Insert size and flanking haplotype in fragile X and normal populations: possible multiple origins for the fragile X mutation

Macpherson, James; Bullman, H.; Youings, Sheila; Jacobs, Patricia A.

doi:10.1093/hmg/3.3.399

Cited by 73 publications

(89 citation statements)

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“…In agreement with other studies, [21][22][23][24][25][26][27][28][29] A-2 and D-6 were also highly prevalent in our sample (38% of patients), supporting the contention that these two haplotypes are present on ancestral European fragile X founder chromosomes. 28,29 The presence of haplotypes C-2 and C-5 in 16 (38%) fragile X chromosomes, suggests the existence of specific founder mutations in Portuguese patients, since no similar findings have been observed in other populations.…”

Section: Discussionsupporting

confidence: 93%

“…27 However, this seems highly unlikely since we are not aware of reports on a higher incidence of fragile X syndrome in individuals, eg with Lynch syndrome and microsatellite instability due to a DNA mismatch repair deficiency. In conclusion, our results reveal significant differences in allele and haplotype frequencies (FRAXAC1 and DXS548 loci) between fragile X and normal chromosomes in Portugal, confirming the existence of specific fragile X founder chromosomes.…”

Section: Discussionmentioning

confidence: 95%

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Analysis of FMR1 and flanking microsatellite markers in normal and fragile X chromosomes in Portugal: evidence for a “protector” haplotype

et al. 1998

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In order to look for linkage disequilibrium between the fragile X locus and its flanking markers, we analysed the FRAXAC1 and DXS548 microsatellites in normal and fragile X individuals of Portuguese origin. We observed differences in allele and haplotype frequencies between these two samples. Four haplotypes (A-2, C-2, C-5 and D-6) accounted for 76% of all fragile X chromosomes, whereas a single haplotype (C-7) accounted for 70% of the normal population and less than 3% of the fragile X chromosomes. Among the four observed high-risk haplotypes, A-2 and D-6 had been previously reported in other studies, but C-2 and C-5 seem characteristic of Portuguese patients, as suggested by the high frequency (38%) in fragile X chromosomes and virtual absence in controls. In accordance with previous studies, a greater heterozygosity of the fragile X sample was noted when compared to that of controls. The high frequency of C-7 haplotype in the normal population and its virtual absence in the fragile X sample may reflect the existence of linkage disequilibrium between the two loci and/or selective advantage (protector effect) of this haplotype.

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Section: Discussionsupporting

confidence: 93%

Section: Discussionmentioning

confidence: 95%

Analysis of FMR1 and flanking microsatellite markers in normal and fragile X chromosomes in Portugal: evidence for a “protector” haplotype

et al. 1998

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“…PCR amplifications of FRAXAC1 and DXS548 alleles were performed as previously described (Mingroni-Netto et al, 1999). The allele nomenclature followed Macpherson et al (1994).…”

Section: Methodsmentioning

confidence: 99%

Structure and stability upon maternal transmission of common and intermediate FMR1 (Fragile X Mental Retardation 1) alleles in a sample of the Brazilian population

2005

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In order to investigate the stability of the FMR1 (Fragile X Mental Retardation 1) alleles from the normal population, when maternally inherited, we analyzed 75 mother-to-son transmissions. Sixty-eight alleles fell within the common range with 20-40 CGG repeats, and seven alleles were intermediate, with 41-48 repeats. No change was observed either in the length or in the structure of these repeats upon transmission. Fifty-three alleles were ascertained in different families, and their size distribution was similar to those described for European and European-derived populations, with three peaks of frequency: 66% of the alleles with (CGG) 29 , (CGG) 30 or (CGG) 31 , 7.5% with (CGG) 20 , and 5.7% with (CGG) 23 . Regarding the AGG interspersion pattern, 69.8% had two AGG repeats, 20.8% had one, 5.7% had three and 3.8% had none. The most common patterns were 10+9+9 (30.2%), 9+9+9 (18.9%), 10+9 (7.5%), and 10+9+10 (7.5%). About 70% of the alleles with up to 40 repeats were linked to the DXS548/FRAXAC1 haplotype 7-3, the most commonly reported in normal populations. Four out of five intermediate alleles were in linkage with the two haplotypes most frequently associated to the FMR1 full mutation, 2-1 and 6-4. These four alleles showed long uninterrupted CGG repeats at the 3' end. The 9+9+22, 9+9+23 and 9+9+28 alleles were linked to the haplotype 2-1, and the 9+37 allele, to the haplotype 6-4. The pattern of AGG interspersion of these alleles and the associated haplotypes were in accordance with the two main pathways toward mutation previously proposed.

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“…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].…”

Section: Introductionmentioning

confidence: 99%

FMR1 Linked haplotype analysis in a mentally retarded male population

Daneberga¹,

Pronina²,

Lāce

et al. 2011

Open Medicine

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AbstractFragile X syndrome is caused by dynamic mutation of FMR1 gene CpG island CGG repeats. The underlying mutational mechanism is not fully understood. Different microsatellite markers and SNP have previously been reported as markers associated with FMR1 CGG repeat instability. The aim of the present study was to identify specific haplotypes among Latvian FXS patients and the control group with respect to allelic stability. Eleven male FXS patients and 122 control male patients participated in the study. In total, 27 different DXS548-FRAXAC1-ATL1-FRAXAC2 haplotypes were found. The prevalent haplotype in the control group was 7-4-A-5+ (rel. frequency 0.327). The prevalent haplotype associated with the FXS group was 2-2-G-4 (rel. frequency 0.818; p < 0.0001). Grey zone alleles with a long uninterrupted CGG tract at the 3’ end were significantly associated with the 2-2-G-4 haplotype (p = 0.0022). Our findings suggest that, for the Latvian population, the haplotype 2-2-G-4 is a marker of CGG tract instability. We conclude that a founder effect could not be an explanation for our findings on the basis of heterogeneity exhibited by the Latvian population and lack of studies throughout this geographical region. This data may provide evidence of different mutational pathways of expansion in the Baltic States region.

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Insert size and flanking haplotype in fragile X and normal populations: possible multiple origins for the fragile X mutation

Cited by 73 publications

References 0 publications

Analysis of FMR1 and flanking microsatellite markers in normal and fragile X chromosomes in Portugal: evidence for a “protector” haplotype

Analysis of FMR1 and flanking microsatellite markers in normal and fragile X chromosomes in Portugal: evidence for a “protector” haplotype

Structure and stability upon maternal transmission of common and intermediate FMR1 (Fragile X Mental Retardation 1) alleles in a sample of the Brazilian population

FMR1 Linked haplotype analysis in a mentally retarded male population

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