Traditionally, “normal”
D4Z4 alleles were considered those ones having 11-100 repeat units, whereas
those associated with facioscapulohumeral muscular dystrophy (FSHD) were thought to have between one and ten repeat
units. However, because there are individuals with reduced D4Z4 alleles that do
not have clinical signs of FSHD, it had been proposed that the genetic
signature of the disease must result from the combination of:
(1) a reduction in the number of D4Z4 elements
(2) the presence of the 4qA allele
(3) the PAS in the pLAM sequence
However, this model does not apply to all FSHD cases. For example,
nonpenetrant carriers have been reported in FSHD families, and there are FSHD
patients carrying full-length D4Z4 alleles (≥11 repeats) that are clinically
indistinguishable from patients carrying D4Z4 alleles of reduced size (≤8
repeats).
Indeed, Isabella Scionti et al found that 2.7% of cases in the Italian
National Registry for FSHD (which contains over 1,100 unrelated FSHD patients)
were compound heterozygotes carrying two D4Z4-reduced alleles (0.5% were
homozygotes for the 4A161 haplotype). Based on this finding, they estimated
that the population frequency of the 4A161PAS haplotype associated with a
D4Z4-reduced allele could be higher than 1%.
Even more recently Isabella Scionti (2012; PMID: 22482803) analyzed a
large cohort of normal controls and patients and established that the 4APAS
structure is a frequent genetic polymorphism that is neither sufficient nor
necessary for the development of FSHD.
Summarizing, recent evidence seems
to demonstrate that D4Z4/4qA/PAS testing is not
specific enough to assess a genetic diagnosis of FSHD.
