FSHD1 and FSHD2 form a disease continuum

Abstract

ObjectiveTo compare the clinical features of patients showing a classical phenotype of facioscapulohumeral muscular dystrophy (FSHD) with genetic and epigenetic characteristics of the FSHD1 and FSHD2 loci D4Z4 and SMCHD1.MethodsThis is a national multicenter cohort study. We measured motor strength, motor function, and disease severity by manual muscle testing sumscore, Brooke and Vignos scores, clinical severity score (CSS), and age-corrected CSS, respectively. We correlated these scores with genetic (D4Z4 repeat size and haplotype; SMCHD1 variant status) and epigenetic (D4Z4 methylation) parameters.ResultsWe included 103 patients: 54 men and 49 women. Among them, we identified 64 patients with FSHD1 and 20 patients with FSHD2. Seven patients had genetic and epigenetic characteristics of FSHD1 and FSHD2, all carrying repeats of 9–10 D4Z4 repeat units (RU) and a pathogenic SMCHD1 variant. In the remaining patients, FSHD was genetically excluded or remained unconfirmed. All clinically affected SMCHD1 mutation carriers had a D4Z4 repeat of 9–16 RU on a disease permissive 4qA haplotype. These patients are significantly more severely affected by all clinical scales when compared to patients with FSHD1 with upper-sized FSHD1 alleles (8–10 RU).ConclusionThe overlap between FSHD1 and FSHD2 patients in the 9–10 D4Z4 RU range suggests that FSHD1 and FSHD2 form a disease continuum. The previously established repeat size threshold for FSHD1 (1–10 RU) and FSHD2 (11–20 RU) needs to be reconsidered.Clinicaltrials.gov identifierNCT01970735.

DNA Methylation in the Diagnosis of Monogenic Diseases

“…The pathogenic mechanism is based on overexpression of the retrogene Double Homeobox Protein 4 (DUX4) located on the D4Z4 macrosatellite repeat of the chromosome 4q35 subtelomeric region. DUX4 is toxic at high levels, because it activates germline genes, impairs RNA and protein metabolism, and triggers inflammation, oxidative stress and apoptotic events in muscle tissue [146,147]. In most normal adult tissues, D4Z4 is hypermethylated and DUX4 is turned-off.…”

“…The main features of DNA methylation abnormalities in human monogenic diseases are listed in Table 1. [145][146][147][148][149][150][151][152][153][154] Loss of methylation (LOM); gain of methylation (GOM); uniparental disomy (UPD); full mutation (FM); premutation (PM); methylation-specific (MS); multiplex ligation probe-dependent amplification (MLPA); paternal (Pat); maternal (Mat); Beckwith-Wiedemann syndrome (BWS); Silver-Russell syndrome (SRS); Transient Neonatal Diabetes Mellitus (TNDM); pseudohypoparathyroidism 1b (PHP1b); Multi-Locus Imprinting Disturbances (MLID); Facioscapulohumeral Muscular Dystrophy (FSHD).…”

DUX4 Signalling in the Pathogenesis of Facioscapulohumeral Muscular Dystrophy

“…Asymptomatic mutation carriers with 7-10 D4Z4 units have been described [20]. FSHD2 patients with ≤10 D4Z4 units have also been found [21]. These suggest a more complex interplay of genetic and epigenetic factors in the manifestation of the disease than initially thought, inviting a re-evaluation of the distinction between FSHD1 and FSHD2.…”

Consequences of epigenetic derepression in facioscapulohumeral muscular dystrophy

“…The nature of these factors is currently only partly understood . Families harboring a 7 to 10 unit D4Z4 allele show more clinical variability among family members with apparent identical FSHD genotypes . This includes non‐penetrant disease allele carrying siblings of symptomatic FSHD patients .…”

“…While the median number of D4Z4 units in controls is 33.7 units, in FSHD2 this is significantly lower with a median of 16.8 units . Sacconi et al provided further evidence for the hypothesis that FSHD1 and FSHD2 form a disease continuum . This was based on the analysis of the combined effect of D4Z4 repeat size and SMCHD1 mutation status on the methylation levels at D4Z4 (Diagnostic Region 1 [DR1]) in a group of FSHD patients.…”