Medical Policy

Policy Num:      11.003.082
Policy Name:    Genetic Testing for Facioscapulohumeral Muscular Dystrophy
Policy ID:          [11.003.082]  [Ac / B / M+ / P+]  [2.04.105]

Last Review:      March 12, 2025
Next Review:      March 20, 2026
 

Related Policies: 

11.003.066 Genetic Testing for Duchenne and Becker Muscular Dystrophy

11.003.085 Genetic Testing for Limb-Girdle Muscular Dystrophies

Genetic Testing for Facioscapulohumeral Muscular Dystrophy

SUMMARY

Description

Facioscapulohumeral muscular dystrophy (FSHD) is an autosomal dominant disease that typically presents before the age of 20 years with the 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.

Summary of Evidence

For individuals who have clinical signs of FSHD who receive genetic testing for FSHD, the relevant outcomes are test validity, morbid events, functional outcomes, quality of life, and resource utilization. Although evidence supporting improved outcomes is generally lacking, studies have reported high test validity, and a definitive diagnosis may end the need for additional testing in the etiologic workup, avoid the need for a muscle biopsy, and initiate and direct clinical management changes that can result in improved health outcomes. The evidence is sufficient to determine that the technology results in an improvement in the net health outcome.

Additional Information

Not applicable.

OBJECTIVE

The objective of this evidence review is to determine whether genetic testing for facioscapulohumeral muscular dystrophy improves the net health outcome in persons with clinical signs of the disease.

POLICY STATEMENTS

Genetic testing for facioscapulohumeral muscular dystrophy may be considered medically necessary to confirm a diagnosis in a patient with clinical signs of the disease (see the Policy Guidelines section).

Genetic testing for facioscapulohumeral muscular dystrophy is considered investigational for all other indications.

POLICY GUIDELINES

Facioscapulohumeral muscular dystrophy (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 (although mildly affected individuals show signs at a later age, and some remain asymptomatic).

Testing Strategy

Because 95% of cases of FSHD are FSHD type 1 (FSHD1), genetic testing for FSHD should begin with testing for contraction in the macrosatellite repeat D4Z4 on chromosome 4q35 using Southern blot analysis. Depending on the index of suspicion for FSHD, if FSHD1 testing is negative, testing for FSHD2, including D4Z4 methylation analysis and testing of the SMCHD1 gene, could be considered.

Targeted testing of the parents of a proband with FSHD and a confirmed genetic variant to identify mode of transmission (germline vs. de novo) may be considered appropriate and guide clinical management of previously undiagnosed mild presentations. It is appropriate in those families with a confirmed germline variant to consider targeted genetic testing of other first degree relatives to the proband.

Genetics Nomenclature Update

The Human Genome Variation Society nomenclature is used to report information on variants found in DNA and serves as an international standard in DNA diagnostics. It was implemented for genetic testing medical evidence review updates starting in 2017 (see Table PG1). The Society’s nomenclature is recommended by the Human Variome Project, the Human Genome Organisation, and by the Human Genome Variation Society itself.

The American College of Medical Genetics and Genomics and the Association for Molecular Pathology standards and guidelines for interpretation of sequence variants represent expert opinion from both organizations, in addition to the College of American Pathologists. These recommendations primarily apply to genetic tests used in clinical laboratories, including genotyping, single genes, panels, exomes, and genomes. Table PG2 shows the recommended standard terminology - “pathogenic,” “likely pathogenic,” “uncertain significance,” “likely benign,” and “benign”—to describe variants identified that cause Mendelian disorders.

Table PG1. Nomenclature to Report on Variants Found in DNA 

Table PG2. ACMG-AMP Standards and Guidelines for Variant Classification

Genetic Counseling

Genetic counseling is primarily aimed at patients who are at risk for inherited disorders, and experts recommend formal genetic counseling in most cases when genetic testing for an inherited condition is considered. The interpretation of the results of genetic tests and the understanding of risk factors can be very difficult and complex. Therefore, genetic counseling will assist individuals in understanding the possible benefits and harms of genetic testing, including the possible impact of the information on the individual's family. Genetic counseling may alter the utilization of genetic testing substantially and may reduce inappropriate testing. Genetic counseling should be performed by an individual with experience and expertise in genetic medicine and genetic testing methods.

Coding

See the Codes table for details.

BENEFIT APPLICATION

BlueCard/National Account Issues

Some Plans may have contract or benefit exclusions for genetic testing.

Benefits are determined by the group contract, member benefit booklet, and/or individual subscriber certificate in effect at the time services were rendered.  Benefit products or negotiated coverages may have all or some of the services discussed in this medical policy excluded from their coverage.

BACKGROUND

Diagnosis

The distribution of muscle involvement that is characteristic of facioscapulohumeral muscular dystrophy (FSHD) often can lead to targeted genetic testing without the need for a muscle biopsy.^1, However, atypical presentations have been reported, which include scapulohumeral dystrophy with facial sparing.^2,,3, A 2012 retrospective review of an academic center database for 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.^4,

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

Genetics

FSHD is likely caused by inappropriate expression of the DUX4 gene 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 to 100 repeat units on normal alleles. The most common form of FSHD (95%) is designated FSHD type 1 (FSHD1), and individuals with FSHD1 have a D4Z4 allele of between 1 and 10 repeat units.^2, There is no absolute linear and inverse correlation between residual repeat size, disease severity, and onset; however, patients with repeat arrays of 1 to 3 units usually have an infantile-onset and rapid progression.^5,

The remaining 5% of patients who do not have FSHD1 are designated as FSHD type 2 (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.^6,SMCHD1 has also been identified as a possible modifier of disease severity in patients with FSHD1.^7,

FSHD is inherited in an autosomal dominant manner. Approximately 70% to 90% of individuals inherit the disease-causing deletion from a parent, and 10% to 30% have FSHD as a result of a de novo deletion. 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.^2,

Treatment

There is currently no treatment or preventive 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 (eg, assistive devices, physical therapy, orthoses to improve mobility and prevent falls).

Commercially Available Testing

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.

RATIONALE

This evidence review was created in August 2013 and has been updated regularly with searches of the PubMed database. The most recent literature update is through December 13, 2024.

Evidence reviews assess whether a medical test is clinically useful. A useful test provides information to make a clinical management decision that improves the net health outcome. That is, the balance of benefits and harms is better when the test is used to manage the condition than when another test or no test is used to manage the condition.

The first step in assessing a medical test is to formulate the clinical context and purpose of the test. The test must be technically reliable, clinically valid, and clinically useful for that purpose. Evidence reviews assess the evidence on whether a test is clinically valid and clinically useful. Technical reliability is outside the scope of these reviews, and credible information on technical reliability is available from other sources.

Promotion of greater diversity and inclusion in clinical research of historically marginalized groups (e.g., People of Color [African-American, Asian, Black, Latino and Native American]; LGBTQIA (Lesbian, Gay, Bisexual, Transgender, Queer, Intersex, Asexual); Women; and People with Disabilities [Physical and Invisible]) allows policy populations to be more reflective of and findings more applicable to our diverse members. While we also strive to use inclusive language related to these groups in our policies, use of gender-specific nouns (e.g., women, men, sisters, etc.) will continue when reflective of language used in publications describing study populations.

Population Reference No. 1

Genetic Testing for Facioscapulohumeral Muscular Dystrophy

Clinical Context and Test Purpose

Facioscapulohumeral muscular dystrophy (FSHD) is the third most common muscular dystrophy and involves progressive weakness and wasting of the facial muscles (facio) as well as shoulder and upper arm (scapulohumeral) muscles. The weakness is often most evident in muscles of the face, resulting in difficulty smiling, whistling, and reduced facial expression. The weakness in the shoulder muscles causes the scapula to protrude from the back (“winging of the scapula”). The muscles are typically affected asymmetrically, and with progression, the lower extremities, both proximal and distal, become involved.^5, The severity of the disease is highly variable, ranging from mildly affected, asymptomatic individuals to severely affected individuals, with approximately 20% of patients eventually requiring a wheelchair for mobility. Nonmuscular manifestations include retinal vascular abnormalities that can result in significant loss of vision; however, only about 1% of patients with FSHD experience visual acuity loss.^5, Most people with FSHD eventually develop high-frequency hearing loss, which is usually not noticeable and only detectable by an audiogram. FSHD usually presents between the ages of 6 and 20 years, and life expectancy is not shortened. It is estimated that 4 to 5 people per 100,000 population have FSHD. FSHD affects males and females equally.

The purpose of testing patients who have clinical signs of FSHD is to inform a decision on clinical surveillance to identify and manage FSHD-related complications (eg, hearing loss, function) and to differentiate FSHD from other similar diagnoses.

The following PICO was used to select literature to inform this review.

Populations

The relevant population of interest is individuals with clinical signs of FSHD.

Interventions

The test being considered is genetic testing for FSHD.

Comparators

Currently, standard clinical diagnosis, which may include muscle biopsy, without genetic testing is being used to make clinical management decisions about FSHD, which may include anti-inflammatory agents and orthotics and possibly surgery.

Outcomes

The general outcomes of interest include a change in management when test results are positive (ie, avoidance of muscle biopsy, increased ophthalmologic surveillance, evaluation for physical therapy).

Study Selection Criteria

For the evaluation of clinical validity of genetic testing for FSHD, methodologically credible studies were selected using the following eligibility criteria:

• Reported on the accuracy of the marketed version of the technology (including any algorithms used to calculate scores).

• Included a suitable reference standard.

• Patient/sample clinical characteristics were described.

• Patient/sample selection criteria were described.

• Included a validation cohort separate from the development cohort.

Clinically Valid

A test must detect the presence or absence of a condition, the risk of developing a condition in the future, or treatment response (beneficial or adverse). Another aspect of clinical validity for FSHD is the degree to which test results correlate with severity or prognosis of the disease.

Identification of a characteristic 4q35 deletion is about 95% specific for the disease.^8,9,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.^10,

Observational Studies

Several studies have reported on correlations between the degree of the variant 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 have described 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 confirmed a correlation between disease severity and degree of D4Z4 contraction variants.^2,

Lutz et al. (2013) retrospectively analyzed 59 patients with FSHD seen at a single-institution to evaluate the relationship between the D4Z4 repeat size and progression of hearing loss.^11, Eleven of the 59 patients evaluated had hearing loss not attributable to another cause. Truncated D4Z4 (1-10 D4Z4 repeats) was evaluated by the size of EcoRI enzyme or EcoRI/BlnI fragment, with an EcoRI fragment of less than 38 kilobases (kb) or an EcoRI/BlnI fragment of less than 35 kb corresponding to 1 to 10 D4Z4 repeats. There was a statistically significant negative association between hearing loss and fragment size in a simple logistic regression model (p=.021). 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 FSHD type 1 enrolled in the National Registry of FSHD Patients and Family Members, Statland et al. (2014) evaluated the association between patient characteristics, including the D4Z4 allele size, and FSHD-related outcomes.^12, 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 (2021).^13, 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.

Konstantonis et al (2022) analyzed 52 patients with FSHD to evaluate the correlation between D4Z4 repeat array fragment size and orofacial muscle weakening.^14, 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 (2022) performed a retrospective chart review of patients with FSHD seen at a single-institution to evaluate systemic manifestations of the disease. ^15, 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).

Clinically Useful

A test is clinically useful if the use of the results informs management decisions that improve the net health outcome of care. The net health outcome can be improved if patients receive correct therapy, or more effective therapy, or avoid unnecessary therapy, or avoid unnecessary testing.

Direct Evidence

Direct evidence of clinical utility is provided by studies that have compared health outcomes for patients managed with and without the test. Because these are intervention studies, the preferred evidence would be from randomized controlled trials.

Chain of Evidence

Indirect evidence on clinical utility rests on clinical validity. If the evidence is insufficient to demonstrate test performance, no inferences can be made about clinical utility. No studies were identified describing how a molecular diagnosis of FSHD would change patient management, so there is no direct evidence supporting the clinical use of genetic testing for suspected FSHD. However, a chain of evidence can be constructed because D4Z4 contraction variant testing for suspected FSHD establishes a diagnosis, avoids further workup including muscle biopsy, and suggests initiating therapies consistent with appropriate guidelines.

Testing Individuals With Suspected Facioscapulohumeral Muscular Dystrophy

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. No studies were identified that have described how a molecular diagnosis of FSHD changed patient management.

It is unclear to what extent the prognostic value of knowing the degree of D4Z4 is clinically useful. However, for patients who are diagnosed with FSHD, the clinical utility of molecular genetic testing to identify a D4Z4 variant includes:

• 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.

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

• Potential avoidance of a muscle biopsy.

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 or 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 guidelines apply^2,,^16,:

• “Regular assessment of pain.”

• “Affected individuals with moderate to severe FSHD…should be routinely screened for hypoventilation.”

• "Yearly forced vital capacity … measurements should be monitored for all affected individuals who are wheelchair bound, have pelvic girdle weakness and superimposed pulmonary disease, and/or have moderate to severe kyphoscoliosis, lumbar hyperlordosis, or chest wall deformities.”

• "Hearing loss assessment in children as “routinely by periodic assessment as part of school-based testing.”

• “Hearing screens are particularly important in severe infantile-onset forms of FSHD, 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; if vascular disease is absent, follow-up exams are only necessary if visual symptoms develop.”

Testing Family Members of Individuals With Facioscapulohumeral Muscular Dystrophy

Evaluation of at-risk relatives may determine that they may be affected but escaped previous diagnosis because of a milder phenotypic presentation. Ricci et al (2013) evaluated the D4Z4 site in 367 relatives of 163 FSHD index cases that carried D4Z4 “alleles of reduced size” of 8 or fewer repeating units.^10, Among relatives, D4Z4 “alleles of reduced size” with 1 to 3 repeating units and 4 to 6 repeating units were identified in 42 and 133 subjects, respectively. Of those relatives with 1 to 3 repeating units, about 40% demonstrated severe muscle symptoms by age 30, whereas none of those with 4 or more repeating units had severe symptoms in that age range. Identification of previously unknown mild cases of FSHD results in knowledge of risk status and potential for transmission to offspring.

Section Summary: Genetic Testing for Facioscapulohumeral Muscular Dystrophy

Some reports on the clinical validity of genetic testing for FSHD have shown a correlation between disease severity and the degree of D4Z4 contraction variants, with larger contractions having earlier onset and faster progression, although other studies have not confirmed this association. One retrospective study showed a negative association between hearing loss and D4Z4 fragment size; another showed earlier wheelchair use with D4Z4 contractions of 18 kb versus 19 to 28 kb. One study reported a positive non-significant correlation between severity of orofacial muscle weakness and D4Z4 fragment size. It has also been reported that patients can have characteristic D4Z4 allele sizes without clinical signs of D4Z4, suggesting that for FSHD to develop, the D4Z4 allele size must occur in a "permissive" background. Overall, evidence suggests genetic testing for FSHD has clinical validity.

Although evidence supporting improved outcomes is generally lacking, studies have reported high test validity, and a definitive diagnosis may end the need for additional testing in the etiologic workup, avoid the need for a muscle biopsy, and initiate and direct clinical management changes that can result in improved health outcomes.

For individuals who have clinical signs of facioscapulohumeral muscular dystrophy(FSHD) who receive genetic testing for FSHD, the evidence includes several observational studies. Relevant outcomes are test validity, morbid events, functional outcomes, quality of life, and resource utilization. Although evidence supporting improved outcomes is generally lacking, studies have reported high test validity, and a definitive diagnosis may end the need for additional testing in the etiologic workup, avoid the need for a muscle biopsy, and initiate and direct clinical management changes that can result in improved health outcomes. The evidence is sufficient to determine that the technology results in an improvement in the net health outcome.

SUPPLEMENTAL INFORMATION

The purpose of the following information is to provide reference material. Inclusion does not imply endorsement or alignment with the evidence review conclusions.

Practice Guidelines and Position Statements

Guidelines or position statements will be considered for inclusion in ‘Supplemental Information’ if they were issued by, or jointly by, a US professional society, an international society with US representation, or National Institute for Health and Care Excellence (NICE). Priority will be given to guidelines that are informed by a systematic review, include strength of evidence ratings, and include a description of management of conflict of interest.

American Academy of Neurology and American Association of Neuromuscular & Electrodiagnostic Medicine

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^17,:

“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.”

This guideline was reaffirmed on September 18, 2021.^18,

U.S. Preventive Services Task Force Recommendations

Not applicable.

Medicare National Coverage

There is no national coverage determination. In the absence of a national coverage determination, coverage decisions are left to the discretion of local Medicare carriers.

Ongoing and Unpublished Clinical Trials

Some currently unpublished trials that might influence this review are listed in Table 1.

Table 1. Summary of Key Trials

REFERENCES

1. Menezes MP, North KN. Inherited neuromuscular disorders: pathway to diagnosis. J Paediatr Child Health. Jun 2012; 48(6): 458-65. PMID 22050238
2. Lemmers RJLF, Miller DG, van der Maarel SM. Facioscapulohumeral Muscular Dystrophy. GeneReviews. 1993 (updated 2014). PMID 20301616
3. Pastorello E, Cao M, Trevisan CP. Atypical onset in a series of 122 cases with FacioScapuloHumeral Muscular Dystrophy. Clin Neurol Neurosurg. Apr 2012; 114(3): 230-4. PMID 22079131
4. Hassan A, Jones LK, Milone M, et al. Focal and other unusual presentations of facioscapulohumeral muscular dystrophy. Muscle Nerve. Sep 2012; 46(3): 421-5. PMID 22907234
5. van der Maarel SM, Tawil R, Tapscott SJ. Facioscapulohumeral muscular dystrophy and DUX4: breaking the silence. Trends Mol Med. May 2011; 17(5): 252-8. PMID 21288772
6. Lemmers RJ, Tawil R, Petek LM, et al. Digenic inheritance of an SMCHD1 mutation and an FSHD-permissive D4Z4 allele causes facioscapulohumeral muscular dystrophy type 2. Nat Genet. Dec 2012; 44(12): 1370-4. PMID 23143600
7. Sacconi S, Lemmers RJ, Balog J, et al. The FSHD2 gene SMCHD1 is a modifier of disease severity in families affected by FSHD1. Am J Hum Genet. Oct 03 2013; 93(4): 744-51. PMID 24075187
8. Lemmers RJLF, Miller DG, van der Maarel SM. Facioscapulohumeral Muscular Dystrophy. In: Adam MP, Ardinger HH, Pagon RA, et al., eds. GeneReviews. Seattle, WA: University of Washington; 2014.
9. Rieken A, Bossler AD, Mathews KD, et al. CLIA Laboratory Testing for Facioscapulohumeral Dystrophy: A Retrospective Analysis. Neurology. Feb 16 2021; 96(7): e1054-e1062. PMID 33443126
10. Ricci G, Scionti I, Sera F, et al. Large scale genotype-phenotype analyses indicate that novel prognostic tools are required for families with facioscapulohumeral muscular dystrophy. Brain. Nov 2013; 136(Pt 11): 3408-17. PMID 24030947
11. Lutz KL, Holte L, Kliethermes SA, et al. Clinical and genetic features of hearing loss in facioscapulohumeral muscular dystrophy. Neurology. Oct 15 2013; 81(16): 1374-7. PMID 24042093
12. Statland JM, Tawil R. Risk of functional impairment in Facioscapulohumeral muscular dystrophy. Muscle Nerve. Apr 2014; 49(4): 520-7. PMID 23873337
13. Katz NK, Hogan J, Delbango R, et al. Predictors of functional outcomes in patients with facioscapulohumeral muscular dystrophy. Brain. Dec 16 2021; 144(11): 3451-3460. PMID 34542603
14. Konstantonis D, Kekou K, Papaefthymiou P, et al. Orofacial Muscle Weakening in Facioscapulohumeral Muscular Dystrophy (FSHD) Patients. Children (Basel). Jan 11 2022; 9(1). PMID 35053721
15. Kelly CR, Saw JL, Thapa P, et al. Systemic manifestations and symptom burden of facioscapulohumeral muscular dystrophy in a referral cohort. Muscle Nerve. Apr 2022; 65(4): 415-421. PMID 35020192
16. Tawil R, van der Maarel S, Padberg GW, et al. 171st ENMC international workshop: Standards of care and management of facioscapulohumeral muscular dystrophy. Neuromuscul Disord. Jul 2010; 20(7): 471-5. PMID 20554202
17. American Academy of Neurology and American Association of Neuromuscular & Electrodiagnostic Medicine. 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 13, 2024.

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