Knowing the phenotypic variations in facioscapulohumeral muscular dystrophy (FSHD) can help clinicians better manage the disease and offer more informed genetic counseling, according to a registry cohort study that found that phenotypes varied in probands and family member carriers with 7 to 8 tandem repeats in the D4Z4 allele at the 4q35 locus.
The classic FSHD phenotype was seen in 52.9% of probands and 16.2% of family members, while incomplete or atypical phenotypes were seen in 47.1% of probands and 34.9% of family members, reported Rossella Tupler, PhD, of the University of Modena in Italy and colleagues in JAMA Network Open. No motor impairment was seen in 52.8% of family members.
“This study found large phenotypic variability associated with individuals carrying a D4Z4 reduced allele [DRA] with 7 to 8 repeat units [RUs], in contrast to the indication that a positive molecular test is the only determining aspect for FSHD diagnosis,” Tupler and colleagues wrote. “These findings suggest that carriers of a D4Z4 reduced allele [DRA] with 7 to 8 RUs constitute a genetic subgroup different from classic FSHD.”
The results “seem to indicate a sustained heterogeneity of phenotypes in individuals carrying DRA with as few as 7 repeat units,” wrote Jerome Robin, PhD, of Aix Marseille University, and Karine Nguyen, MD, PhD, of Hopital de la Timone in Marseille, France, in an accompanying editorial. “Echoing former studies on smaller cohorts reporting clinical heterogeneity, incomplete penetrance, and atypical cases, the current study underlines the difficulties of genetic counseling and prediction of the course of the disease with such variability.”
FSHD is a hereditary myopathy linked to the 4q35 locus with a classic or typical presentation of young patients (first and second decade) with progressive, often asymmetric, weakness and atrophy in the face, shoulder girdle, and pectoral muscles. It may also involve abdominal, distal lower extremity, and pelvic girdle muscles. Autosomal dominant inheritance is associated with variable penetrance and multiple phenotypes.
FSHD1, accounting for 95% of cases, is associated with 10 or fewer RUs in the DRA. Having 7 to 10 repeats is associated with milder disease and older age of onset, compared with 1 to 6 repeats.
Guidelines published in 2015 for the diagnosis and management of FSHD emphasized genetic testing (including D4Z4 allele size and D4Z4 methylation status) and stated: “D4Z4 deletion size should be used cautiously for predicting disease progression rate in any particular individual due to other sources of variation affecting disease severity, including intrafamilial factors.”
In the present study, researchers studied patients with 7 to 8 DRA repeat units (about one-fifth of patients with FSHD1 in the Italian National Registry for FSHD). Those with 7 to 8 repeat units represent the threshold of the so-called “grey zone” of DRAs with 8 to 10 repeats.
“By including relatives and narrowing down the DRA to a single genomic factor causative for FSHD, the authors artificially reduced the genetic heterogeneity to solely focus on clinical classification parameters,” the editorialists observed.
Tupler and colleagues analyzed data from 422 carriers of a reduced DRA with 7 to 8 repetitive units collected between 2008 and 2016 from the Italian National Registry for FSHD. The cohort included 187 unrelated probands (mean age 53.5 and 55% men) and 235 relatives from 106 unrelated families (mean age 45 and about 45% men).
Phenotypes were classified as:
- Category A: (typical) facial and scapular girdle muscle weakness typical of FSHD; seen in 52.9% of probands and 16.2% of relatives.
- Category B: (incomplete) muscle weakness limited to scapular girdle or facial muscles; seen in 19.3% of probands and 21.7% of relatives.
- Category C: (healthy) asymptomatic participants; seen in 52.8% of relatives.
- Category D: (atypical) myopathic presenting clinical features not consistent with FSHD canonical phenotype; seen in 26.7% of probands and 9.3% of relatives.
Men were more likely to have a face-sparing phenotype than women (72.7% versus 27.5%), but atypical phenotypes were more frequent in women (66.0% versus 34.0%). Mean age at onset also differed between men and women (28.8 versus 39.1 years, respectively, P<0.001).
Age of onset also differed by category, with earlier onset in the classic phenotype (category A) versus atypical presentations (category D) with mean ages of 29.1 versus 40.9, respectively (P=0.001).
In about one-third of families (95% CI 25.9%-44.8%), the proband was the only participant presenting with a myopathic phenotype, and only 20 families (18.9%; 95% CI 11.9%-27.6%) had a member with autosomal dominant FSHD.
“Most affected participants in this cohort reported symptom onset after the age of 20 years, confirming the late onset of the disease for individuals with DRA with 7 to 8 repeat units. However, the authors also reported that 35% of families included only one affected individual (i.e., the proband), whereas other carriers remained asymptomatic, independent of the proband’s category. This high percentage highlights the variable penetrance of FSHD and advocates for complex cofactors yet to be identified,” the editorialists wrote.
Motor impairment severity was greater in group A (typical FSHD) than B (incomplete), though no difference was seen between group A and group D (atypical).
“By highlighting the heterogeneous nature of FSHD, the study by Ruggiero et al brings FSHD back to the clinics,” Robin and Nguyen noted. “This work underlines the need for combinatory approaches (i.e., genetics and clinics) and the importance of standardized assessments.”
Limitations include a technically demanding categorization tool that requires expertise in neuromuscular disease to apply correctly. In addition, several patients with atypical phenotypes developed disease when older than 40.
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Facioscapulohumeral muscular dystrophy (FSHD) phenotypes varied in probands and family carriers with 7 to 8 tandem repeats in the D4Z4 allele at the 4q35 locus: incomplete or atypical phenotypes were seen in 47.1% of probands and 43.9% of families, while the classic phenotype was seen in 52.9% of probands and 16.2% of family members.
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Knowledge of this phenotypic variation may be informative for clinical management and genetic counseling.
Paul Smyth, MD, Contributing Writer, BreakingMED™
The Telethon Italy Foundation supported the creation of Italian National Registry for Facioscapulohumeral Muscular Dystrophy and the Italian Clinical Network for Facioscapulohumeral Muscular Dystrophy with grants. Tupler was supported by grants from Regione Emilia Romagna, Italy.
Tupler reported no disclosures.
Nguyen and Robin reported no disclosures.
Cat ID: 496
Topic ID: 495,496,496,730,36,192,925
