A large Italian cohort confirms the complexity in interpreting borderline FSHD genotypes

Facioscapulohumeral muscular dystrophy (FSHD) affects 4.5 per 100,000 people in Europe. It typically manifests as muscle weakness with a specific pattern, since it affects the muscles of the face and those around the shoulder blades.

The most common form, FSHD type 1, is the result of contraction of the repeated D4Z4 units in the 4qA region of chromosome 4. Diagnosis is based on molecular analysis: the number of D4Z4 repeats is between 1 and 10 in FSH1, versus 11 to 100 normally. A total of 9 to 10 repeats corresponds to a borderline situation, in which diagnosis and genetic counselling can prove to be complex, due to a high degree of variability in expression: normal phenotype, typical or non-typical FSHD, or other muscular dystrophy.


Low penetrance and very diverse clinical picture

A team has conducted a new study on genotype–phenotype correlation in this borderline population, based on the national Italian register dedicated to FSHD, and using the CCEF (Comprehensive Clinical Evaluation Form) clinical evaluation tool. This work relates to 244 patients, 134 of which were index cases and 110 carrier relatives (related to at least one FSHD patient). These results, published in December 2020, showed that:

  • only 54.5% of index cases presented a conventional FSHD phenotype, 20.1% presented an incomplete phenotype, 6.7% presented minor signs (scapular winging, etc.), and 18.7% an atypical clinical picture (weakness of the pelvic girdle, isolated axial involvement, etc.), observable in many other myopathies of genetic origin;
  • 70.9% of carrier relatives did not have any motor impairment, 10% had a phenotype typical of FSHD, 13.6% had an incomplete form of the disease (scapular or facial), and 5.5% had a myopathic phenotype that was not compatible with FSHD;
  • disease penetrance was 40% on average in the 12 families that had at least 4 carriers of 9–10 D4Z4 repeats, a figure similar to that found by a previous study conducted in France and Switzerland.

The authors are suggesting that one should consider the existence of 9-10 D4Z4 repeats more as a genetic susceptibility factor, rather than as an FSHD diagnostic marker.


Large genotype-phenotype study in carriers of D4Z4 borderline alleles provides guidance for facioscapulohumeral muscular dystrophy diagnosis. Ricci G, Mele F, Govi M et al. Sci Rep. 2020 Dec 10;10(1):21648