The FRAXA and FRAXE allele repeat size of boys from the Avon Longitudinal Study of Parents and Children (ALSPAC)

Abstract

The FRAXA and FRAXE alleles of the FMR1 and FMR2 genes located on the X chromosome contain varying numbers of trinucleotide repeats. Large numbers of repeats at FRAXA (full mutations) manifest as Fragile X syndrome, associated with mental impairment that affects males more severely. In this paper, we present the dataset of frequencies of FRAXA and FRAXE repeat size extracted from DNA samples collected from boys enrolled in the Avon Longitudinal Study of Parents and Children (ALSPAC). DNA data were extracted from samples collected in ALSPAC clinics from several types of samples: cord blood, venepuncture blood taken at 43 months, 61 months, seven years or nine years. The DNA was amplified at FRAXA and FRAXE using fluorescent PCR in the Wessex Regional Genetics Laboratory, Salisbury District Hospital. The mean repeat size for FRAXA is 28.92 (S.D. 5.44), the median 30 and the range 8 to 68. There were particularly high numbers of boys with repeat sizes of 20 (10.67%) and 23 (7.35%). The mean repeat size for FRAXE is 17.41 (S.D. 3.94), with median of 16 and range of 0 to 61. There is a relatively high degree of variation of the FRAXA repeat size particularly and we suggest the extensive data available from the ALSPAC study opens up areas of research into understanding phenotypes associated with relatively unexplored repeat sizes. This could be particularly interesting for the lower repeat sizes occurring with high frequency at FRAXA in this population. As the data can be linked to exposures and phenotypes, it will provide a resource for researchers worldwide.

Development and validation in 500 female samples of a TP-PCR assay to identify AFF2 GCC expansions

“…The most common genotype was 15/15 which is expected because the 15 GCC allele is the most common in the European population. Allele distribution is similar to that obtained by Clark et al, with the 15 (n = 692), 18 (n = 84) and 16 (n = 76) GCC alleles being the most common, followed by those with 20 GCC (n = 29) suggesting a bimodal distribution (Table 1 ) 8 . The unique design of the “CGG primer” in the reverse sense, with a 5′ tail and (CGG)5C at its 3′ terminus, enables the annealing anywhere within the GCC tract as well as rs1333167094 “T” SNP overriding leading to primer ligation in a second distal site.…”

“…Alleles with 31–60 GCC repeats are considered intermediate or grey-zone and may vary slightly upon transmission. Alleles with repeats ranging from 61 to 200 GCC repeats are considered unstable and named premutations 7 , 8 . When the repeats expand to over 200 GCC repeats, the so-called full mutation, gene transcription is silenced due to methylation, causing intellectual disability 9 – 11 .…”

WITHDRAWN: Development and validation in 500 female samples of a TP-PCR assay to identify AFF2 GCC expansions

“…The most common genotype was [15;15] which is expected because the 15 GCC allele is the most common in the European population. Allele distribution is similar to that obtained by Clark et al 2019, with the 15, 18 and 16 GCC alleles being the most common, followed by those with 20 GCC suggesting a bimodal distribution (Table 1) 8 . Unlike the presence of AGG interruption(s) in the FMR1 gene repetitive region, no interspersions were observed among the samples tested.…”

“…Alleles with 31 to 60 repeats are considered intermediate or grey-zone and may vary slightly upon transmission. Alleles with repeats ranging from 61 to 200 GCC are considered unstable and named premutations 7,8 . When the repeats expand to over 200 repeats, the so-called full mutation, gene transcription is silenced due to methylation, causing intellectual disability [9][10][11] .…”

Simultaneous Screening of the FRAXA and FRAXE Loci for Rapid Detection of FMR1 CGG and/or AFF2 CCG Repeat Expansions by Triplet-Primed PCR

“…Allele size ranges were wider in Chinese and Malays (6-37) compared to Indians (10-27), Caucasians (9-26) and African Americans (14-28), which could be partially attributed to a larger sample size for Chinese and Malays. Using the conventional categorization 26,27 , 24 samples have minimal alleles (<11 repeats), 440 samples have normal alleles (11 -30 repeats) and the remaining 2 samples have intermediate alleles (31 -60 repeats). No premutation and full mutation alleles were observed.…”