No mental retardation in a man with 40% abnormal methylation at the FMR-1 locus and transmission of sperm cell mutations as premutations.
We report the case of a mentally normal male carrier of a fragile X full mutation with a 'methylation mosaic' hybridization pattern, who carried premutation-size mutations in his sperm cells and transmitted one of them to a daughter. Clinical evaluation of the father revealed a phenotype resembling that of the fragile X syndrome but without mental impairment and 4% fragile sites on cytogenetic analysis. Direct FRAXA genotyping revealed 40% abnormal methylation at the classical EagI FMR-1 restriction site, a delta of 400 bp to 1400 bp associated, in the non-methylated region, to a widely spread smear. This is thus a rare occurrence of a male carrier of a fragile X full mutation with significant methylation of the EagI site and no mental impairment. A premutation of 400 bp was detected in his daughter's leukocytes and analysis of sperm cells from the father revealed a normal spermogram and only 400 bp premutations. This is the first documented case of transmission (with analysis of sperm DNA) of a fragile X mutation from a male carrier of a full fragile X mutation to a girl. This may be due to the early setting apart of progenitor germ cells in males having inherited a premutation from their mother. It is more likely that there could be a strong selection process favouring those cells with a reverted full mutation which produced a small and unmethylated FMR-1 CpG island allowing for re-expression of the FMR-1 gene, especially in male germ cells.
Unité de Recherche en Génétique Humaine et Moléculaire, Hôpital St-François-d'Assise, Québec, Canada.
F
F
Rousseau
L J
LJ
Robb
P
P
Rouillard
V M
VM
Der Kaloustian
D000328:Adult; D002648:Child; D004247:DNA / Q000235:genetics* / Q000378:metabolism; D005260:Female; D051860:Fragile X Messenger Ribonucleoprotein 1; D005600:Fragile X Syndrome / Q000235:genetics*; D006580:Genetic Carrier Screening; D006801:Humans; D008607:Intellectual Disability / Q000235:genetics*; D007962:Leukocytes / Q000378:metabolism; D008297:Male; D008745:Methylation; D009419:Nerve Tissue Proteins / Q000235:genetics*; D010375:Pedigree; D010641:Phenotype; D016601:RNA-Binding Proteins / Q000235:genetics; D013094:Spermatozoa / Q000502:physiology*
D004247:DNA; D051860:Fragile X Messenger Ribonucleoprotein 1; D009419:Nerve Tissue Proteins; D016601:RNA-Binding Proteins; C497683:FMR1 protein, human