Germline mosaicism in 4q35 facioscapulohumeral muscular dystrophy (FSHD1A) occurring predominantly in oogenesis

Abstract

Facioscapulohumeral muscular dystrophy (FSHD) is an autosomal dominantly inherited neuromuscular disorder affecting facial and shoulder girdle muscles with subsequent progression to the pelvic girdle and lower extremities. The major gene involved has been localized to chromosome 4q35 (FSHD1A). The 4q35 DNA marker p13E-11 (D4F104S1) detects a de novo EcoRI DNA rearrangement of < 30 kb in isolated and familial cases. The intrafamilial size of the fragment is constant, inversely correlated with the severity, and directly correlated with the age of onset of the condition. There has been evidence of parental mosaicism in FSHD1A for the D4F104S1 locus. Four female and three male clinically unaffected parents have been described to be carriers of EcoRI fragments of the same size as their affected offspring, but with a markedly less intensive hybridization signal (semi-quantitative evidence). In our total sample of 42 FSHD1A families, we found semi-quantitative evidence of parental D4F104S1 mosaicism in 11 families (EcoRI fragment size range: 12-27 kb). On analysis with adjacent 4q35 probes (D4S163, D4S139), additional qualitative evidence of germline mosaicism could be obtained in two families. In our mosaic families and in the families reported in the literature, a female predominance of mosaicism carriers (13 females versus 5 males) could be noted. In our sample, mosaicism was observed in multigeneration families, in families with isolated cases, and in families with two and three affected children from seemingly unaffected parents. A short EcoRI fragment once having emerged in a mosaicism carrier was found to be transmitted autosomal dominantly to subsequent generations. Of all reported sporadic patients, 19% have a mosaic parent. Finding evidence of parental mosaicism in all our families with more than one affected child of seemingly unaffected parents suggests that there is no autosomal recessively inherited form of FSHD1A.

Somatic mosaicism in FSHD often goes undetected

“…14,17 Because some individuals are mosaic for the disease allele in blood, germline, 14,16 and skin (unpublished results, R.J.F.L., G.W.P., R.R.F., S.V.D.M. ), mitotic D4Z4 rearrangements probably occur in early embryogenesis.…”

“…As a consequence, a combination of the residual repeat length and the fraction of peripheral blood lymphocytes (PBLs) carrying the disease allele were found to contribute to the clinical severity. 14,16,17 Considerable differences (12-40%) in the proportion of mitotic rearrangements among new FSHD mu-tations have been reported. [12][13][14][15][16][17] Remarkably, in previous studies, somatic mosaicism was almost exclusively detected in asymptomatic carriers.…”

Comparative multiplex dosage analysis detects whole exon deletions at the phenylalanine hydroxylase locus

“…Germinal and somatic mosaicism are reported most often in relation to autosomal-dominant or X-linked recessive disorders [Cohn et al, 1990;Fabrizi et al, 2001;Kohler et al, 1996;van Essen et al, 1992]. Its occurrence in an autosomal recessive disorder is unusual and at the PAH locus, in particular, is novel .…”

Equal proportions of affected cells in muscle and blood of a mosaic carrier of facioscapulohumeral muscular dystrophy

“…A relationship has been established between the severity of the disease and the percentage of peripheral blood lymphocytes (PBL) carrying the FSHD allele in combination with the residual repeat size . It has been reported, by these researchers and others, (Kohler et al 1996;Upadhyaya et al 1995;Zatz et al 1998) that a significant proportion of FSHD mosaic carriers are asymptomatic. However, it is not known if this occurs because the mosaicism is unequally distributed between different tissues and that in some cases, muscle is relatively spared for the presence of the disease allele or due to a mechanism that has not been identified yet.…”

“…De novo mutations are reported in 10-30% of FSHD cases Zatz et al 1995) and somatic, as well as germline mosaicism, has been described both in patients and in asymptomatic parents (Galluzzi et al 1999;Kohler et al 1996Kohler et al , 1998Upadhyaya et al 1995;. Mitotic contractions of D4Z4 resulting in somatic mosaicism for the disease allele are observed in almost 50% of the families with de novo FSHD.…”