Clinical characteristics.

Facioscapulohumeral muscular dystrophy (FSHD) typically presents with weakness of the facial muscles, the stabilizers of the scapula, and/or the dorsiflexors of the foot. Severity is highly variable. Weakness can be slowly progressive and approximately 20% of affected individuals eventually require a wheelchair. Life expectancy is not shortened.

Diagnosis/testing.

The diagnosis of FSHD1 is established in a proband with characteristic clinical features and a heterozygous pathogenic contraction of the D4Z4 repeat array in the subtelomeric region of chromosome 4q35 on a permissive chromosome 4 haplotype. The diagnosis of FSHD2 is established in a proband with characteristic clinical features and hypomethylation of the D4Z4 repeat array in the subtelomeric region of chromosome 4q35 on a permissive chromosome 4 haplotype. Hypomethylation of the D4Z4 repeat array can be the result of a heterozygous pathogenic variant in SMCHD1 or DNMT3B, or biallelic pathogenic variants in LRIF1.

Management.

Treatment of manifestations: Consultation with a physical therapist to establish appropriate exercise regimen; ankle-foot orthoses to improve mobility and prevent falls; occupational and speech therapy in individuals with infantile onset; surgical fixation of the scapula to the chest wall may improve range of motion of the arms; management of chronic pain by physical therapy and medication; ventilatory support as needed; ocular lubricants or taping the eyes shut during sleep to treat exposure keratitis; treatment for retinal vasculopathy per ophthalmologist; standard treatment of sensorineural hearing loss.

Surveillance: Physical therapy assessment annually or more frequently as needed; pain should be assessed at regular visits to the primary care physician or physical therapist; occupational and speech therapy assessment as needed throughout childhood in those with infantile onset; screening for hypoventilation in individuals with abnormal pulmonary function tests, severe proximal weakness, kyphoscoliosis, wheelchair dependence, or comorbid disease affecting ventilation; pulmonary consultation for forced vital capacity <60%, excessive daytime somnolence, or nonrestorative sleep, and prior to surgical procedures requiring anesthesia; annual dilated ophthalmoscopy in individuals with early childhood-onset FSHD with large pathogenic contraction of D4Z4 and adults with visual symptoms; audiometry in infants at each visit and annually in children.

Genetic counseling.

FSHD1: FSHD1 is inherited in an autosomal dominant manner. Approximately 70%-90% of individuals diagnosed with FSHD1 have a parent with clinical findings of FSHD and one D4Z4 repeat array with a pathogenic contraction; ~10%-30% of probands have the disorder as the result of a de novo constitutional or mosaic pathogenic contraction of the D4Z4 repeat array. Each offspring of a proband with FSHD1 has a 50% chance of inheriting the pathogenic D4Z4 repeat array contraction. Once a diagnosis of FSHD1 has been established in an affected family member, predictive testing for at-risk relatives and prenatal testing are possible. Preimplantation genetic testing (PGT) may be possible but verification of PGT results using prenatal testing is typically recommended.

FSHD2: FSHD2 is associated with complex inheritance. If the proband has a heterozygous pathogenic variant in SMCHD1 or DNMT3B and a permissive chromosome 4 haplotype and the proband's reproductive partner does not have FSHD2-related genetic alteration(s), each child of the proband has a 25% chance of being affected, a 50% chance of being an asymptomatic heterozygote, and a 25% chance of inheriting neither of the FSHD2-related genetic alterations. If the proband has homozygous nonsense variants in LRIF1 and a permissive chromosome 4 haplotype and the proband's reproductive partner does not have FSHD2-related genetic alteration(s), each child of the proband will be an obligate heterozygote for an LRIF1 pathogenic variant; each child has an additional 50% chance of inheriting a permissive chromosome 4 haplotype. Offspring who inherit a heterozygous LRIF1 pathogenic variant and a permissive chromosome 4 haplotype are not expected to be affected with FSHD2. If the proband has hypomethylation of the D4Z4 repeat array of unknown cause, offspring are presumed to be at risk of inheriting FSHD2-related genetic alterations and being affected with FSHD2. Once a diagnosis of FSHD2 has been established in an affected family member, predictive testing for at-risk relatives is possible. Prenatal testing and PGT for FSHD2 are not available to date.

Suggestive Findings

FSHD should be suspected in individuals with the following:

• Weakness that predominantly involves the facial, scapular stabilizer, and/or foot dorsiflexor muscles without associated ocular or bulbar muscle weakness. Weakness is often asymmetric.
• Progression of weakness after pregnancy [Ciafaloni et al 2006]
• Prior diagnosis with inflammatory myopathy that is refractory to immunosuppression

Family history of FSHD is most often consistent with autosomal dominant inheritance (e.g., affected males and females in multiple generations).

Supportive Findings

Serum concentration of creatine kinase (CK) is normal to elevated in individuals with FSHD and usually does not exceed three to five times the upper limit of the normal range. Serum concentration of CK that is more than 1,500 IU/L suggests an alternate diagnosis.

EMG can show mild myopathic changes in symptomatic muscles.

Muscle biopsy most often shows nonspecific chronic myopathic changes. Mononuclear inflammatory reaction, typically perivascular, is present in muscle biopsies in up to 40% of individuals with FSHD. Rarely, the inflammatory reaction is intense enough to suggest an inflammatory myopathy. Muscle biopsy is now performed only in individuals in whom FSHD is suspected but not confirmed by molecular genetic testing.

Establishing the Diagnosis

The diagnosis of FSHD is established in a proband who has one of the following identified on molecular genetic testing (see Table 1):

• A heterozygous pathogenic contraction of the D4Z4 repeat array in the subtelomeric region of chromosome 4q35 on a permissive chromosome 4 haplotype (FSHD1; ~95% of FSHD)
• Hypomethylation of a shortened (but not to the extent of FSHD1) D4Z4 repeat array in the subtelomeric region of chromosome 4q35 on a permissive chromosome 4 haplotype (FSHD2; ~5% of FSHD), as a result of one of the following:
  • A heterozygous SMCHD1 pathogenic (or likely pathogenic) variant (<5% of individuals with FSHD; ~85% of individuals with FSHD2) [Lemmers et al 2015]
  • A heterozygous DNMT3B pathogenic (or likely pathogenic) variant (3 families reported) [van den Boogaard et al 2016]
  • A homozygous nonsense variant in LRIF1 (1 individual reported) [Hamanaka et al 2020]
  • Unknown cause of hypomethylation of D4Z4 repeat array at 4q35 (affected individuals in 1 family) [Lemmers et al 2012]

Allele sizes

• Normal alleles. A D4Z4 locus with ≥11 repeat units (i.e., fragments of ≥43 kb using EcoRI and the p13E-11 probe), or a D4Z4 locus with any number of repeat units on a non-permissive haplotype
• Contracted, reduced-penetrance alleles. A D4Z4 locus that has 8-10 repeat units AND is on a permissive haplotype
  Note: (1) Affected individuals from India, Japan, and South Korea have lower penetrance in allele sizes 8-10 than affected individuals from Europe [Vishnu et al 2024]. (2) Affected individuals from China more commonly have allele sizes 1-6 than 7-10 [Wang et al 2021].
• Contracted, full-penetrance alleles. A D4Z4 locus that has ≤7 repeat units AND is on a permissive haplotype

Note: (1) Penetrance of allele sizes is dependent on multiple factors (see Penetrance) and patient-specific manifestations may vary. (2) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [Richards et al 2015]. Reference to "pathogenic variants" in this GeneReview is understood to include likely pathogenic variants.

Molecular genetic testing approaches can include targeted analysis for the repeat size of D4Z4 repeat array in the subtelomeric region of chromosome 4q35 with Southern blot analysis or optical genome mapping (OGM) and haplotype analysis, DNA methylation studies, and single-gene testing.

Clinical Description

Facioscapulohumeral muscular dystrophy (FSHD) is characterized by progressive muscle weakness involving the face, shoulder girdle, upper arm, lower leg (peroneal muscles), and hip girdle in later stages [Hamel et al 2019]. Asymmetry of facial, limb, and shoulder weakness is common [Wang et al 2025]. Typically, individuals with FSHD become symptomatic in their teens, but age of onset is variable [Zheng et al 2025]. Earlier onset is associated with more progression. Individuals with severe infantile FSHD have muscle weakness at birth. In contrast, some individuals remain asymptomatic throughout their lives. Progression is usually slow; however, many affected individuals describe a stuttering course with periods of disease inactivity followed by periods of rapid deterioration. Eventually 20% of affected individuals require a wheelchair.

Scapular winging is the most common initial finding; preferential weakness of the lower trapezius muscle results in characteristic upward movement of the scapula when attempting to flex or abduct the arms. The shoulders tend to slope forward with straight clavicles and pectoral muscle atrophy.

Affected individuals show facial weakness, with symptoms more pronounced in the lower facial muscles than the upper. Some affected individuals recall having facial weakness before the onset of shoulder weakness. Earliest signs are often difficulty whistling or sleeping with eyes partially open in childhood. Individuals with FSHD are often unable to purse their lips, turn up the corners of their mouth when smiling, or bury their eyelashes when attempting to close their eyelids tightly. Extraocular, eyelid, and bulbar muscles are spared.

The deltoids remain minimally affected until late in the disease; however, the biceps and triceps are selectively involved, resulting in atrophy of the upper arm and sparing of the forearm muscles. The latter results in the appearance of "Popeye arms." In more severely affected individuals, distal upper extremity weakness typically involves the wrist and finger extensors.

Abdominal muscle weakness results in protuberance of the abdomen and exaggerated lumbar lordosis. The lower abdominal muscles are selectively involved, resulting in Beevor sign (upward displacement of the umbilicus upon flexion of the neck in a supine position).

The legs are variably involved, with peroneal muscle weakness with or without weakness of the hip girdle muscles, resulting in foot drop.

Sensation is preserved; reflexes are often diminished when the reflex involves weak muscles.

Respiratory dysfunction prevalence is unclear, with up to 50% of those tested in a cohort having abnormal results, though the majority of individuals have not had testing. Individuals with respiratory weakness have a restrictive pattern on pulmonary function testing with reduced forced vital capacity. Respiratory weakness is typically mild or subclinical [Kelly et al 2022].

Other manifestations

• Chronic pain is a common symptom in FSHD, seen in 82% of individuals, with a negative impact on quality of life. Chronic pain can occur regardless of duration of disease or age [Hamel et al 2019]. Chronic fatigue is also common and is the most pronounced symptom after muscle weakness [Kools et al 2023]. This can have a significant negative impact on social engagement and employment [Murray et al 2024].
• Retinal arterial tortuosity may be prevalent in individuals with FSHD; however, these retinal vascular changes seem subclinical and are not symptomatic (i.e., do not cause visual changes) [Maceroni et al 2023]. An exudative retinopathy clinically indistinguishable from Coats disease that can result in retinal detachment and vision loss has also been described.
• Approximately 15% of individuals with FSHD have an abnormal audiogram. An abnormal audiogram was identified in up to 32% of individuals with a large pathogenic contraction of D4Z4 (D4Z4 fragments <20 kb) [Lutz et al 2013].
• Cardiac conduction abnormalities can be seen in 5%-13% of individuals and are typically atrial arrhythmias that are mild or asymptomatic [Kelly et al 2022].

Atypical presentations. Clinical variants of typical FSHD in individuals with a pathogenic contraction of the D4Z4 locus in the subtelomeric region of chromosome 4q35 include the following:

• Scapulohumeral dystrophy onset with facial sparing
• Early-onset disease (age <10 years) is associated with earlier median age of lower extremity involvement and more severe disease overall. De novo pathogenic variants are more common in early-onset FSHD1 and are commonly associated with 1-3 D4Z4 repeats [Zheng et al 2025].

Mosaicism for FSHD-associated alleles. Approximately half of de novo cases of FSHD (i.e., affected offspring of unaffected parents) show a mosaic distribution of D4Z4 repeat array lengths in peripheral blood. This mosaicism likely results from a postzygotic array contraction during the first few cell divisions in embryogenesis. In such instances, a proportion of cells have two normal-sized D4Z4 alleles, while the remaining cells have one normal-sized D4Z4 allele and one pathogenic contracted D4Z4 allele. Depending on when in embryogenesis the pathogenic contraction occurs at the D4Z4 locus and the proportion of cells with the contracted D4Z4 repeat, individuals with mosaicism can be affected or asymptomatic. FSHD with somatic mosaicism of D4Z4 array lengths is more penetrant in males than in females.

Genotype-Phenotype Correlations

D4Z4 repeat array contraction size. Evidence-based guidelines published in 2015 recommend that a large pathogenic contraction of D4Z4 (D4Z4 fragments of 10-20 kb) should alert clinicians to the increased likelihood of significant disability, earlier onset of symptoms, and increased likelihood of extramuscular manifestations [Tawil et al 2015].

Allele size explains roughly 10% of variability in phenotype [Mul et al 2018]. A correlation has been reported between the degree of the pathogenic contraction of the D4Z4 locus and the age at onset of symptoms, age at loss of ambulation, and muscle strength. Individuals with a large contraction of D4Z4 (1-3 repeats) have a higher probability of earlier-onset disease and more rapid progression than those with smaller contractions of the D4Z4 locus [Zheng et al 2025]. However, significant variation exists even with small repeats, and others have not been able to confirm a correlation between disease severity and degree of D4Z4 pathogenic contractions.

A study of Italy's National Registry concluded that 76% of early-onset (age <10 years) disease was a result of de novo pathogenic variants. However, neither de novo pathogenic variants nor earlier disease onset were associated with a more severe phenotype [Nikolic et al 2016], contrasting with other studies showing that earlier onset is associated with more severe symptoms [Mah et al 2018, Goselink et al 2019]. Caution must be noted, as this correlation may represent an ascertainment bias, where more mild forms of FSHD are detected when inheritance of a known pathogenic variant in a family is suspected.

Mosaicism. The phenotypic severity of individuals with mosaic distributions of one or more array sizes, which is typically less than that of individuals without mosaicism, may reflect the proportion of cells carrying the pathogenic contracted D4Z4 locus in addition to the degree of the contraction of the D4Z4 locus in those cells.

Compound heterozygosity. Two unrelated affected individuals compound heterozygous for a D4Z4 pathogenic contraction were reported by Wohlgemuth et al [2003], suggesting that the presence of two FSHD-associated alleles can be compatible with life. However, both families demonstrated reduced penetrance for FSHD, leaving open the possibility that in other genetic/environmental settings, compound heterozygosity could be a lethal condition. In support of this possibility, the authors report a phenotypic dosage effect in both of the compound heterozygotes compared to other family members.

Homozygosity. Tonini et al [2004] reported an individual homozygous for the contraction on two D4Z4 4A alleles whose clinical phenotype is not more severe than those of some of his heterozygous relatives. Within the same family, the authors also observed a large number of asymptomatic or minimally affected heterozygotes, reflecting the wide range of clinical variability that can occur in a given kindred.

Penetrance

Penetrance is increased with smaller D4Z4 repeat arrays; however, significant variation exists. In one study, penetrance of FSHD varied by age and sex; it was 83% by age 30 years, but significantly greater for males (95%) than for females (69%) [Wohlgemuth et al 2018]. The effect of the affected individual's sex on penetrance and disease variability is uncertain, with data showing a lack of significant effect of lifetime estrogen exposures [Mul et al 2018] or methylation status between sexes [Lemmers et al 2015]. Effects from epigenetic factors such as methylation status (for both FSHD1 and FSHD2) and other unknown environmental or genetic factors likely contribute [Mul et al 2018].

Anticipation

Anticipation is not reported in FSHD and repeat size remains stable throughout generations [Vincenten et al [2022].

Nomenclature

The term "Landouzy-Dejerine muscular dystrophy," used in the past for a syndrome similar or identical to FSHD, is no longer in use.

Persons with FSHD are sometimes included under the descriptive terms "scapulo-humeral" or "scapulo-peroneal" syndromes.

Prevalence

The estimated prevalence of FSHD is between four and ten in 100,000. Sposìto et al [2005] found a prevalence in central Italy of 4.6:100,000. Lunt & Harper [1991] noted reports of 1:435,000 in Wisconsin and figures for Europe from 1:17,000 to 1:250,000. In Wales, the prevalence was 4.4:100,000. In the Netherlands, the prevalence of FSHD may be 2.4:20,000, higher than prior estimates [Deenen et al 2014].

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with FSHD, the evaluations summarized in Table 4 (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Treatment of Manifestations

Standards of care and management of FSHD were agreed upon at the 171st ENMC International Workshop. A consensus on the following topics and the recommendations from that conference [Tawil et al 2010] are outlined in Table 5.

Surveillance

To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in Table 6 are recommended.

Evaluation of Relatives at Risk

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Pregnancy Management

Outcome of 105 pregnancies in 38 women with FSHD was generally favorable [Ciafaloni et al 2006]. However, rates for low-birth-weight infants, augmented extraction procedures such as forceps and vacuum-assisted deliveries, delivery by cesarean section, and anesthetic complications were higher than for the general population. Worsening of weakness occurred in 24% of the pregnancies, beginning during the pregnancy and generally not resolving after delivery.

Therapies Under Investigation

Genetic treatments such as siRNA treatment to silence DUX4 are being studied, as is an epigenic 4q35 silencing treatment delivered by adenovirus, EPI-321. Losmapimod, an inhibitor of p38α/β mitogen-activated protein kinase (MAPK), resulted in improved reachable workspace and strength in both treatment and placebo groups. A monoclonal antibody to myostatin is in Phase II trials.

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for information on clinical studies for a wide range of diseases and conditions.

Mode of Inheritance

Facioscapulohumeral muscular dystrophy 1 (FSHD1) is an autosomal dominant disorder caused by a heterozygous pathogenic contraction of the D4Z4 repeat array in the subtelomeric region of chromosome 4q35 on a permissive chromosome 4 haplotype.

FSHD2 is caused by hypomethylation of a shortened (but not to the extent of FSHD1) D4Z4 repeat array in the subtelomeric region of chromosome 4q35 on a permissive chromosome 4 haplotype, as a result of one of the following:

• A heterozygous SMCHD1 pathogenic variant;
• A heterozygous DNMT3B pathogenic variant;
• A homozygous LRIF1 nonsense variant;
• An unknown cause.

Autosomal Dominant Inheritance (FSHD1) – Risk to Family Members

Parents of a proband

• Approximately 70%-90% of individuals diagnosed with FSHD1 have a parent with clinical findings of FSHD and one D4Z4 repeat array with a pathogenic contraction.
• Approximately 10%-30% of probands with FSHD1 have the disorder as the result of a de novo constitutional or mosaic pathogenic contraction of the D4Z4 repeat array [Mostacciuolo et al 2009, Strafella et al 2024, Giardina et al 2024].
• If the proband appears to be the only affected family member (i.e., a simplex case), molecular genetic testing is recommended for the parents of a proband to evaluate their genetic status and inform recurrence risk assessment.
• Note: An individual with FSHD1 may appear to be the only affected family member because of failure to recognize the disorder in family members, reduced penetrance, early death of the parent before the onset of symptoms, or late onset of the disease in the affected parent. Therefore, de novo contraction of a D4Z4 repeat array cannot be confirmed unless molecular genetic testing has demonstrated that neither parent has a contraction of the D4Z4 repeat array.
• If a pathogenic contraction of the D4Z4 repeat array is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
  • The proband has a de novo contraction of the of the D4Z4 repeat array.
  • The proband inherited a pathogenic contraction of the D4Z4 repeat array from an asymptomatic parent who has a deletion of the region subtelomeric to the D4Z4 locus where the probe hybridizes (and is therefore probe negative) [Nguyen et al 2017].
  • The proband inherited the D4Z4 contraction from a parent with gonadal (or somatic and gonadal) mosaicism.* Gonadal mosaicism has been reported [Köhler et al 1996] but the incidence is unknown. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only.
    * If the parent is the individual in whom the pathogenic contraction first occurred, the parent may have somatic mosaicism for the contraction and may be mildly/minimally affected.

Sibs of a proband. The risk to the sibs of a proband depends on the genetic status of the parents:

• If a parent of the proband is affected and/or is known to have the pathogenic D4Z4 repeat array contraction, the risk to the sibs of inheriting the pathogenic D4Z4 repeat array contraction is 50%.
  • Clinical variability may be observed among family members with a pathogenic D4Z4 repeat array contraction [Wohlgemuth et al 2018].
  • Clinical manifestations in a sib who inherits a familial D4Z4 pathogenic repeat array contraction may be impacted by the age and sex of the sib and the size of the D4Z4 repeat array contraction (see Genotype-Phenotype Correlations and Penetrance).
• If a pathogenic D4Z4 repeat array contraction cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is slightly greater than that of the general population because of the possibility of parental gonadal mosaicism [Köhler et al 1996] and the possibility that an asymptomatic parent has a deletion of the region subtelomeric to the D4Z4 locus where the probe hybridizes (and is therefore probe negative) [Nguyen et al 2017].
• If the parents have not been tested for the pathogenic D4Z4 repeat array contraction but are clinically unaffected, sibs of a proband are presumed to be at increased risk for FSHD1 because of the possibility of reduced penetrance in a heterozygous parent and the possibility of parental gonadal mosaicism.

Offspring of a proband

• Each offspring of a proband who is heterozygous for a pathogenic contraction of the D4Z4 repeat array has a 50% chance of inheriting the pathogenic D4Z4 repeat array contraction.
• Each offspring of a proband who is mosaic for a pathogenic contraction of the D4Z4 repeat array has up to a 50% chance of inheriting the pathogenic D4Z4 repeat array contraction. Offspring who inherit a D4Z4 repeat array contraction from a mosaic proband will be heterozygous for the contraction (i.e., the contraction will be constitutional rather than mosaic) and may be more severely affected than the proband [Giardina et al 2024].

Other family members. The risk to other family members depends on the status of the proband's parents: if a parent is affected and/or has the pathogenic D4Z4 repeat array contraction, the parent's family members may be at risk.

Complex Inheritance (FSHD2) – Risk to Family Members

Parents of a proband

• Proband with a heterozygous pathogenic variant in SMCHD1 or DNMT3B and a permissive chromosome 4 haplotype:
  • Both parents of an individual with FSHD2 may be heterozygous for an FSHD2-related genetic alteration (either a pathogenic variant in a chromatin modifier gene or a permissive chromosome 4 haplotype). A parent who is heterozygous for one FSHD2-related genetic alteration is asymptomatic and is not at risk of developing FSHD2.
  • Alternatively, one parent may have both FSHD2-related genetic alterations (a pathogenic variant in a chromatin modifier gene and a permissive chromosome 4 haplotype) (and may or may not be clinically affected) and the other parent may have no FSHD2-related genetic alterations.
• In the one individual reported to date with FSHD2 involving homozygous nonsense variants in LRIF1 and a permissive chromosome 4 haplotype, the unaffected mother of the proband was heterozygous for a LRIF1 pathogenic variant and had normal D4Z4 methylation; the genetic status of the father was not reported [Hamanaka et al 2020].
• Paternal inheritance was described in the one family reported to date in which the genetic etiology underlying hypomethylation of the D4Z4 repeat array was not identified [Lemmers et al 2012, van den Boogaard et al 2016].
• Molecular genetic testing is recommended for the parents of the proband to evaluate their genetic status and inform recurrence risk assessment. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only.

Sibs of a proband

• Proband with a heterozygous pathogenic variant in SMCHD1 or DNMT3B and a permissive chromosome 4 haplotype:
  • If each parent has one FSHD2-related genetic alteration, each sib has at conception a 25% chance of inheriting FSHD2-related genetic alterations from both parents, a 50% chance of inheriting one FSHD2-related genetic alteration, and a 25% chance of inheriting neither of the FSHD2-related genetic alterations.
  • If one parent is heterozygous for both FSHD2-related genetic alterations and the other parent does not have an FSHD2-related genetic alteration, each sib has at conception a 25% chance of inheriting both FSHD2-related genetic alterations from one parent, a 50% chance of inheriting one FSHD2-related genetic alteration, and a 25% chance of inheriting neither of the FSHD2-related genetic alterations.
  • Sibs who inherit a pathogenic variant in SMCHD1 or DNMT3B and a permissive chromosome 4 haplotype are at risk of developing FSHD2.
  • Sibs who are heterozygous for one FSHD2-related genetic alteration are asymptomatic and are not at risk of developing FSHD2.
  • Sibs who inherit a pathogenic variant in a chromatin modifier gene and a D4Z4 repeat array of ≤10 repeat units on a permissive chromosome 4 haplotype are at risk of developing FSHD. They would have a genetic condition that is contributed by FSHD1 and FSHD2 and may be more severely affected.
• Proband with homozygous nonsense variants in LRIF1 and a permissive chromosome 4 haplotype: sibs are at risk of inheriting the FSHD2-related genetic alterations and being affected with FSHD2 [Vincenten et al 2022].
• Proband with hypomethylation of the D4Z4 repeat array of unknown cause: sibs are presumed to be at risk of inheriting FSHD2-related genetic alterations and being affected with FSHD2.

Offspring of a proband

• Proband with a heterozygous pathogenic variant in SMCHD1 or DNMT3B and a permissive chromosome 4 haplotype:
  • If the proband's reproductive partner is not affected and not heterozygous for an FSHD2-related genetic alteration, each child of the proband has a 25% chance of being affected, a 50% chance of being an asymptomatic heterozygote, and a 25% chance of inheriting neither of the FSHD2-related genetic alterations.
  • If the proband's reproductive partner has a permissive chromosome 4 haplotype, each child of the proband has a 37.5% chance of being affected, a 50% chance of inheriting either the permissive chromosome 4 haplotype from one or both parents OR a heterozygous pathogenic variant in SMCHD1 or DNMT3B – but not both – and being asymptomatic, and a 12.5% chance of inheriting neither of the FSHD2-related genetic alterations [Vincenten et al 2022].
• Proband with homozygous nonsense variants in LRIF1 and a permissive chromosome 4 haplotype: if the proband's reproductive partner is not affected and not heterozygous for an FSHD2-related genetic alteration, each child of the proband will be an obligate heterozygote for an LRIF1 pathogenic variant; each child has an additional 50% chance of inheriting a permissive chromosome 4 haplotype. Offspring who inherit a heterozygous LRIF1 pathogenic variant and a permissive chromosome 4 haplotype are not expected to be affected with FSHD2.
• Proband with hypomethylation of the D4Z4 repeat array of unknown cause: offspring are presumed to be at risk of inheriting FSHD2-related genetic alterations and being affected with FSHD2.

Other family members. Each sib of a parent with FSHD2-related genetic alteration(s) has a 50% chance of having FSHD2-related genetic alteration(s).

Related Genetic Counseling Issues

Predictive testing (i.e., testing of asymptomatic at-risk individuals)

• Predictive testing for at-risk relatives is possible once the FSHD-related genetic alterations been identified in an affected family member.
• Potential consequences of such testing (including, but not limited to, socioeconomic changes and the need for long-term follow up and evaluation arrangements for individuals with a positive test result) as well as the capabilities and limitations of predictive testing should be discussed in the context of formal genetic counseling prior to testing.

Predictive testing in minors (i.e., testing of asymptomatic at-risk individuals younger than age 18 years) for typically adult-onset conditions for which early treatment would have no beneficial effect on disease morbidity and mortality should be discussed in the context of formal genetic counseling. The autonomy of the minor is a primary concern and consideration should be given to delay of predictive genetic testing until the at-risk individual is capable of informed decision making.

In a family with an established diagnosis of FSHD, it is appropriate to consider testing of symptomatic individuals regardless of age.

Family planning

• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.

Prenatal Testing and Preimplantation Genetic Testing

FSHD1. Once a pathogenic contraction of the D4Z4 repeat array in the subtelomeric region of chromosome 4q35 on a permissive chromosome 4 haplotype has been identified in an affected family member, prenatal testing for a pregnancy at increased risk is possible. Preimplantation genetic testing (PGT) may be possible but verification of PGT results using prenatal testing is typically recommended [Vincenten et al 2022]. Accurate prediction of future possible clinical manifestations in a fetus found to have a pathogenic contraction of the D4Z4 repeat array on a permissive chromosome 4 haplotype is not possible.

FSHD2. Prenatal testing and PGT for FSHD2 are not available to date.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider use of prenatal preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful.

Molecular Pathogenesis

Facioscapulohumeral muscular dystrophy (FSHD) results from expression of a gene that is not typically expressed in somatic tissue. This happens because of an opening of the chromatin structure either as a result of loss of D4Z4 copy number repeats or hypomethylation of D4Z4 due to a heterozygous pathogenic variant in SMCHD1 or DNMT3B, or biallelic pathogenic variants in LRIF1. FSHD1 (from D4Z4 array contraction) and FSHD2 (with resultant D4Z4 array hypomethylation) [Lemmers et al 2012] ultimately lead to the inappropriate expression of DUX4; the two pathomechanisms lead to similar clinical features.

Each 3.3-kb D4Z4 repeat unit has an open reading frame (named DUX4) that encodes two homeoboxes (see Figure 1) [Hewitt et al 1994, Gabriëls et al 1999]. Immediately distal to the D4Z4 region on the 4A variant is an additional DUX4 exon that carries the polyadenylation signal of the gene required for stable gene expression [Lemmers et al 2010a]. Only transcripts that are spliced with the additional DUX4 exon are stabilized sufficiently for protein production; therefore, 4A haplotypes can be permissive to DUX4 expression.

Figure 1.

Schematic comparison of the structure of the normal D4Z4 allele and the pathogenic contracted D4Z4 allele that causes FSHD1. The normal D4Z4 allele has between 11 and 100 units of the 3.3-kb repeat sequence (depicted by triangles), whereas the pathogenic (more...)

Chromosome variants 4A and 4B (sometimes referred to as 4qA and 4qB) are almost equally common in the population and can be further divided into at least nine distinct haplotypes [Lemmers et al 2007, Lemmers et al 2010b]. FSHD1 is associated with contractions of the D4Z4 repeat array on the polyA exon encoding the 4A variant [Lemmers et al 2002, Lemmers et al 2010a].

• 4A161 is the most common 4A permissive haplotype.
• 4A159, 4A163, 4A166H, and 4A168 are less common permissive haplotypes.
• Contraction of the D4Z4 allele on 4A166, a less common 4A haplotype found in two Dutch families, is not associated with FSHD.
• Contraction of the D4Z4 allele on 4B haplotypes is non-pathogenic.

In FSHD2, chromatin relaxation results from a heterozygous pathogenic variant in SMCHD1 or DNMT3B, or biallelic pathogenic variants in LRIF1. SMCHD1 encodes structural maintenance of chromosomes flexible hinge domain-containing protein 1 (SMCHD1), which regulates chromatin repression at the inactive X chromosome and autosomal transgenes, like D4Z4, by CpG DNA methylation. Similar to FSHD1, FSHD2 requires a haplotype that is permissive to DUX4 expression. SMCHD1 can also be a modifier in FSHD1 families, as has been shown in two families with FSHD in which pathogenic variants for both FSHD1 and FSHD2 have been identified [Larsen et al 2015].

Mechanism of disease causation. Gain of function as a result of inappropriate expression of DUX4

Gene- and locus-specific laboratory technical considerations. Testing for FSHD requires non-sequencing-based techniques such as Southern blot analysis, haplotype analysis, and methylation analysis (see Table 1), which are not widely performed by clinical laboratories. Other technical challenges include:

• D4Z4 variant on chromosome 10. A repeat sequence almost identical to D4Z4 has been identified on chromosome 10q26; contractions of this repeat are not associated with FSHD. The chromosome 10 DUX4-like gene in the D4Z4 array has nucleotide variants in the polyadenylation signal, which prevent the production of a stable transcript [Lemmers et al 2010a].
• Translocated alleles. Approximately 20% of the general population carries either a chromosome 4q35-type D4Z4 repeat array on chromosome 10 or a D4Z4 array that consists of both 4q35- and 10q26-type sequence repeats on chromosome 4q35. Translocated arrays on chromosome 10q are non-permissive to FSHD, while the contractions on the hybrid arrays on chromosome 4q35 cause FSHD. Therefore, the finding of a D4Z4 array that appears to be contracted in an individual who carries these translocations must be interpreted with caution and reconciled with clinical findings [Lemmers et al 2010b, Lemmers et al 2012]. Although these are commonly known as "translocated alleles," the mechanism is unknown [Giardina et al 2024].

Acknowledgments

The authors would like to acknowledge the authors of the prior versions of this chapter (see Author History).

Author History

Denise A Figlewicz, PhD; University of Michigan Medical School (1998-2009)
Richard JLF Lemmers, PhD; Leiden University Medical Center (2009-2020)
Daniel G Miller, MD, PhD; University of Washington (2012-2020)
Matthew K Preston, MD (2020-present)
Rabi Tawil, MD (1998-2009; 2020-2025)
Silvere M van der Maarel, MD; Leiden University Medical Center (2009-2020)
Leo H Wang, MD, PhD (2020-present)

Revision History

• 10 July 2025 (sw) Comprehensive update posted live
• 6 February 2020 (sw) Comprehensive update posted live
• 21 June 2012 (me) Comprehensive update posted live
• 9 July 2009 (me) Comprehensive update posted live
• 17 March 2005 (me) Comprehensive update posted live
• 18 March 2003 (me) Comprehensive update posted live
• 8 March 1999 (pb) Review posted live
• 10 July 1998 (df) Original submission

Published Guidelines / Consensus Statements

• Giardina E, Camaño P, Burton-Jones S, Ravenscroft G, Henning F, Magdinier F, van der Stoep N, van der Vliet PJ, Bernard R, Tomaselli PJ, Davis MR, Nishino I, Oflazer P, Race V, Vishnu VY, Williams V, Sobreira CFR, van der Maarel SM, Moore SA, Voermans NC, Lemmers RJLF. Best practice guidelines on genetic diagnostics of facioscapulohumeral muscular dystrophy: Update of the 2012 guidelines. Clin Genet. 2024;106:13-26.
• Tawil R, Kissel JT, Heatwole C, Pandya S, Gronseth G, Benatar M. Evidence-based guideline summary: Evaluation, diagnosis, and management of facioscapulohumeral muscular dystrophy. Neurology. 2015;85:357–64.

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