Transmission of the FRAXA haplotype from three nonpenetrant brothers to their affected grandsons: An update with AGG interspersion analysis

Recently, we reported on a family showing transmission of the FRAXA gene by three nonpenetrant, normally intelligent, full and half brothers to their affected grandsons [Kirkilionis et al., 1992]. We have reanalyzed this family for CGG repeat size by polymerase chain reaction (PCR) amplification/Southern blot and FMR1 methylation status using EcoRI/BssHII double digests with pE5‐1 as the hybridization probe. The half brother was found to have a premutation allele size of 59 CGG repeats. MnlI digestion of PCR products showed the absence of intervening AGG sequences. All of his obligate carrier daughters had CGG alleles ranging from 65 to 90 repeats, with a final expansion of more than 200 repeats in his FRAXA‐affected grandson and 131 repeats in his carrier granddaughter. Two full brothers were shown to have inherited a 47‐CGG repeat premutation allele. Analysis of one brother showed that he stably transmitted the 47‐repeat allele to his daughter. Analysis of the second brother, his daughter, and his granddaughter showed that this allele was meiotically unstable, with the allele size increasing from 47, to 48, to 49 from the father, to the daughter to the granddaughter, respectively. MnlI digestion and DNA sequencing of PCR products showed the absence of intervening AGG sequences. This is the first case in which the lack of AGG interspersions has been associated with instability of a gray zone allele resulting in a one‐repeat increase in two successive generations. Am. J. Med. Genet. 75:28–34, 1998. © 1998 Wiley‐Liss, Inc.