Distribution of AGG interruption patterns within nine world populations

Abstract

The CGG trinucleotide repeat within the FMR1 gene is associated with multiple clinical disorders, including fragile X-associated tremor/ataxia syndrome, fragile X-associated primary ovarian insufficiency, and fragile X syndrome. Differences in the distribution and prevalence of CGG repeat length and of AGG interruption patterns have been reported among different populations and ethnicities. In this study we characterized the AGG interruption patterns within 3,065 normal CGG repeat alleles from nine world populations including Australia, Chile, United Arab Emirates, Guatemala, Indonesia, Italy, Mexico, Spain, and United States. Additionally, we compared these populations with those previously reported, and summarized the similarities and differences. We observed significant differences in AGG interruption patterns. Frequencies of longer alleles, longer uninterrupted CGG repeat segments and alleles with greater than 2 AGG interruptions varied between cohorts. The prevalence of fragile X syndrome and FMR1 associated disorders in various populations is thought to be affected by the total length of the CGG repeat and may also be influenced by the AGG distribution pattern. Thus, the results of this study may be important in considering the risk of fragile X-related conditions in various populations

FMRI CGG Repeats:Reference Levels and Race-Ethnic Variation in Women With Normal Fertility (Study of Women’s Health Across the Nation)

“…In the past 10 years, reports have suggested that 35 to 44 CGG, 4,5 35 to 54 CGG, 6 and <28 CGG repeat lengths 7 may be associated with early ovarian aging. It has recently been reported that women who have both alleles with fewer than 23 repeats have an increased odds of having a child with a disability.…”

Mutational mechanism for DAB1 (ATTTC) n insertion in SCA37: ATTTT repeat lengthening and nucleotide substitution

“…In some diseases, as SCA1 (MIM# 164400), SCA2 (MIM# 183090), fragile-X syndrome (MIM# 300624), myotonic dystrophy type 2 (DM2; MIM# 602668), and Friedrich ataxia (FRDA; MIM# 229300), nonpathogenic alleles are more likely to be interrupted than expanded alleles, whereas in SCA8 (MIM# 608768), SCA10 (MIM# 603516), and DM1 (MIM# 160900) interruptions are more expected in expanded alleles (Braida et al, 2010;Chung et al, 1993;Hu et al, 2017;Imbert et al, 1996;Landrian et al, 2017;Liquori et al, 2003;Maia et al, 2017;Martins et al, 2005;Menon et al, 2013;Montermini et al, 1997;Moseley et al, 2000;Musova et al, 2009;Ramos et al, 2010;Yrigollen et al, 2014;Zuhlke et al, 2002). Depending on the gene, interruptions in the repetitive tract may be randomly positioned, as in ATXN2, ATXN8OS, and ATXN10, or follow a pattern (Chung et al, 1993;Landrian et al, 2017;Yrigollen et al, 2014). In FMR1, AGG interruptions are usually located every nine or 10 CGGs, whereas in ATXN1 interrupted alleles have one to three CAT interruptions in the middle of the allele intercalated with one CAG, following a configuration from (CAG) n CAT (CAG) n to (CAG) n CAT CAG CAT CAG CAT (CAG) n (Chung et al, 1993;Yrigollen et al, 2014).…”

“…Depending on the gene, interruptions in the repetitive tract may be randomly positioned, as in ATXN2, ATXN8OS, and ATXN10, or follow a pattern (Chung et al, 1993;Landrian et al, 2017;Yrigollen et al, 2014). In FMR1, AGG interruptions are usually located every nine or 10 CGGs, whereas in ATXN1 interrupted alleles have one to three CAT interruptions in the middle of the allele intercalated with one CAG, following a configuration from (CAG) n CAT (CAG) n to (CAG) n CAT CAG CAT CAG CAT (CAG) n (Chung et al, 1993;Yrigollen et al, 2014). Repeat interruptions in nonpathogenic alleles stabilize the repeat tract (Choudhry, Mukerji, Srivastava, Jain, & Brahmachari, 2001;Chung et al, 1993;Yrigollen et al, 2012); in expanded alleles at specific loci interruptions may decrease penetrance or delay age-of-onset, as in SCA1 and DM1 (Botta et al, 2017;Matsuyama, Izumi, Kameyama, Kawakami, & Nakamura, 1999;Menon et al, 2013;Zuhlke et al, 2002).…”

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

“…FMR1 contains a 5′ noncoding CGG repeat region that may expand beyond the normal range and cause fragile X syndrome (FXS) if fully mutated (4200 CGGs) or other fraxopathies (fragile X tremor/ataxia syndrome, FXTAS and fragile X premature ovarian failure, FXPOF) if in the premutation range (55oCGGso200). Full mutations are generally methylated in the promoter region, with the consequent transcriptional silencing and absence of FMRP translation.1 On the basis of repeat size and instability, FMR1 alleles can be designated as normal (stable 5-44 CGGs), intermediate (slightly unstable 45-54 CGGs) and premutated (very unstable 55-200 CGGs, with the risk of expansion to full mutation dependent on the progenitor gender and allele size).2-4 A complex mechanism involving multiple steps seems to be on the origin of de novo FMR1 expansions, reason why this has been under debate for the last decades.5-8 Cis-acting factors such as AGG interspersions in the CGG repeat region are, however, well known important stability elements.9-12 Normal alleles have AGG interruptions usually after every 9 or 10 CGG triplets, 13 whereas in other allele classes, the number of AGGs tends to be progressively lower as the repeat size increases. In approximately 50% of premutated alleles, an AGG interruption is observed, reducing the risk of expansion upon maternal transmission, particularly in alleles with less than 100 CGGs.…”

“…In approximately 50% of premutated alleles, an AGG interruption is observed, reducing the risk of expansion upon maternal transmission, particularly in alleles with less than 100 CGGs. [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.…”