EVIDENCE FOR SUBTELOMERIC EXCHANGE OF 3.3 KB TANDEMLY REPEATED UNITS BETWEEN CHROMOSOMES 4Q35 AND 10Q26 - IMPLICATIONS FOR GENETIC-COUNSELING AND ETIOLOGY OF FSHD1

Facioscapulohumeral muscular dystrophy (FSHD) is an autosomal dominant myopathy clinically characterized by asymmetric weakness of muscles i n the face, shoulder girdle and upper arm, Deletion of an integral num ber of 3.3 kb repeated units within a highly polymorphic EcoRI fragmen t at chromosome 4q35, generating a relatively short EcoRI fragment (<3 5 kb), has been shown to cause FSHD1, Probe p13E-11 detects these shor t fragments in FSHD1 patients, and has therefore been used for diagnos tic DNA analysis, However, the reliability of this analysis has been h ampered by cross-hybridization of p13E-11 to chromosome 10q26-linked E coRI fragments of comparable size, which also contain a variable numbe r of 3.3 kb repeated units, Recently, a Blnl restriction site was iden tified within each of the repeated units derived from chromosome 10q26 , which enables differentiation of the two polymorphic p13E-11 loci in most cases without haplotype analysis, Remarkably, applying the diffe rential analysis to screen DNA of 160 Dutch cases referred to us for F SHD1 diagnosis, we obtained evidence for subtelomeric exchange of 3.3 kb repeated units between chromosomes 4q35 and 10q26 in affected and u naffected individuals, Subsequently, analysis of 50 unrelated control samples indicated such exchange between chromosomes 4q35 and 10q26 in at least 20% of the population, These subtelomeric rearrangements have generated a novel interchromosomal polymorphism, which has implicatio ns for the specificity and sensitivity of the differential restriction analysis for diagnostic purposes, Moreover, the high frequency of the interchromosomal exchanges of 3.3 kb repeated units suggests that the y probably do not contain (part of) the FSHD1 gene, and supports posit ion effect variegation as the most likely mechanism for FSHD1.