Analysis of CGG variation through 642 meioses in Fragile X families

Abstract

Fragile X syndrome is the commonest familial form of inherited mental retardation. The molecular defect is an expansion of the CGG trinucleotide repeats in the 5' untranslated region of the FMR1 gene that is inherited in an unstable fashion in fragile X families. In an attempt to provide more information about the CGG tract intergenerational variation, we have evaluated 642 transmissions in 175 Fragile X families. PCR and Southern blot (StB12.3) was used to analyse the CGG number. Among premutated alleles, 90.2% showed expansion, two-thirds to a full mutation while the rest remained in the premutation range, 5.5% of alleles did not vary and finally 4.3% of them reduced in size. Premutated females showed an increased risk of expansion to the full mutation depending on the CGG tract. The estimated risk for 80 triplets is more than seven times that of a woman carrying 59 CGG, the risk being 100% for alleles of >100 repeats. Fifty-nine repeats was the smallest allele that expanded to full mutation. Contractions were detected more frequently in males than in females, being statistically significant. This study contributes to the literature by increasing the data available regarding transmissions in Fragile X families and it allows us to perform more precise genetic counselling for women with the CGG repeat in the premutation range.

ACMG Standards and Guidelines for fragile X testing: a revision to the disease-specific supplements to the Standards and Guidelines for Clinical Genetics Laboratories of the American College of Medical Genetics and Genomics

“…An extremely rare phenomenon involves unaffected males with premutations who have had affected daughters, apparently by gonadal mosaicism for full mutations. [97][98][99] The sons of men with premutations are not at risk for developing the fragile X syndrome or FXTAS. FX 3.3.5.5: To date, there have been no reports of male or female carriers of intermediate alleles having offspring with an FMR1 allele in the full mutation range.…”

FMR1 Linked haplotype analysis in a mentally retarded male population

“…Intermediate or grey zone alleles are poorly defined. Boundaries for the grey zone range vary among studies, from 34 or 35 CGG repeats for the lower boundary to 58/60 repeats for the upper boundary [7][8][9][10]. These alleles are often transmitted stably, but are more likely to exhibit unstable transmission with increasing size within this range.…”

“…The gender of the parent carrying an expanded repeat (maternal imprinting), the number of repeats (dynamic mutation) and the absence of AGG interruptions in long tracts of CGG repeats have been described as the main factors related to this instability [5,9,11]. The microsatellite markers DXS548-FRAXAC1-FRAXAC2 and the ATL1 SNP have previously been reported as markers associated with FMR1 CGG repeat instability [5,[12][13][14][15][16][17].…”

Genes involved in human premature ovarian failure

“…Repeats between 55 and 79 may, on one hand, lead to an increased production of fragile X mental retardation protein (FMRP), an RNA-binding protein regulating the translation of a subset of mRNAs through a suppression mechanism (Jin & Warren 2000). Since FMRP is highly expressed in germ cells of the fetal ovary (Rifé et al 2004), the accumulation of FMRP may impair the expression of genes required for oocyte development. Longer repeats may instead be translated less efficiently.…”