Unique AGG Interruption in the CGG Repeats of the FMR1 Gene Exclusively Found in Asians Linked to a Specific SNP Haplotype

Abstract

Fragile X syndrome (FXS) is the most common inherited intellectual disability. It is caused by the occurrence of more than 200 pure CGG repeats in the FMR1 gene. Normal individuals have 6–54 CGG repeats with two or more stabilizing AGG interruptions occurring once every 9- or 10-CGG-repeat blocks in various populations. However, the unique (CGG)6AGG pattern, designated as 6A, has been exclusively reported in Asians. To examine the genetic background of AGG interruptions in the CGG repeats of the FMR1 gene, we studied 8 SNPs near the CGG repeats in 176 unrelated Thai males with 19–56 CGG repeats. Of these 176 samples, we identified AGG interruption patterns from 95 samples using direct DNA sequencing. We found that the common CGG repeat groups (29, 30, and 36) were associated with 3 common haplotypes, GCGGATAA (Hap A), TTCATCGC (Hap C), and GCCGTTAA (Hap B), respectively. The configurations of 9A9A9, 10A9A9, and 9A9A6A9 were commonly found in chromosomes with 29, 30, and 36 CGG repeats, respectively. Almost all chromosomes with Hap B (22/23) carried at least one 6A pattern, suggesting that the 6A pattern is linked to Hap B and may have originally occurred in the ancestors of Asian populations.

Prenatal Diagnosis of Fragile X: Can a Full Mutation Allele in the FMR1 Gene Contract to a Normal Size?

“…However, it has been found that increased instability seems to be correlated with the presence of the first interruption at the 10th triplet ( Gunter et al, 1998 ) and to the total number of AGGs. The loss of AGGs occurs in a polarized way at the 3′-end, creating a long pure (CGG)n with higher mutability ( Kunst and Warren, 1994 ; Limprasert et al, 2016 ). In the presented case, the allele was a pure stretch of CGG without any AGG interruption.…”

Contraction of fully expanded FMR1 alleles to the normal range: predisposing haplotype or rare events?

“…[11][12][13][14][15][16] The loss of AGGs occurs in a polarized way at the 3′-end, creating a long pure (CGG)n with higher mutability. 17,18 On the other hand, while analyzing the interspersion pattern of the repeat, an increased instability seems to be correlated with the presence of the first interruption at the tenth triplet, as the configuration (CGG)9AGG (CGG)n is frequently observed in large normal alleles. 19 In addition, normal-sized alleles with more than 24 pure CGGs at the 3′-end frequently share the typically studied DXS548-FRAXAC1 FXS haplotype, suggesting that these alleles could be more prone to expand.…”

The role of AGG interruptions in the FMR1 gene stability: A survey in ethnic groups with low and high rate of consanguinity

“…Also Falik-Zaccai et al (1997) showed high prevalence of premutation and full mutation in the Tunisian ethnicity among the Jewish population, likely related to unique founder effect and genetic drift phenomena for accumulation of predisposed alleles in the population. Limprasert et al (2016) showed that specific haplotype were associated with the loss of AGG interruptions. Recently, Sun et al (2018) showed that disease-associated tandem repeats are located to TAD boundaries and affect their insulation.…”

“…It has been demonstrated that, in addition to the CGG repeat number, increased instability correlates with AGG loss (Gunter et al, 1998;Nolin et al, 2015Nolin et al, , 2013Yrigollen et al, 2012Yrigollen et al, , 2014. The loss of AGG repeat occurs at the 3'end, creating a long pure (CGG)n stretch with higher mutability (Kunst & Warren, 1994;Limprasert, Thanakitgosate, Jaruthamsophon, & Sripo, 2016).…”