Asymptomatic carriers and gender differences in facioscapulohumeral muscular dystrophy (FSHD)

Facioscapulohumeral Muscular Dystrophy: From Clinical Data to Molecular Genetics and Return

“…Through the years the threshold size of D4Z4 alleles has been increased from the original 28 kb (6 D4Z4 repeats) (Wimenga et al, 1999b) to 35 kb (8 D4Z4 repeats) ( Van Deutekom et al, 2003), with FSHD cases carrying D4Z4 alleles of 38-41 kb (9-11 D4Z4 repeats) considered borderline alleles (Butz et al, 2003;Vitelli et al, 1999). A further analysis of genotype-phenotype correlation led in time to the identification of subjects carrying D4Z4 reduced alleles with no sign of muscle weakness in FSHD families (Ricci et al, 1999;Tonini et al, 2004) as well as in normal controls Weiffenbach et al, 1992). The genotype-phenotype correlation conducted more recently on a large scale using a standardized method of evaluation allowed to estimate that 1) 20% of FSHD patients carry full-length D4Z4 alleles, 2) over 25% of relatives carrying D4Z4 reduced alleles do not have FSHD, 3) 3% of healthy subjects from the general population carry D4Z4 reduced alleles 4) no specific 4q haplotype is uniquely associated with FSHD.…”

“…In his work, Ricci et al detected D4Z4 reduced alleles in several unaffected family members, named nonpenetrant carriers, who are capable of transmitting the disease to their offspring. In addition reduced penetrance for D4Z4 reduced alleles was described in families in which patients heterozygous for FSHD alleles on both 4q chromosomes were present (Wohlgemuth et al, 2003;Tonini et al, 2004). Gender differences have been also described in FSHD, with males apparently more affected than females (Tonini et al, 2004).…”

“…In addition reduced penetrance for D4Z4 reduced alleles was described in families in which patients heterozygous for FSHD alleles on both 4q chromosomes were present (Wohlgemuth et al, 2003;Tonini et al, 2004). Gender differences have been also described in FSHD, with males apparently more affected than females (Tonini et al, 2004). Nowadays correlation between penetrance of FSHD, length of the repeat array, age and sex is unsettled.…”

MRI of Lower Limb Muscle in Patients with 4q35-linked Facio-Scapulo-Limb, Type 2 (the Same as a Facioscapuloperoneal or a FSHD1) Autosomal Dominant Muscular Dystrophy

“…As well, the significant correlation between MRC scores and degree of MRI involvement of the tibialis anterior muscles was revealed in 7 FSHD patients by Kan et al [14]. In last decade there are many articles in which was not found the significant correlation between DNA fragment size and phenotype, age of onset and the severity of the disease [19][20][21][22][23][24][25]. On Padberg's opinion "… since age of onset and severity of the disease roughly relates to the size of the deletion…" [26].…”

Double SMCHD1 variants in FSHD2: the synergistic effect of two SMCHD1 variants on D4Z4 hypomethylation and disease penetrance in FSHD2

“…21 Furthermore, variability in clinical representation is a hallmark of FSHD, which is seen both within and between families, and more often in females than in males. [30][31][32] Some, but not all, of this variability can be explained by the size of the permissive D4Z4 repeat and presence and type of an SMCHD1 variant. 21 Both variants in this family are ORF-preserving variants, which have in general a more profound effect on D4Z4 methylation level than ORF-disrupting variants.…”