Facioscapulohumeral muscular dystrophy: new insights from compound heterozygotes and implication for prenatal genetic counselling

Abstract

Background Facioscapulohumeral muscular dystrophy (FSHD) is considered an autosomal dominant disease with a prevalence of 1 in 20 000. Almost all patients with FSHD carry deletions of integral copies of tandem 3.3 kb repeats (D4Z4) located on chromosome 4q35. However, FSHD families have been reported in which individuals carrying a D4Z4-reduced allele remain asymptomatic. Recently, it has been proposed that the D4Z4-reduced allele is pathogenic only in association with the permissive haplotype, 4APAS. Methods and results Through the Italian National Registry for FSHD (INRF), genotype-phenotype correlations were extensively studied in 11 non-consanguineous families in which two D4Z4-reduced alleles segregate. Overall, 68 subjects carrying D4Z4-reduced alleles were examined, including 15 compound heterozygotes. It was found that in four families the only FSHD-affected subject was the compound heterozygote for the D4Z4-reduced allele, and 52.6% of subjects carrying a single D4Z4-reduced 4A161PAS haplotype were non-penetrant carriers; moreover, the population frequency of the 4A161PAS haplotype associated with a D4Z4-reduced allele was found to be as high as 1.2%. Conclusions This study reveals a high frequency of compound heterozygotes in the Italian population and the presence of D4Z4-reduced alleles with the 4A161PAS pathogenic haplotype in the majority of non-penetrant subjects in FSHD families with compound heterozygosity. These data suggest that carriers of FSHD-sized alleles with 4A161PAS haplotype are more common in the general population than expected on the basis of FSHD prevalence. These findings challenge the notion that FSHD is a fully penetrant autosomal dominant disorder uniquely associated with the 4A161PAS haplotype, with relevant repercussions for genetic counselling and prenatal diagnosis.

Diagnostic approach for FSHD revisited: SMCHD1 mutations cause FSHD2 and act as modifiers of disease severity in FSHD1

“…In Italy, a frequency of 1.2% was observed for the permissive FSHD allele associated with a D4Z4 contraction in the general population. 45 For FSHD2, 19% of patients showing all three disease criteria were not affected. 23 Another aspect is the known clinical variability even within the families that was already observed by the first describers of the disease, Landouzy and Dejerine in 1886.…”

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

“…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. Remarkably, these studies established as a general rule rather than an exception that detection of a D4Z4 reduced allele is not sufficient to predict FSHD (Scionti et al, 2012a;Scionti et al, 2012b). Over the years, the molecular etiology of FSHD has remained enigmatic, and the literature is filled with claims of causes that fail to be confirmed by other groups.…”

“…First a study conducted on 750 unrelated FSHD families from Italy revealed that the frequency of individuals carrying two D4Z4 reduced alleles (compound heterozygotes) is 2,7%, a frequency much higher than expected for a fully penetrant autosomal dominant disorder with prevalence of 1 in 20,000. Interestingly in these families with compound heterozygosity, 25% of relatives carrying D4Z4-reduced alleles and 4A161PAS are healthy (Scionti et al, 2012a). Second, characterization of 253 unrelated FSHD probands from the Italian National Registry for FSHD showed that only 127 of them (50.1%) carry D4Z4 alleles with 1-8 D4Z4 associated with 4A161PAS, whereas the remaining FSHD probands carry different haplotypes or alleles with greater number of D4Z4 repeats (Scionti et al, 2012b).…”

Facioscapulohumeral Muscular Dystrophy As a Model for Epigenetic Regulation and Disease

“…While there is no linear relationship, there is an imperfect correlation among the extremes of pathogenic sized arrays, as FSHD1 subjects with 1-3 repeat units tend to be clinically severe cases while subjects with 8-10 repeats often present with milder symptoms or can be asymptomatic (104,127,148,160,170). In addition, the current accepted genetic requirements for FSHD are present in *1-3% of the general population, typical of a common genetic variant and two orders of magnitude higher than the reported incidence of FSHD, highlighting that these genetic conditions are merely disease permissive (128,140).…”