Premutation for the Martin-Bell syndrome analyzed in a large pedigree segregating also for G6PD-deficiency. I: A working hypothesis on the nature of the FRAX-mutations.

A large Sardinian family including 13 Martin-Bell syndrome (MBS) patients, several instances of normal transmitting males or females, and the G6PD-Mediterranean mutant segregating in some of its branches, has been thoroughly investigated with the hope of gaining further insight on the nature of the FRAX-mutation. All the MBS patients and the 15 obligate heterozygous women present in the pedigree could be traced back through their X-chromosome lineage to the same ancestress, who must have been heterozygous for a silent premutation at the FRAX-locus. This premutation appears to have turned into a true FRAX-mutation at least 9 times during the gametogenesis of the ancestress' X-related descendants of whom four are males. This finding alone suggests that the transition from the FRAX premutation to the true mutation can be the result of intra- as well as interchromosomal events. This conclusion is supported by the additional observation that the genetic phase between the FRAX and the G6PD loci remained unaltered when the transition occurred in a repulsion double heterozygote for the premutation and the G6PD-Mediterranean mutant. The data described are compatible with the hypothesis that MBS patients and normal transmitting males are, respectively, hemizygous for deletion or duplication products generated by aberrant recombination events at a highly recombinogenic site of the region Xq27-Xqter. The overall message stemming from this report is that no firm conclusion can be drawn on the genetic linkage between the FRAX-locus and other markers of this region until the nature of the FRAX-mutations and the mechanism of their occurrence are fully understood.