndrome characterized by childhood-onset elbow, posterior cervical, and ankle contractures and progressive humeroperoneal weakness, autosomal dominant LGMD (LGMD1B), and congenital muscular dystrophy.8 All forms have been associated with cardiac involvement, including atrial and ventricular arrhythmias and dilated cardiomyopathy.
 
Clinical Diagnosis
A diagnosis of LGMD is suspected in patients who have myopathy in the proximal musculature in the shoulder and pelvic girdles, but the distribution of weakness and the degree of involvement of distal muscles is variable, particularly early in the disease course (Norwood, 2007). Certain LGMD subtypes may be suspected on the basis of family history, patterns of weakness, CK level, and associated clinical findings. However, there is considerable clinical heterogeneity and overlap across the LGMD subtypes.
 
Without genetic testing, diagnostic testing can typically lead to a general diagnosis of a LGMD, with limited ability to determine the subcategory. Most cases of LGMD will have elevated CK levels, with some variation in the degree of elevation based on subtype. Muscle imaging with computed tomography (CT) or magnetic resonance imaging (MRI) may be obtained to assess areas of involvement and guide muscle biopsy. MRI or CT may be used to evaluate patterns of muscle involvement. At least for calpainopathy (LGMD2A) and dysferlinopathy (LGMD2B), MRI may show particular patterns distinct from other neuromuscular disorders, including hyaline body myopathy and myotonic dystrophy (Stramare, 2010). In 1 study that evaluated muscle CT in 118 patients with LGMD and 32 controls, there was generally poor overall interobserver agreement (k=0.27), and low sensitivity (40%) and specificity (58%) for LGMD (ten Dam, 2012).
 
Electromyography (EMG) has limited value in LGMD, although it may have clinical utility if there is clinical concern for type III spinal muscular atrophy. EMG typically shows myopathic changes with small polyphasic potentials (Rocha, 2010).
 
Muscle biopsy may be used in suspected LGMD to rule out other, treatable causes of weakness (in some cases), and to attempt to identify a LGMD subtype. All LGMD subtypes are characterized on muscle biopsy by dystrophic features, with degeneration and regeneration of muscle fibers, variation in fiber size, fiber splitting, increased numbers of central nuclei, and endomysial fibrosis (Norwood, 2007; Rocha, 2010). Certain subtypes, particularly in dysferlin deficiency (LGMD2B) may show inflammatory infiltrates, which may lead to an inaccurate diagnosis of polymyositis.
Following standard histologic analysis, immunohistochemistry and immunoblotting are typically used to evaluate myocyte protein components, which may include sarcolemma-related proteins (eg, α-dystroglycan, sarcoglycans, dysferlin, caveolin-3), cytoplasmic proteins (eg, calpain-3, desmin), or nuclear proteins (eg, lamin A/C). Characteristic findings on muscle biopsy immunostaining or immunoblotting can be seen for calpainopathy (LGMD2A), sarcoglycanopathies (LGMD2C-2F), dysferlinopathy (LGMD2B), and O-linked glycosylation defects (dystroglycanopathies; LGMD2I, LGMD2K, LGMD2M, LGMD2O, LGMD2N) (Pegoraro, 2012). However, muscle biopsy is imperfect: secondary deficiencies in protein expression can be seen in some LGMD. In the Moore et al study previously described, 9% of all muscle biopsy samples had reduced expression of more than 1 protein tested (Moore, 2006). In some types of mutations, muscle immunohistochemistry results may be misleading because the mutation leads to normal protein amounts but abnormal function. For example, Western blot analysis for calpain 3, with loss of all calpain 3 bands, may be diagnostic of LGMD2A, but the test is specific but not sensitive, because some LGMD2A patients may retain normal amounts of nonfunctional protein (Nigro, 2011).
 
A blood-based dysferlin protein assay, which evaluates dysferlin levels in peripheral blood CD14+ monocytes, has been evaluated in a sample of 77 individuals with suspected dysferlinopathy (Ankala, 2014). However, the test is not yet in widespread use.
 
Therapies
At present, no therapies have been clearly shown to slow the progression of muscle weakness for the LGMDs. Treatment is focused on supportive care to improve muscle strength, slow decline in strength, preserve ambulation, and treat and prevent musculoskeletal complications that may result from skeletal muscle weakness, such as contractures or scoliosis. Clinical management guidelines are available from the American Academy of Neurology.
 
Monitoring for Complications
Different genetic mutations associated with clinical LGMD are associated with different rates of complications and the speed and extent of disease progression.
 
Monitoring for respiratory depression and cardiac dysfunction is indicated for LGMD subtypes that are associated with respiratory or cardiac involvement, because patients are often asymptomatic until they have significant organ involvement. When respiratory depression is present, patients may be candidates for invasive or noninvasive mechanical ventilation. Treatments for cardiac dysfunction potentially include medical or device-based therapies for heart failure or conduction abnormalities.
 
Patients may need monitoring and treatment for swallowing dysfunction, if it is present, along with physical and occupation therapy and bracing for management of weakness.
 
Investigational Therapies
A number of therapies are under investigation for LGMD. Glucocorticoids have been reported to have some benefit in certain subtypes (LGMD2D, LGMD2I, LGMD2L). However, 1 small (N=25) randomized, double-blind, placebo controlled trial of the glucocorticoid deflazacort in patients with genetically confirmed LGMD2B (dysferlinopathy) showed no benefit and a trend toward worsening strength associated with deflazacort therapy (Walter, 2013). Autologous bone marrow transplant has been investigated for LGMD, but is not in general clinical use (Sharma, 2013). Adeno-associated virus-mediated gene transfer to the extensor digitorum brevis muscle has been investigated in LGMD2D, and in a phase 1 trial in LGMD2C (Herson, 2012). Exon-skipping therapies have been investigated as a treatment for dysferlin gene mutations (LGMD2B) given the gene’s large size.
 
Molecular Diagnosis of LGMDs
Because most mutations leading to LGMD are point mutations, the primary method of mutation detection is gene sequencing using Sanger sequencing or NGS methods. In cases in which an LGMD is suspected but gene sequencing is normal, deletion/duplication analysis through targeted comparative genomic hybridization (CGH) or multiplex ligation-dependent probe amplification (MLPA) may also be obtained.
 
A number of laboratories offer panels of tests for LGMD that rely on either Sanger sequencing or NGS, including:
    • GeneDx (Limb-Girdle Muscular Dystrophy Panel; Gaithersburg, MD [GeneDx, 2014]): NGS, with reporting only on panel genes, with concurrent targeted array CGH analysis to evaluate for deletions/duplications for most genes (exceptions, GMPPB and TNPO3). Multiplex polymerase chain reaction (PCR) assay is performed to assess the presence of the 3¢ untranslated region insertion in the FKTN gene. All reported sequence variants are confirmed by conventional di-deoxy DNA sequence analysis, quantitative PCR, MLPA, repeat PCR analysis, or another appropriate method.
    • Prevention Genetics offers several LGMD tests (Prevention Genetics, 2014). These include an autosomal dominant LGMD Sanger sequencing panel, which includes MYOT, LMNA, DNAJB6, and CAV3 sequencing either individually or as a panel, followed by array-CGH for deletions/duplications. The company also offers an autosomal recessive LGMD Sanger sequencing panel, which includes sequencing of SGCG, SGCA, SGCB, SGCD, TRIM32, CAPN3, DYSF, FKRP, TTN, TCAP, GMPPB, ANO5, and TRAPPC11, either individually or as a panel, followed by array-CGH for deletions/duplications. In addition, Prevention Genetics offers 2 NGS panels for LGMD, which involve NGS followed by array-CGH if mutation analysis is negative. Additional Sanger sequencing is performed for any regions not captured or with insufficient number of sequence reads. All pathogenic, undocumented and questionable variant calls are confirmed by Sanger sequencing.
    • Counsyl offers a Family Prep Screen, which includes testing for multiple diseases that may require early intervention or cause shortened life or intellectual disability and is designed to be used for carrier testing in reproductive planning. Testing for LGMD2D and LGMD2E may be added to the panel. Testing is conducted by NGS, without evaluation for large duplications or deletions
    • Centogene (Rostock, Germany) offers an NGS panel for LGMD, which includes sequencing of the included mutations (with hot spot testing for TTN), followed by deletion/duplication testing by MLPA (if ordered), with whole exome sequencing if no mutations are identified (Centogene, 2015).
    • Athena Diagnostics offers NGS testing for FKRP, LMNA, DYSF, CAV3, CAPN3 (NGS followed by dosage analysis), along with a NGS panel, with deletion/duplication testing for SGCA, SGCG, and CAPN3.
 
Mutations included in some of the currently available NGS testing panels are summarized below:
 
GeneDx (MYOT, LMNA, CAV3, DNAJB6, DES, TNPO3, CAPN3, DYSF, SGCG, SGCA, SGCB, SGCD, TCAP, TRIM32, FKRP, TTN, POMT1, ANO5, FKTN, POMT2, POMGnT1, GMPPB)
 
Prevention Genetics: Autosomal Dominant (MYOT, LMNA, CAV3, DNAJB6, DES, TNPO3).This panel also includes testing for SMCHD1, which is associated with facioscapulohumeral muscular dystrophy.
 
Prevention Genetics: Autosomal Recessive (CAPN3, DYSF, SGCG, SGCA, SGCB, SGCD, TCAP, TRIM32, FKRP, TTN, ANO5, DES, TRAPPC11, GMPPB, ISPD, LIMS2)
 
Centogene (MYOT, LMNA, CAV3, DNAJB6, CAPN3, DYSF, SGCG, SGCA, SGCB, SGCD, TCAP, TRIM32, FKRP, TTN, POMT1, ANO5, FKTN, POMT2, POMGnT, DAG1, PLEC1
 
Athena Daignostics (MYOT, LMNA, CAV3, DNAJB6, DES, CAPN3, DYSF, SGCG, SGCA, SGCB, SGCD, TCAP, TRIM32, FKRP, TTN, POMT1, ANO5, FKTN, POMT2, POMGnT, DAG1, PLEC, TRAPPC11). This panel also includes testing for PNPLA2, which is associated with neutral lipid storage disease with myopathy, and TOR1AIP1.
 
Regulatory Status
There are no currently available genetic tests for LGMD that are cleared for marketing by the U.S. Food and Drug Administration. Clinical laboratories may develop and validate tests in-house and market them as a laboratory service; laboratory-developed tests (LDTs) must meet the general regulatory standards of the Clinical Improvement Act (CLIA). Laboratories that offer LDTs must be licensed by CLIA for high-complexity testing.
 
Coding
There are no specific CPT codes for this testing. Several of these tests can be reported with Tier 2 CPT codes.
Code 81400 includes FKTN retrotransposon insertion variant
Code 81404 includes CAV3, FKRP, and SCGC duplication/deletion
Code 81405 includes DES, ISPD, SGCA, SGCB, SGCD, and full gene sequencing of SGCG and FKTN
Code 81406 includes ANO5, CAPN3, LMNA, POMT1, POMT2, POMGnT1, and GAA
 
 
 
Policy/
Coverage:
Effective September 2023
 
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
 
Genetic testing for genes associated with limb-girdle muscular dystrophy (LGMD) to confirm a diagnosis of LGMD meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness when:
 
    • Signs and symptoms of LGMD are present but a definitive diagnosis cannot be made without genetic testing; AND
    • The individual has received genetic counseling or has been counseled by a provider who has received specialized training in the genetics of LGMD; AND
    • At least one of the following criteria are met:
      • Results of testing may lead to changes in clinical management that improve outcomes (e.g., confirming or excluding the need for cardiac surveillance); OR
      • Genetic testing will allow the affected individual to avoid invasive testing, including muscle biopsy.
 
Targeted genetic testing for a known familial variant associated with limb-girdle muscular dystrophy meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in asymptomatic individuals to determine future risk of disease when the following criteria are met:
 
    • The individual has a close (i.e., first- or second-degree) relative with a known familial variant consistent with limb-girdle muscular dystrophy, AND
    • Results of testing will lead to changes in clinical management (e.g., confirming or excluding the need for cardiac surveillance).
 
Genetic testing for genes associated with limb-girdle muscular dystrophy meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in asymptomatic individuals to determine future risk of disease when the following criteria are met:
 
    • The individual has a close (i.e., first- or second-degree) relative with a known familial variant consistent with limb-girdle muscular dystrophy, AND
    • Results of testing will lead to changes in clinical management (e.g., confirming or excluding the need for cardiac surveillance).
 
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
 
Genetic testing for genes associated with LGMD in all other situations does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness.
 
For members with contracts without primary coverage criteria, genetic testing for genes associated with LGMD is considered investigational in all other situations. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
 
Effective Prior to September 2023
 
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
 
Genetic testing for mutations associated with limb-girdle muscular dystrophy (LGMD) to confirm a diagnosis of LGMD meets member benefit certificate primary coverage criteria and is covered when:
 
1. Signs and symptoms of LGMD are present but a definitive diagnosis cannot be made without genetic testing; AND
2. The member has received genetic counseling or has been counseled by a provider who has received specialized training in the genetics of LGMD; AND
3. At least one of the following criteria are met:
a. Results of testing may lead to changes in clinical management that improve outcomes (eg, confirming or excluding the need for cardiac surveillance); OR
b. Genetic testing will allow the affected patient to avoid invasive testing, including muscle biopsy.
 
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
 
Genetic testing to determine the likelihood of passing an inheritable disease, condition or congenital abnormality to an offspring is a contract exclusion in most member benefit certificates of coverage. Therefore, genetic testing for mutations associated with limb-girdle muscular dystrophy (LGMD) in the reproductive setting is not covered.
 
Genetic testing to determine the likelihood of developing a disease or condition is a specific contract exclusion in most member benefit certificates of coverage. Therefore, genetic testing for mutations associated with LGMD in an asymptomatic individual to determine future risk of disease is not covered.
 
Genetic testing for mutations associated with LGMD in all other situations does not meet member benefit certificate primary coverage criteria.
 
For members with contracts without primary coverage criteria, genetic testing for mutations associated with LGMD is considered investigational in all other situations. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
 
 
Rationale:
Analytic Validity
Analytic validity refers to the technical accuracy of the test in detecting a mutation that is present or in excluding a mutation that is absent.
 
Sanger sequencing is expected to have high analytic validity. For next-generation sequencing (NGS) panels, the analytic validity is expected to be very high. One laboratory offering NGS panel reports an analytic sensitivity of greater than 99% for single nucleotide changes and insertions and deletions of less than 20 base pairs (bp) (Piluso, 2011). Other laboratories offering NGS panels similarly report a sensitivity of greater than 99% (GeneDx, 2014; PreventionGenetics, 2014; Centogene, 2015).
 
Less information was identified for the analytic validity of multiplex ligation-dependent probe amplification (MLPA) or comparative genomic hybridization (CGH) for the detection of large deletions and duplications. Piluso et al described the development and analytic validation of a customized exon-specific oligonucleotide CGH array focusing on genes involved in neuromuscular disorders, including 26 muscular dystrophy (MD)‒related genes (specific mutations not specified), 34 DYSF-interacting mutations and 10 TRIM32-interacting mutations (Piluso, 2011). The authors reported 100% concordance between mutations detected with the novel array and those detected by other methods.
 
Clinical Validity
Clinical validity refers to the diagnostic performance of the test (sensitivity, specificity, positive and negative predictive values).
 
For limb-girdle muscular dystrophy (LGMD), clinical validity may refer to the overall yield of testing for any LGMD-associated mutation in patients with clinically suspected disease, or the yield of testing for specific mutations. The genetic test is generally considered the criterion standard for determining a specific LGMD subtype.
 
Clinical Validity in Unselected LGMD Populations
One potential role for genetic testing in LGMD is among patients with clinically suspected LGMD, but who do not necessarily have results of a muscle biopsy available.
 
In 2009, Norwood et al reported the prevalence of genetic mutations in a large, single-clinic population of patients with genetic muscle disorders (included in the AAN systematic review) (Maggi, 2014). The population included 1105 cases with a variety of inherited muscle diseases diagnosed and treated by at a single neuromuscular clinic, which was considered to be the only neuromuscular disorders referral center for northern England. Of the total patient population, 75.7% (n=836) had a confirmed genetic diagnosis. Myotonic dystrophy was the most commonly represented single diagnosis, representing 28.1% of the total sample, while 22.9% had a dystrophinopathy. Sixty-eight patients had a clinical diagnosis of LGMD, of whom 43 (6.15%) had positive genetic testing for a gene known to be associated with LGMD. Of patients with a clinical diagnosis of LGMD, 72.1% had positive genetic testing, most commonly for LGMD2A (26.5%; 95% confidence interval [CI], 16.0% to 37.0%).
 
Variable Gene Expression
For some LGMD subtypes, there is variable expressivity for a given gene mutation, which has been characterized in several retrospective analyses of clinical features for patients with a specific gene mutation. Maggi et al conducted a retrospective cohort study to characterize the clinical phenotypes of myopathic patients (n=78) and nonmyopathic patients with LMNA mutations (n=78) (Maggi, 2014). Of the 78 myopathic patients, 37 (47%) had an LGMD phenotype (LGMD1B), 18 (23%) had congenital muscular dystrophy, 17 (22%) had autosomal dominant Emery-Dreifuss muscular dystrophy, and 6 (8%) had an atypical myopathy. Of the myopathic patients, 54 (69.2%) had cardiac involvement, and 41 (52.6%) underwent implantation of an implantable cardioverter defibrillator (ICD). Among 30 family members without myopathy but with LMNA mutations, 20 (66.7%) had cardiac involvement, and 35% underwent ICD implantation. Among all patients, frameshift mutations were associated with a higher risk of heart involvement.
 
Sarkozy et al evaluated the prevalence of ANO5 mutations and associated clinical features among 205 patients without a genetic diagnosis but with a clinical suspicion of ANO5 mutation, or LGMD2L, who were evaluated a single European center (Sarkozy, 2013). A clinical suspicion of ANO5 mutation (anoctaminopathy) could be based on clinical examination, muscle assessment, and clinical evaluations including CK analysis, electromyography, muscle magnetic resonance imaging (MRI), and/or muscle biopsy. ANO5 gene sequence variants were identified in 90 unrelated individuals (44%) and 5 affected relatives. Sixty-one percent of variants were a c.191dupA mutation, which is a founder mutation found in most British and German LGMD2L patients. Age of onset was variable, ranging from teens to late 70s, with lower-limb predominance of symptoms. Three individuals with ANO5 mutations had very mild clinical disease, and 1 patient was asymptomatic, but no specific genotype-phenotype correlations were demonstrated.
 
Panel Testing
Ghosh et al described the yield of a LGMD panel, which included testing for genes associated with lamin A/C (LGMD1B), caveolin-3 (LGMD1C), calpain-3 (LGMD2A), dysferlin (LGMD2B), the sarcoglycans (LGMD2C-2F), and Fukutin-related protein (LGMD2I), among 27 patients with a clinical suspicion of LGMD seen at a single center (Ghosh, 2012). Ten patients (37%) had positive testing, most commonly for LGMD2A (n=4). The yield of testing was higher among children (3/6 [50%] patients tested), although the sample was limited by a small number of children.
 
Clinical Validity in LGMD Patients With Muscle Biopsy Results
A smaller number of studies have evaluated the yield of genetic mutation testing for LGMD in patients who are suspected of having 1 particular LGMD subtype on the basis of muscle biopsy.
 
In 2009, Fanin et al evaluated the yield of molecular diagnostics among 550 cases with specific LGMD-related phenotypes, including severe childhood-onset LGMD, adult-onset LGMD, distoproximal myopathy, and asymptomatic hyper-CK-emia, who had undergone muscle biopsy with multiple protein screening (Fanin, 2009). Patients had all had exclusion of recent physical exercise or toxic or endocrinologic causes of myopathy before muscle biopsy. Dystrophinopathy was excluded in all cases. Muscle biopsy samples underwent a systematic evaluation of calpain-3 (for LGMD2A), dysferlin (for LGMD2B), and α-sarcoglycan (for LGMD2D) by immunoblotting and of caveolin-3 (for LGMD1C) by immunohistochemistry. Calpain-3 autolytic activity was also evaluated by a functional in vitro assay. Genetic testing of DYSF, CAPN3, sarcoglycans, FKRP, and LMNA was conducted single-strand conformational polymorphism or denaturing high performance liquid chromatography analysis, which are older methods of gene mutation analysis. Of the 550 cases with muscle biopsies, 122 had childhood-onset LGMD, 186 had adult-onset LGMD, 38 had distoproximal myopathy, and 204 had asymptomatic hyper-CK-emia. In the entire cohort, a molecular diagnosis (positive genetic testing) was made in 234 cases (42.5%), most commonly a calpain-3 mutation, consistent with LGMD2A. Excluding patients with asymptomatic hyper-CK-emia, a molecular diagnosis was made in 205 cases (59.2% of 346 with LGMD phenotype). Patients with childhood-onset LGMD were more likely to have a molecular diagnosis (94/122 [77.0%]). Of the 226 patients with a protein abnormality on muscle biopsy, 193 (85.4%) had a genetic diagnosis.
In an earlier, smaller study, Guglieri et al reported results from molecular diagnostic testing on a series of 181 patients (155 families) with clinical signs of LGMD and muscle biopsy with dystrophic features (Guglieri, 2008). The yield of genetic testing varied by muscle biopsy protein (Western blotting and immunohistochemistry) findings: among 72 subjects with calpain-3 deficiency on protein testing, the mutation detection rate was 61%, compared with 93.5% of the 31 subjects with dysferlin deficiency, 87% (for any sarcoglycan gene mutation) of the 32 subjects with sarcoglycan deficiency, and 1005 of the 52 subjects with caveolin-3 deficiency. The frequency of LGMD subtypes was as follows: LGMD1C (caveolin-3) 1.3%; LGMD2A (calpain-3) 28.4%; LGMD2B (dysferlin) 18.7%; LGMD2C (g-sarcoglycan) 4.5%; LGMD2D (α-sarcoglycan) 8.4%; LGMD2E (β-sarcoglycan) 4.5%; LGMD2F (δ-sarcoglycan) 0.7%; LGMD2I (Fukutin-related protein) 6.4%; and undetermined 27.1%.
 
In another smaller study, Fanin et al reported rates of sarcoglycan gene mutations among 18 subjects with muscular dystrophy and α-sarcoglycan deficiency on immunohistochemistry and immunoblotting of muscle biopsy samples (Fanin, 1997). Pathogenic mutations in one gene involved in the sarcoglycan complex were identified in 13 patients.
 
Krahn et al evaluated the yield of testing for DYSF mutation in a cohort of 134 patients who had a clinical phenotype consistent with LGMD2B, loss or strong reduction of dysferlin protein expression on muscle biopsy Western blot and/or immunohistochemistry, or both (Krahn, 2009). DYSF mutations known to be associated with myopathy were detected in 89 patients (66%). Bartoli et al reported results of whole exome sequencing in a follow up analysis of 37 patients who had negative targeted DYSF mutation testing (Bartoli, 2014). In 5 cases (13.5%), molecular diagnosis could be made directly by identification of compound heterozygous or homozygous mutations previously associated with LGMD on whole exome sequencing, including 2 CAPN3 mutations, 1 ANO5 mutation, 1 GNE mutation, and 1 DYSF mutation, with 1 additional case requiring additional Sanger sequencing for complete identification.
 
Section Summary
Estimates of the yield of genetic testing for mutations associated with LGMD vary depending on the mutations included and the characteristics of the patient populations tested. The true clinical sensitivity and specificity of genetic testing for LGMD mutations in general cannot be determined, because there is no criterion standard test for diagnosing LGMD. Studies report a yield of genetic testing from 37% to greater than 70% in patients with clinically suspected LGMD. The criterion standard for diagnosing a LGMD subtype is the genetic test. The specificity of a positive LGMD genetic test result in predicting the clinical phenotype of LGMD is not well-defined. However, there is some evidence to support that some mutations associated with LGMD predict the presence of cardiac complications.
 
Clinical Utility
Clinical utility is how the results of the diagnostic test will be used to change management of the patient and whether these changes in management lead to clinically important improvements in health outcomes.
 
The clinical utility of testing for mutations associated with LGMD for an index case (a patient with clinically suspected LGMD) includes:
    • Confirming the diagnosis of LGMD and initiating/directing treatment of the disease, including evaluation by a cardiologist/cardiac testing, respiratory function testing/monitoring, and prevention of secondary complications (eg, through immunizations, physical therapy/bracing, fracture risk reduction).
    • Avoidance of treatments that might be initiated for other neuromuscular disorders not known to be efficacious for LGMD, such as glucocorticoids for suspected dystrophinopathy or immunosuppressants for suspected myositis.
    • Potential discontinuation of routine cardiac and respiratory surveillance in patients who have an identified mutation not known to be associated with cardiac or respiratory dysfunction.
    • Potential avoidance of invasive testing (eg, muscle biopsy).
    • Reproductive planning.
 
The clinical utility of testing for mutations associated with LGMD for an at-risk family member (ie, first- or second-degree relative of a proband) includes:
    • Confirming or excluding the need for cardiac surveillance.
    • Reproductive planning in individuals considering offspring who would alter reproductive decision making based on test results.
 
Management of Cardiac Complications
Similar to Duchenne and Becker muscular dystrophies, patients with LGMD are at higher risk of cardiac abnormalities, including dilated cardiomyopathy and various arrhythmias (Finsterer, 2012). Specific LGMD subtypes are more likely to be associated with cardiac disorders. Potential device-based therapies for patients at risk of arrhythmias include cardiac pacing and implantation of an implantable cardioverter-defibrillator. Guidelines from the American College of Cardiology/American Heart Association regarding the use of device-based therapy of cardiac rhythm abnormalities published in 2008 recommend that indications for a permanent pacemaker should account for the presence of MD (Epstein, 2008). These guidelines recommend the consideration of implantation of a permanent pacemaker for patients with LGMD with any degree of atrioventricular (AV) block (class IIb recommendation; level of evidence: B), or bifascicular block or any fascicular block (class IIb recommendation; level of evidence: C), with or without symptoms, because there may be unpredictable progression of AV conduction disease
 
Certain LGMD subtypes are more strongly associated with cardiac disorders than others. LGMD types 2C-2F and 2I are associated with a primary dilated cardiomyopathy, with conduction disorders occurring as a secondary phenomenon (Groh, 2012). In contrast, some LGMD subtypes are recognized to not have associations with cardiomyopathy or conduction disorders. In these cases, recommendations from AAN indicate that routine cardiac surveillance in asymptomatic individuals is not required (Narayanaswami, 2014).
 
There is clinical utility for identifying a specific LGMD gene mutation for patients presenting with signs/symptoms of LGMD to allow discontinuation of cardiac surveillance in patients who are found to have a mutation not associated with cardiac disorders.
 
On the other hand, there may be clinical utility for testing of asymptomatic family members of a proband with an identified LGMD mutation to determine cardiovascular risk. Patients with LMNA mutations, regardless of whether they have an LGMD1B phenotype, are at risk for cardiac arrhythmias (Finsterer, 2012). Similarly, FKTN mutations can be associated with dilated cardiomyopathy, with or without the presence of myopathy. Murakami et al reported a cases series of 6 patients from 4 families with compound heterozygous FKTN mutations who presented with dilated cardiomyopathy and no or minimal myopathic symptoms (Murakami, 2006).
 
Section Summary
In patients with clinically suspected LGMD, genetic testing is primarily to confirm a diagnosis, but may also have a prognostic role given the clinical variability across LGMD subtypes. For asymptomatic but at-risk family members, testing may also confirm a diagnosis or allow prediction of symptoms. No direct evidence exists of the impact of testing on outcomes. However, an indirect chain of evidence suggests that the establishment of a specific genetic diagnosis has the potential to change clinical management.
 
Ongoing and Unpublished Clinical Trials
A search of ClinicalTrials.gov in May 2015 did not identify any ongoing or unpublished trials that would likely influence this policy.
 
Summary of Evidence
The analytic validity of genetic testing for mutations associated with limb-girdle muscular dystrophy (LGMD) is likely to be high. The true clinical sensitivity and specificity of genetic testing for LGMD in general cannot be determined. While the yield of genetic testing in patients with clinically suspected LGMD varies depending on the population characteristics (ie, patients with only clinical symptoms versus patients with biopsy findings suggestive of LGMD), the available body of evidence suggests that the yield of testing is reasonably high. Genetic testing is generally considered the criterion standard for diagnosis of a specific LGMD subtype.
 
For patients with clinically suspected LGMD, there is the potential for clinical utility in genetic testing to confirm a diagnosis of LGMD and direct treatment and monitoring on the basis of a specific genetic diagnosis (including discontinuation of routine cardiac and/or respiratory surveillance if a specific genetic diagnosis not associated with these complications can be maid), avoid therapies not known to be efficacious for LGMD, potentially avoid invasive testing, and allow reproductive planning. For at risk relatives of a proband, there is potential for clinical utility in genetic testing to identify the need for routine cardiac surveillance and allow reproductive planning. There is no direct evidence about the impact of genetic testing on outcomes, but an indirect chain of evidence indicates that the use of genetic testing in general may allow avoidance of invasive testing and/or initiation of appropriate therapies, and the establishment of a specific genetic diagnosis can allow increased surveillance for cardiac dysfunction, for which there are effective medical- and device-based therapies.
 
Therefore, the use of genetic testing for mutations associated with LGMD may be considered medically necessary to confirm a diagnosis of LGMD in a patient with clinically suspected LGMD. In addition, testing for mutations associated with LGMD may be considered medically necessary to identify a mutation in an at-risk family member of a proband when the results of testing may confirm or exclude the need for cardiac surveillance or inform reproductive decision making.
 
Practice Guidelines and Position Statements
In 2014, the American Academy of Neurology and the Practices Issues review Panel of the American Association of Neuromuscular and Electrodiagnostic Medicine issued evidenced-based guidelines for the diagnosis and treatment of limb-girdle and distal dystrophies, which makes the following recommendations (Narayanaswami, 2014):
For the diagnosis of LGMD:
    • For patients with suspected muscular dystrophy, clinicians should use a clinical approach to guide genetic diagnosis based on the clinical phenotype, including the pattern of muscle involvement, inheritance pattern, age at onset, and associated manifestations (e.g., early contractures, cardiac or respiratory involvement) (Level B recommendation).
    • In patients with suspected muscular dystrophy in whom initial clinically directed genetic testing does not provide a diagnosis, clinicians may obtain genetic consultation or perform parallel sequencing of targeted exomes, whole-exome sequencing, whole genome screening, or next-generation sequencing to identify the genetic abnormality (Level C recommendation).
 
For the management of cardiac complications in LGMD:
    • Clinicians should refer newly diagnosed patients with (1) LGMD1A, LGMD1B, LGMD1D, LGMD1E, LGMD2C–K, LGMD2M–P or (2) muscular dystrophy without a specific genetic diagnosis for cardiology evaluation, including ECG and structural evaluation (echocardiography or cardiac MRI), even if they are asymptomatic from a cardiac standpoint, to guide appropriate management (Level B recommendation).
    • If ECG or structural cardiac evaluation (e.g., echocardiography) has abnormal results, or if the patient has episodes of syncope, near-syncope, or palpitations, clinicians should order rhythm evaluation (e.g., Holter monitor or event monitor) to guide appropriate management (Level B recommendation).
    • Clinicians should refer muscular dystrophy patients with palpitations, symptomatic or asymptomatic tachycardia or arrhythmias, or signs and symptoms of cardiac failure for cardiology evaluation (Level B).
    • It is not obligatory for clinicians to refer patients with LGMD2A, LGMD2B, and LGMD2L for cardiac evaluation unless they develop overt cardiac signs or symptoms (Level B recommendation).
 
For the management of respiratory complications in LGMD:
    • Clinicians should order pulmonary function testing (spirometry and maximal inspiratory/ expiratory force in the upright and, if normal, supine positions) or refer for pulmonary evaluation (to identify and treat respiratory insufficiency) in muscular dystrophy patients at the time of diagnosis, or if they develop pulmonary symptoms later in their course (Level B recommendation).
    • In patients with a known high risk of respiratory failure (e.g., those with LGMD2I), clinicians should obtain periodic pulmonary function testing (spirometry and maximal inspiratory/expiratory force in the upright position and, if normal, in the supine position) or evaluation by a pulmonologist to identify and treat respiratory insufficiency (Level B recommendation).
    • It is not obligatory for clinicians to refer patients with LGMD2B and LGMD2L for pulmonary evaluation unless they are symptomatic (Level C recommendation).
    • Clinicians should refer muscular dystrophy patients with excessive daytime somnolence, nonrestorative sleep (e.g., frequent nocturnal arousals, morning headaches, excessive daytime fatigue), or respiratory insufficiency based on pulmonary function tests for pulmonary or sleep medicine consultation for consideration of noninvasive ventilation to improve quality of life (Level B recommendation).
 
2018 Update
Annual policy review completed with a literature search using the MEDLINE database through July 2018. No new literature was identified that would prompt a change in the coverage statement.  
 
2019 Update
A literature search was conducted through July 2019.  There was no new information identified that would prompt a change in the coverage statement.  
 
2020 Update
Annual policy review completed with a literature search using the MEDLINE database through July 2020. No new literature was 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 July 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 July 2022. No new literature was identified that would prompt a change in the coverage statement.
 
2023 Update
Annual policy review completed with a literature search using the MEDLINE database through July 2023. No new literature was identified that would prompt a change in the coverage statement.
CPT/HCPCS:
81400Molecular pathology procedure, Level 1 (eg, identification of single germline variant [eg, SNP] by techniques such as restriction enzyme digestion or melt curve analysis)
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
81408Molecular pathology procedure, Level 9 (eg, analysis of >50 exons in a single gene by DNA sequence analysis)
81479Unlisted molecular pathology procedure
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