Coverage Policy Manual - Arkansas Blue Cross and Blue Shield

Genetic Test: Facioscapulohumeral Muscular Dystrophy

Description:

Facioscapulohumeral muscular dystrophy (FSHD) is an autosomal dominant disease that typically presents before the age of 20 with weakness of the facial muscles and the scapular stabilizer muscles. The usual clinical course is a slowly progressive weakness, although the severity is highly variable, and atypical presentations occur. Genetic testing for FSHD has been evaluated as a tool to confirm the diagnosis.

Clinical diagnosis of FSHD

The distribution of muscle involvement that is characteristic of FSHD often can lead to targeted genetic testing without the need for a muscle biopsy (Menezes, 2012). However, atypical presentations have been reported, which include scapulohumeral dystrophy with facial sparing (Lemmers, 1993; Pastorello, 2012). A retrospective review of an academic center database of the period 1996 to 2011 determined that, of 139 genetically confirmed FSHD cases, 7 had atypical disease, including late age of onset of disease, focal weakness and dyspnea (Hassan, 2012).

Electromyography (EMG) and muscle biopsy to confirm the clinical diagnosis of FSHD has largely been supplanted by genetic testing. EMG usually shows mild myopathic changes, and muscle biopsy most often shows nonspecific chronic myopathic changes.

Genetics of FSHD

FSHD is likely to be caused by inappropriate expression of the gene DUX4 in muscle cells. DUX4 is a double homeobox-containing gene (a homeobox gene being one in a large family of genes that direct the formation of many body structures during early embryonic development). DUX4 lies in the macrosatellite repeat D4Z4, which is on chromosome 4q35. D4Z4 has a length of 11-100 repeat units on normal alleles. The most common form of FSHD (95%) is designated FSHD1, and these individuals have a D4Z4 allele of between one and ten repeat units (Lemmers, 1993). There is no absolute linear and inverse correlation between residual repeat size and disease severity and onset, however, patients with repeat arrays of 1-3 units usually have an infantile onset and rapid progression, (van der Maarel, 2011)

The remaining 5% of patients who don’t have FSHD1 are designated as FSHD2, which is clinically indistinguishable from FSHD1. Patients with FSHD2 show loss of DNA methylation and heterochromatin markers at the D4Z4 repeat that are similar to patients with D4Z4 contractions (FSHD1), suggesting that a change in D4Z4 chromatin structure unifies FSHD1 and FSHD2. Variants in the SMCHD1 gene on chromosome 18, which encodes a protein known as structural maintenance of chromosomes flexible hinge domain containing 1, have been associated with FSHD2. Reductions in SMCHD1 gene product levels have been associated with D4Z4 contraction-independent DUX4 expression, suggesting that SMCHD1 acts as an epigenetic modifier of the D4Z4 allele (Lemmers, 2012b). SMCHD1 has also been identified as a possible modifier of disease severity in patients with FSHD1 (Sacconi, 2013).

FSHD is inherited in an autosomal dominant manner. Approximately 70-90% of individuals inherit the disease-causing deletion from a parent, and 10-30% have FSHD as a result of a de novo deletion (Lemmers, 1993). On average, de novo variants are associated with larger contractions of D4Z4 compared with the degree of D4Z4 contraction variants observed segregating in families, and individuals with de novo variants tend to have findings at the more severe end of the phenotypic spectrum (Lemmers, 2014).

Treatment of FSHD

There is currently no treatment or prevention therapy to control symptoms of FSHD. Clinical management is directed at surveillance to identify possible FSHD-related complications, such as hearing loss, and to improve quality of life (e.g., assist devices, physical therapy, orthoses to improve mobility and prevent falls).

Commercially available testing for FSHD

The methodology for testing for FSHD1 uses pulsed field gel electrophoresis and Southern blot to detect deletions on chromosome 4q35. Laboratories that offer FSHD1 testing include Athena Diagnostics and the University of Iowa Diagnostic Laboratories.

At least 1 commercial laboratory (Prevention Genetics, Marshfield, Wisconsin) was identified that offers testing for FSHD2 through sequencing of the SMCHD1 gene via bidirectional Sanger sequencing. Prevention Genetics also offers testing for FSHD2 through next-generation sequencing of the SMCHD1 gene as part of a panel test for limb-girdle muscular dystrophy.

Regulatory Status

Clinical laboratories may develop and validate tests in-house and market them as a laboratory service; laboratory-developed tests must meet the general regulatory standards of the Clinical Laboratory Improvement Amendments (CLIA). Genetic testing for FSHD is available under the auspices of the CLIA. Laboratories that offer laboratory-developed tests must be licensed by the CLIA for high-complexity testing. To date, the U.S. Food and Drug Administration has chosen not to require any regulatory review of this test.

Coding

CPT code 81404 includes the following testing for FSHD:

FSHMD1A (facioscapulohumeral muscular dystrophy 1A) (e.g., facioscapulohumeral muscular dystrophy), evaluation to detect abnormal (e.g., deleted) alleles

FSHMD1A (facioscapulohumeral muscular dystrophy 1A) (e.g., facioscapulohumeral muscular dystrophy), characterization of haplotype(s) (i.e., chromosome 4A and 4B haplotypes)

Policy/
Coverage:

Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria

Genetic testing for facioscapulohumeral muscular dystrophy meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes and is covered to confirm a diagnosis in a patient with clinical signs of the disease.

*Note: FSHD is typically suspected in an individual with the following: weakness that predominantly involves the facial, scapular stabilizer, and foot dorsiflexor muscles without associated ocular or bulbar muscle weakness, and age of onset usually by 20 years of age (although mildly affected individuals show signs at a later age and some remain asymptomatic) (Lemmers, 1993).

Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria

Genetic testing for facioscapulohumeral muscular dystrophy for all other indications does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes.

For members with contracts without primary coverage criteria, genetic testing for facioscapulohumeral muscular dystrophy for all other indications is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.

Rationale:

This policy was created in 2013 and is based on a search of the MEDLINE database through June 2013. Literature that describes the analytic validity, clinical validity, and clinical utility of testing for FSHD was sought.

Analytic validity (the technical accuracy of the test in detecting a mutation that is present or in excluding a mutation that is absent)

Published data on the analytic validity of testing for FSHD is not identified.

Clinical validity (the diagnostic performance of the test [sensitivity, specificity, positive and negative predictive values] in detecting clinical disease)

According to a large reference laboratory, the identification of a characteristic 4q35 deletion is more than 90% specific for the disease.

There are reports of a correlation between the degree of the mutation of the D4Z4 locus and the age at onset of symptoms, age at loss of ambulation, and muscle strength as measured by quantitative isometric myometry. Some reports in the literature describe individuals with a large contraction of the D4Z4 locus having earlier-onset disease and more rapid progression than those with smaller contractions of the D4Z4 locus, although other reports have not been able to confirm a correlation between disease severity and degree of D4Z4 contraction mutations (Lemmers, 1993).

On average, de novo mutations are associated with larger contractions of D4Z4 compared to the degree of D4Z4 contraction mutations observed segregating in families, and individuals with de novo mutations tend to have findings at the more severe end of the phenotypic spectrum (Lemmers, 1993).

Clinical utility (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)

Individual

The clinical utility for patients with suspected FSHD depends on the ability of genetic testing to make a definitive diagnosis and for that diagnosis to lead to management changes that improve outcomes. There is no direct evidence for the clinical utility of genetic testing in these patients as no studies were identified that described how a molecular diagnosis of FSHD changed patient management.

However, for patients who are diagnosed with FSHD by identifying a D4Z4 contraction mutation, the clinical utility of molecular genetic testing for FSHD includes:

o Establishing the diagnosis and initiating/directing treatment, such as evaluation for physical therapy and the need for assistive devices, assessment for hearing loss, ophthalmologic examination for the presence of retinal telangiectasias and continued ophthalmologic surveillance, and possible orthopedic intervention.

o Distinguishing from other disorders that are similar clinically to FSHD, especially the limb-girdle muscular dystrophies and scapuloperoneal muscular dystrophy syndromes,

o Avoidance of a muscle biopsy in the majority of cases.

Treatment after a confirmed diagnosis of FSHD includes physical therapy and rehabilitation, exercise, pain management, ventilator support for those with hypoventilation, therapy for hearing loss, orthopedic intervention (ankle/foot orthoses; surgical fixation of the scapula to the chest wall to improve range of motion) and ophthalmologic management including lubricants or taping the eyes shut at night for exposure keratitis.

For those with a confirmed diagnosis of FSHD, the following surveillance applies (Lemmers, 1993) (Tawil, 2010):

· Regular assessment of pain

· Routine screening for hypoventilation in those with moderate to severe disease, and yearly forced vital capacity (FVC) measurements for all affected individuals who are wheel chair bound, have pelvic girdle weakness and superimposed pulmonary disease, and/or have moderate to severe kyphoscoliosis, lumber hyperlordosis, or chest wall deformities.

· Hearing loss assessment in children as routinely performed as part of school-based testing. In severe infantile onset forms of FSHD, hearing screens are important as hearing loss can result in delayed language acquisition. Adults should have a formal hearing evaluation based on symptoms.

· Annual dilated ophthalmoscopy in childhood is indicated. In adults, a dilated retinal exam should be performed at the time of diagnosis, and if vascular disease is absent, follow-up exams are only necessary if visual symptoms develop.

Family members

Most individuals diagnosed with FSHD have a parent with clinical findings of FSHD and one D4Z4 allele with a contraction mutation (70-90% of individuals with FSHD), although 10-30% of probands with FSHD have the disorder as a result of a D4Z4 de novo contraction mutation (Lemmers, 1993). Evaluation of at risk relatives may determine that they may be affected but escaped previous diagnosis because of a milder phenotypic presentation. However, for this population, no evidence was identified that compared outcomes in family members tested for genetic mutations compared to family members not tested for genetic mutations, and conclusions cannot be made on whether genetic testing of asymptomatic family members of a patient with known FSHD improves outcomes.

Summary

Facioscapulohumeral muscular dystrophy (FSHD) is an autosomal dominant disease that typically presents before the age of 20 years with weakness of the facial muscles and the scapular stabilizer muscles; however, atypical presentations occur. The clinical course is usually of slowly progressive weakness, although the severity is highly variable. Approximately 95% of individuals with FSHD have contraction mutation of the D4Z4 locus. For the 5% of individuals with FSHD who do not have a contraction mutation of the D4Z4 locus, mutations in the gene SMCHD1 have been associated with FSHD.

The clinical utility of genetic testing for FSHD is that it leads to a definitive diagnosis, and can distinguish FSHD from other myopathies, with possible avoidance of a muscle biopsy. Changes in clinical management include supportive management involving physical therapy and rehabilitation, exercise, pain control and orthopedic interventions. Other potential benefits include increased surveillance for potential pulmonary, ophthalmologic and auditory problems related to FSHD. Therefore, genetic testing for FSHD may be considered medically necessary when a presumptive diagnosis of FSHD has been made based on clinical signs. Genetic testing for facioscapulohumeral muscular dystrophy is considered investigational for all other indications.

Practice Guidelines and Position Statements

In a report from the 171st European Neuromuscular Centre Internati0onal Workshop Standards of Care and Management of FSHD held in January 2010, it is stated that when a physician concludes facioscapulohumeral syndrome based on clinical findings, the odds are in favor of FSHD and genetic testing is the preferred diagnostic choice (Tawil, 2010).

Regulatory Status

No U.S. Food and Drug Administration (FDA)-cleared genotyping tests were found. Thus, genotyping is offered as a laboratory-developed test. Clinical laboratories may develop and validate tests in-house (“home-brew”) and market them as a laboratory service; such tests must meet the general regulatory standards of the Clinical Laboratory Improvement Act (CLIA).

2014 Update

A literature search conducted through July 2014 did not reveal any new information that would prompt a change in the coverage statement. The key identified literature is summarized below.

Analytic Validity

No studies that assessed the analytic validity of SMCHD1 gene testing were identified.

Clinical Validity

(diagnostic performance of the test [sensitivity, specificity, positive and negative predictive values] in detecting clinical disease)

According to a large reference laboratory, the identification of a characteristic 4q35 deletion is more than 90% specific for the disease. However, several studies have identified patients with no clinical signs of FSHD who have characteristic D4Z4 contractures, which has prompted the hypothesis that FSHD occurs only when the D4Z4 contracture occurs in a characteristic “permissive” background (Ricci, 2013).

No studies that assessed clinical validity of SMCHD1 gene testing were identified.

Clinical utility

Testing in individuals with suspected FSHD. The clinical utility for patients with suspected FSHD depends on the ability of genetic testing to make a definitive diagnosis and for that diagnosis to lead to management changes that improve outcomes.

Several studies suggest that the size of the D4Z4 repeat contraction is associated with differences in patients’ outcomes. Lutz et al conducted a retrospective analysis of 59 patients with FSHD seen at a single institution to evaluate the relationship between the D4Z4 repeat size and progression of hearing loss (Lutz, 2013). Eleven of the 59 patients evaluated had hearing loss that was not attributable to another cause. Truncated D4Z4 (1-10 D4Z4 repeats) was evaluated by the size of EcoRI or EcoRI/BlnI fragment, with an EcoRI fragment of less than 38 kB or an EcoRI/BlnI fragment of less than 35 kg corresponding to 1-10 D4Z4 repeats. There was a statistically significant negative association between hearing loss and fragment size in a simple logistic regression model (P = 0.0207). Six of the 11 patients with hearing loss had a history of hearing loss progression.

In a retrospective analysis of a cohort of patients with FSHD1 enrolled in the National Registry of FSHD Patients and Family Members, Statland et al evaluated the association between patient characteristics, including size of the D4Z4 contraction, and FSHD-related outcomes (Statland, 2014). Three hundred thirteen clinically affected participants with D4Z4 contractions of less than or equal to 38 kB were included. Those with D4Z4 contractions of less than or equal to 18 kg started using wheelchairs earlier than those with contractions from 19 to 28 kb (24.1 years vs 48.1 years, P<0.001) or those with contractions of greater than 38 kb (58.6 years, P<0.001).

Testing of family members with individuals with FSHD.

In 2013, Ricci et al evaluated the D4Z4 site in 367 relatives of 163 FSHD index cases who carried D4Z4 “alleles of reduced size” of less than or equal to 8 repeating units (Ricci, 2013). Among relatives, a D4Z4 “alleles of reduced size” with 1-3 repeating units and 4-6 repeating units was identified in 42 and 133 subjects, respectively. Of those relatives with 1-3 repeating units, about 40% demonstrated severe muscle symptoms by age 30, while none of those with 4 or more repeating units had severe symptoms in that age range.

In contrast to patients with diagnosed FSHD, there are no established treatment guidelines or follow-up guidelines for at-risk relatives.

D4Z4 contractions are associated with FSHD, and the size of the contracture is associated with more severe symptoms. Although there is no direct evidence for the clinical utility of genetic testing for patients with suspected FSHD, as no studies were identified that described how a molecular diagnosis of FSHD changed patient management, a chain of evidence supports the use of D4Z4 contraction mutation testing for suspected FSHD to establish a diagnosis and initiate therapies consistent with appropriate guidelines and avoid a muscle biopsy in the majority of cases.

Ongoing Clinical Trials: A search of the online site ClinicalTrials.gov in June 2014 found several ongoing trials related to genetic testing for FSHD:

A Multicenter Collaborative Study on the Clinical Features, Expression Profiling, and Quality of Life of Infantile Onset Facioscapulohumeral Muscular Dystrophy (FSHD) (NCT01437345) – This is an observational cohort study to evaluate muscle function, clinical phenotypes, possible genetic modifiers, and quality of life measures in patients with infantile onset and genetically confirmed FSHD. Enrollment is planned for 60 subjects; the estimated study completion date is March 2015.
Clinical, Genetic and Epigenetic Characterization of Patients with FSHD Type 1 and FSHD Type 2 (NCT01970735) – This study aims to compare the severity of illness in patients with FSHD1 and FSFHD2 in adults with clinical FSHD with or without genetic confirmation. Enrollment is planned for 100 subjects; the estimated study completion date is October 2016.

2015 Update

A literature search conducted through July 2015 did not reveal any new information that would prompt a change in the coverage statement.

2017 Update

A literature search conducted through July 2017 did not reveal any new information that would prompt a change in the coverage statement.

2018 Update

A literature search was conducted through July 2018. There was no new information identified that would prompt a change in the coverage statement.

2019 Update

Annual policy review completed with a literature search using the MEDLINE database through July 2019. No new literature was 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. The key identified literature is summarized below.

In 2015, the American Academy of Neurology and American Association of Neuromuscular & Electrodiagnostic Medicine guidelines on FSHD for patients and their families stated the following (American Academy of Neurology, 2015):

“Genetic testing can confirm the diagnosis in many patients with FSHD type 1….If the patient tests negative for the D4Z4 contraction, the doctor will test for FSHD type 2 or other myopathies. Although these cases are rare, they are important to diagnose. Research on FSHD type 2 is increasing….If a family member’s diagnosis was confirmed by genetic testing, the patient [with the family member] may not need to be tested.”

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. The key identified literature is summarized below.

Identification of a characteristic 4q35 deletion is about 95% specific for the disease (Lemmers, 2014; Rieken, 2021). However, although the penetrance of FSHD is considered to be high, several studies have identified patients with no clinical signs of FSHD who have characteristic D4Z4 allele sizes, which has prompted the hypothesis that FSHD occurs only when the D4Z4 allele size occurs in a characteristic “permissive” background (Ricci, 2013).

In a retrospective analysis of a cohort of patients with FSHD type 1 enrolled in the National Registry of FSHD Patients and Family Members, Statland et al evaluated the association between patient characteristics, including the D4Z4 allele size, and FSHD-related outcomes (Statland, 2014). Three hundred thirteen clinically affected participants with D4Z4 contractions of 38 kb or less were included. Those with D4Z4 contractions of 18 kb or less started using wheelchairs earlier than those with contractions from 19 to 28 kb (24.1 years vs. 48.1 years, p<.001) or those with contractions of greater than 38 kb (58.6 years, p<.001). Updated outcomes from this cohort (data through September 2019) were published by Katz et al (Katz, 2021). Results were consistent with the previous report. Patients with D4Z4 contractions of 10 to 18 kb demonstrated an earlier median age of wheelchair use (14 years; 95% confidence interval [CI], 13 to 38) compared to individuals with D4Z4 contractions 18 to 30 kb (46 years; 95% CI, 44 to 52) and larger (60 years; 95% CI, 55 to 68). The hazard ratio for the likelihood of wheelchair use was 4.14 (95% CI, 2.87 to 5.67) for the comparison of D4Z4 contractions 10 to 18 kb versus 18 to 30 kb and 0.56 (95% CI, 0.40 to 0.78) for the comparison of larger allele sizes versus 18 to 30 kb allele size.

In 2015, the American Academy of Neurology and American Association of Neuromuscular & Electrodiagnostic Medicine guideline on facioscapulohumeral muscular dystrophy (FSHD) for patients and their families stated the following (AAN and AANEM, 2015):

This guideline was reaffirmed on September 18, 2021 (AAN and AANEM, 2021)

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. The key identified literature is summarized below.

Konstantonis et al analyzed 52 patients with FSHD to evaluate the correlation between D4Z4 repeat array fragment size and orofacial muscle weakening (Konstantonis, 2022). Genetic confirmation of FSHD was established using the Southern blotting technique using EcoRI/Avrll double digestion, and fragments were detected by a p13E-11 telomeric probe. Investigators found a positive non-significant correlation between severity of muscle weakness and D4Z4 fragment size for the forehead (Spearman’s correlation coefficient [r]=0.27; p=.187), periocular (r=0.24; p=.232), and the left (r=0.29; p=.122) and right (r=0.32; p=.085) perioral muscles.

Kelly et al performed a retrospective chart review of patients with FSHD seen at a single-institution to evaluate systemic manifestations of the disease (Kelly, 2022). Eighty-seven patients were identified and genetic confirmation of FSHD was established using the Southern blotting for 4q35 deletion detection. There were 86 patients that had FSHD type 1, and 1 patient had FSHD type 2. Patients were also evaluated depending on age of onset: typical onset (n=67) versus early onset (n=18). Early-onset was defined as onset of symptoms before 12 years of age, and typical onset was defined as disease onset at or after age 12. Early onset patients had smaller 4q allele fragments size (p=.0055) and D4Z4 repeat units (p=.0068). Commonly reported patient symptoms included pain, difficulty sleeping, headaches, and altered mood. When tested, patients were also found to have abnormalities including sensorineural hearing loss (7 of 16 patients), cardiac arrhythmias or conduction defects (20 of 60 patients), reduced forced vital capacity (12 of 25 patients), echocardiogram abnormalities (17 of 45 patients), and oropharyngeal dysphagia (4 of 10 patients).

2024 Update

Annual policy review completed with a literature search using the MEDLINE database through February 2024. No new literature was identified that would prompt a change in the coverage statement.

CPT/HCPCS:

81404

Molecular 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

References:

American Academy of Neurology (AAN) and American Association of Neuromuscular & Electrodiagnostic Medicine (AANEM).(2021) 2015 EVIDENCE-BASED GUIDELINE SUMMARY: EVALUATION, DIAGNOSIS, AND MANAGEMENT OF FACIOSCAPULOHUMERAL MUSCULAR DYSTROPHY. American Academy of Neurology. https://www.aan.com/Guidelines/home/GuidelineDetail/701. Accessed December 10, 2021.

American Academy of Neurology and American Association of Neuromuscular & Electrodiagnostic Medicine.(2015) Summary of evidence-based guideline for patients and their families: facioscapulohumeral muscular dystrophy. American Academy of Neurology. 2015. https://www.aan.com/Guidelines/home/GetGuidelineContent/702. Accessed December 16, 2019.

Hassan A, Jones LK, Jr., Milone M et al.(2012) Focal and other unusual presentations of facioscapulohumeral muscular dystrophy. Muscle Nerve 2012; 46(3):421-5.

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