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Features include always present findings: Angulated muscle fibers, Difficulty climbing stairs, Scapular winging, and Fatigue and others.
Organ System | Phenotype Count | Example Features |
|---|---|---|
Muscles | 6 | Angulated muscle fibers, Difficulty climbing stairs, Weakness of facial musculature |
LRIF1 encodes ligand dependent nuclear receptor interacting factor 1 (769 aa). Together with SMCHD1, involved in chromosome X inactivation in females by promoting the compaction of heterochromatin. Highest expression in Testis (40.4 TPM) and Cells EBV-transformed lymphocytes (30.0 TPM).
Facioscapulohumeral muscular dystrophy 3, digenic is associated with mutations in the LRIF1 gene on chromosome 1.
LRIF1 is classified as a druggable target (Nuclear Hormone Receptor category) with score 0.0.
Evidence-based guidelines for diagnosis of facioscapulohumeral muscular dystrophy (FSHD) are available .
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.
No approved treatments are currently available for facioscapulohumeral muscular dystrophy 3, digenic. The disease remains an area of unmet medical need.
Clinical practice guidelines for facioscapulohumeral muscular dystrophy (FSHD) have been published .
To establish the extent of disease and needs in an individual diagnosed with FSHD, the evaluations summarized (if not performed as part of the evaluation that led to the diagnosis) are recommended.
To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in are recommended. Table 6. Facioscapulohumeral Muscular Dystrophy: Recommended Surveillance
No clinical trials have been registered for facioscapulohumeral muscular dystrophy 3, digenic.
3 publications have been identified in PubMed for facioscapulohumeral muscular dystrophy 3, digenic. Research spans Diagnostic / Biomarker (33%), Case Report / Case Series (33%), and Basic Science / Preclinical (33%).
Tammam G (2026). [PMID: 41542987](https://pubmed.ncbi.nlm.nih.gov/41542987/). *European journal of neurology*. [Case Report / Case Series]
Tardy C (2026). [PMID: 41642686](https://pubmed.ncbi.nlm.nih.gov/41642686/). *Brain*. [Basic Science / Preclinical]
Yeow D (2025). [PMID: 40357124](https://pubmed.ncbi.nlm.nih.gov/40357124/). *BMJ neurology open*. [Diagnostic / Biomarker]
Data assembled from 6 of 12 sources · Last updated Oct 4, 2026, 6:17 AM UTC
Online Mendelian Inheritance in Man
1 |
Fatigue |
Head and neck | 1 | Weakness of facial musculature |
Lungs and breathing | 1 | Aspiration pneumonia |
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 . Asymmetry of facial, limb, and shoulder weakness is common . Typically, individuals with FSHD become symptomatic in their teens, but age of onset is variable . 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.
Source: GeneReviews — "Facioscapulohumeral Muscular Dystrophy"
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 . Allele size explains roughly 10% of variability in phenotype . 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 .
Source: GeneReviews — "Facioscapulohumeral Muscular Dystrophy"
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%) . 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 or methylation status between sexes . Effects from epigenetic factors such as methylation status (for both FSHD1 and FSHD2) and other unknown environmental or genetic factors likely contribute .
Source: GeneReviews — "Facioscapulohumeral Muscular Dystrophy"
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).
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 ...
Source: GeneReviews — "Facioscapulohumeral Muscular Dystrophy"
Genetic disorders that are similar clinically to facioscapulohumeral muscular dystrophy (FSHD) are listed in . Table 3. Genetic Disorders of Interest in the Differential Diagnosis of Facioscapulohumeral Muscular Dystrophy
Gene(s) | Disorder | MOI |
|---|---|---|
35 genes incl:ANO5CAPN3DYSF | Limb-girdle muscular dystrophy (OMIM PS603511 PS253600) | ADAR |
350 genes1 | Mitochondrial myopathies (See Primary Mitochondrial Disorders Overview.) | ADARXLMT BAG3 CRYAB DES FLNC HSPB8 KY LDB3 MYL2 MYOT PYROXD1 SVIL TTN |
UNC45B | Myofibrillar myopathy (OMIM PS601419) | ADAR |
CNBP | Myotonic dystrophy type 2 (proximal myotonic myopathy [PROMM]) | AD DMPK |
GAA | Late-onset Pompe Disease | AR |
GNE | GNE myopathy (inclusion body myopathy type 2) | AR AD = autosomal dominant; AR = autosomal recessive; FSHD = facioscapulohumeral muscular dystrophy; MOI = mode of inheritance; MT = mitochondrial; XL = X-linked 1. |
Source: GeneReviews — "Facioscapulohumeral Muscular Dystrophy"
Genetic testing for LRIF1 is available. Testing is considered confirmatory for diagnosis.
Biomarker and diagnostic research for facioscapulohumeral muscular dystrophy 3, digenic has been reported in the published literature.
Facioscapulohumeral Muscular Dystrophy: Recommended Evaluations Following Initial Diagnosis
System/Concern | Evaluation | Comment
| Physical exam | To assess strength functional limitations
Eval for PT need for assistive devices |
Pain assessment |
| OT speech therapy assessment | In persons w/infantile onset
| • Eval for hypoventilation
Screen for daytime somnolence, nonrestorative sleep
| • Baseline PFTs
Low threshold for pulmonary/sleep eval if abnormal PFTs or sleep symptoms
| Ophthalmologic eval | • In persons w/large pathogenic contraction of D4Z4 (D4Z4 fragments of 10-20 kb) or visual symptoms
For presence of retinal vasculopathy
| Assessment of hearing | • In all affected infants children
In adults w/symptomatic hearing loss
| By genetics professionals1 | To obtain a pedigree inform affected persons their families re nature, MOI, implications of FSHD to facilitate medical personal decision making
FSHD = facioscapulohumeral muscular dystrophy; MOI = mode of inheritance; OT = occupational therapy; PFT = pulmonary function test; PT = physical therapy
Source: GeneReviews — "Facioscapulohumeral Muscular Dystrophy"
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 p38/ 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.
Source: GeneReviews — "Facioscapulohumeral Muscular Dystrophy"
View trials for facioscapulohumeral muscular dystrophy 3, digenic
Evaluation |
|---|
Frequency |
|---|
Musculoskeletal | PT assessment | Annually or more frequently as determined by disease severity Pain assessment |
Respiratory | Screening for hypoventilation | At each visit for persons w/abnormal PFTs, severe proximal weakness, kyphoscoliosis, wheelchair dependence, or comorbid disease affecting ventilation Pulmonary consultation |
Ophthalmologic | Dilated ophthalmoscopy | Annually in those w/large pathogenic contraction of D4Z4 (D4Z4 fragments of 10-20 kb); In adults only if visual symptoms develop |
Audiology | Audiometry | At each visit in infants w/early-onset FSHD; Annually in children until starting school; In adults only if symptoms of hearing loss reported |
Cardiology | Cardiac eval | If overt signs or symptoms of cardiac disease (regular screening not required) FSHD = facioscapulohumeral muscular dystrophy; FVC = forced vital capacity; OT = occupational therapy; PCP = primary care physician; PFT = pulmonary function test; PT = physical therapy/therapist |
Source: GeneReviews — "Facioscapulohumeral Muscular Dystrophy"
Phenotype severity distribution: 9 always present features.
AI-curated news mentioning facioscapulohumeral muscular dystrophy 3, digenic
Updated Sep 3, 2026
A recent study highlights de novo facioscapulohumeral muscular dystrophy as a severe subtype linked to D4Z4 repeat contractions. This discovery enhances understanding of the genetic mechanisms underlying this condition.
A response has been published addressing concerns raised in a letter to the editor about mortality associated with facioscapulohumeral muscular dystrophy (FSHD). This systematic literature review highlights the complexities of mortality in FSHD, contributing to the ongoing discourse in the scientific community.
Epicrispr secures funding to support clinical development of EPI-321, a gene therapy targeting muscular dystrophy treatment Ultimately, our vision is to establish programmable epigenetic medicines as an entirely new therapeutic modality, with the potential to treat diseases that have historically been beyond the reach of conventional approaches.” · Related:Poolbeg CEO delves inside the UK’s record $2.84bn fundraising quarter ... The LSX USA Congress gathers leaders from the US biotech, medtech, and healthtech sectors to network, showcase innovations, and explore partnership opportunities. Related:Vaderis secures $152m to advance rare disease treatment · EPI-321 is designed to be delivered intravenously via a single adeno-associated virus (AAV) vector. The drug aims to durably suppress pathological DUX4 expression without permanently altering the underlying DNA sequence. This Series C marks a shift in the company's fundraising approach compared with earlier rounds, according to Salzman. Facioscapulohumeral muscular dystrophy (FSHD) is one of the most common forms of muscular dystrophy, affecting hundreds of thousands of people worldwide. There are currently no approved disease-modifying therapies. Salzman shared that the disease is a perfect match for the company's approach.
Epicrispr Biotechnologies and Infinimmune have secured a combined $165 million in venture capital funding. Epicrispr aims to develop an epigenetic treatment for facioscapulohumeral muscular dystrophy, while Infinimmune will focus on advancing antibodies for atopic dermatitis.
Epicrispr secures $90 million in funding to advance its epigenetic editing drug for facioscapulohumeral muscular dystrophy. The company has completed enrollment for an early-stage study, positioning itself in a competitive landscape with multiple drugmakers targeting this rare muscle disease.