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. 2019 Jul;179(7):1148-1156.
doi: 10.1002/ajmg.a.61165. Epub 2019 May 2.

Expansions and contractions of the FMR1 CGG repeat in 5,508 transmissions of normal, intermediate, and premutation alleles

Sarah L Nolin  1 , Anne Glicksman  1 , Nicole Tortora  1 , Emily Allen  2 , James Macpherson  3 , Montserrat Mila  4 , Angela M Vianna-Morgante  5 , Stephanie L Sherman  2 , Carl Dobkin  1 , Gary J Latham  6 , Andrew G Hadd  6
Affiliations

Expansions and contractions of the FMR1 CGG repeat in 5,508 transmissions of normal, intermediate, and premutation alleles

Sarah L Nolin et al. Am J Med Genet A. 2019 Jul.

Abstract

Instability of the FMR1 repeat, commonly observed in transmissions of premutation alleles (55-200 repeats), is influenced by the size of the repeat, its internal structure and the sex of the transmitting parent. We assessed these three factors in unstable transmissions of 14/3,335 normal (~5 to 44 repeats), 54/293 intermediate (45-54 repeats), and 1561/1,880 premutation alleles. While most unstable transmissions led to expansions, contractions to smaller repeats were observed in all size classes. For normal alleles, instability was more frequent in paternal transmissions and in alleles with long 3' uninterrupted repeat lengths. For premutation alleles, contractions also occurred more often in paternal than maternal transmissions and the frequency of paternal contractions increased linearly with repeat size. All paternal premutation allele contractions were transmitted as premutation alleles, but maternal premutation allele contractions were transmitted as premutation, intermediate, or normal alleles. The eight losses of AGG interruptions in the FMR1 repeat occurred exclusively in contractions of maternal premutation alleles. We propose a refined model of FMR1 repeat progression from normal to premutation size and suggest that most normal alleles without AGG interruptions are derived from contractions of maternal premutation alleles.

Keywords: FMR1; fragile X; trinucleotide repeat instability.

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Conflict of interest statement

Gary Latham is a full‐time employee of Asuragen, Inc. He and Andrew Hadd have stock options in Asurgen, Inc. The other authors declare no competing interests.

Figures

Figure 1
Figure 1
Repeat structure in normal, intermediate, and premutation alleles: presence or absence of AGG interruptions and position of the first AGG triplet within the repeat
Figure 2
Figure 2
Model with two pathways for fragile X repeat expansion. The black arrows represent transmissions from males and the white arrows transmissions from females. The curved white arrows represent loss of AGGs in contractions of maternal premutation alleles. The width of the arrows indicates greater or less instability on transmission
See this image and copyright information in PMC

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