Ethnic effect on FMR1 carrier rate and AGG repeat interruptions among Ashkenazi women

Abstract

introductionFragile X syndrome (FXS; OMIM 300624) is the most common form of inherited mental impairment, with a prevalence of approximately 1/4,500 in males. The syndrome is characterized by moderate intellectual disability and behavioral abnormalities, including autistic-like behavior.1,2 The vast majority of FXS cases are caused by an expansion of CGG nucleic-base repeats in the Fragile X mental retardation gene (FMR1). Normal individuals usually have ~30 CGG repeats. An expansion to greater than 200 repeats is associated with abnormal methylation and suppression of FMR1 transcription, causing the absence of the gene product, the FMR protein. 3 The lack of FMR protein, an RNA-binding protein, is responsible for the syndrome. 4 There are four allelic forms of the FMR1 gene with respect to the repeat length. The normal allele form has approximately 5-44 CGG repeats and it is stable on transmission. In these normal alleles, the CGG repeat region is usually interrupted by AGG triplets after every 9 or 10 CGG repeats. These AGG interruptions are believed to maintain repeat integrity by preventing DNA slippage during replication, therefore increasing the repeats' stability.5 The full-mutation allele form has more than 200 repeats, with several hundred to several thousand repeats being typical. In between those two forms fall the intermediate allele form and the premutation allele form. The intermediate allele form falls between the normal and premutation size ranges (45-54 repeats). A proportion of these alleles are unstable and may expand by a few repeats during meiosis. In this range, expansion to the full-mutation allele may occur over two or more generations but not in a single transmission. 6 The premutation allele form is about 55-200 repeats long. It is unstable and commonly expands during transmission. Individuals with the premutations are defined as carriers of the disease. Expansion of an abnormal allele usually occurs when it is transmitted from the mother but not from the father. 7 However, although alleles of 55-59 repeats are defined as premutations, only a very few cases of expansion to a full mutation have actually been reported, emphasizing the fact that such allele sizes are generally stable. 8In general, the risk of expansion of a premutation to a full mutation upon transmission to the offspring is associated with three factors. First, it correlates with the number of CGG repeats.9 Second, the number of AGG interruptions also affects stability on transmission, such that alleles with a high number of CGG repeats that lack AGG interruptions are more prone to expansion. 5,10 A third factor affecting risk of transmission is the genetic background because some haplotypes are associated with an increased instability as compared with others. Purpose: Fragile X syndrome, a common cause of intellectual disability, is usually caused by CGG trinucleotide expansion in the FMR1 gene. CGG repeat size correlates with expansion risk. Premutation alleles (55-200 repeats) may expand to full mutations in female mei...

Genetic analysis of FMR1 repeat expansion in essential tremor

“…A subset of the sample in our study is AJ. A recent study that evaluated 4,344 AJ and 4,985 non-AJ subjects reported a higher rate of premutations in the 55–59 repeat range (1:114 vs. 1:277) among the AJ women and concluded that AJ women have a high fragile X syndrome carrier rate and mostly low-range premutations [11]. In the AJ ET cases (including AJ ET females) and non-AJ ET cases that we analyzed in the current study we did not observe a higher proportion of premutations.…”

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

“…Also, there was insufficient funding to measure potential variation in the repeat structure within different race/ethnic groups, such as AGG interruptions, which would have been informative given the reported differences in AGG interruption patterns across 9 countries 35 and ethnicity. 11 The primary strength of this study is the ability to examine race-ethnic genetic differences within a single study due to the SWAN recruitment design. Additional study strengths include the known normal fertility history, the large cohort size, and the community-based sample (so that founder effects are not influencing the distributions).…”

“…12 Five of these articles reported separate results for females. [9][10][11]16,19 Nine of the 10 studies that included females reported the total allelic distribution, 9,11,[15][16][17][18][19][20][21] and none of those publications reported the FMR1 distribution of the higher allele separate from the lower allele. The recent article by Voorhuis et al 10 did report separate results for the higher and lower alleles among females from the general population, but their population included women with early menopause at ages 40 to 45 and infertility.…”

Association between the FMR1 CGG repeat lengths and the severity of idiopathic primary ovarian insufficiency: a meta analysis

“…One of the important limitations of this study concerns the lack of analyses stratified by other related susceptible factors, such as race and ethnicity have not been conducted in the present study because insufficient data were available from the primary studies. Race/ethnic differences in the FMR1 CGG repeat distribution have been reported [37][38][39]. However, the results from individual studies were inconsistent.…”