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Am J Med Genet A. 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.

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Department of Human Genetics, New York State Institute for Basic Research in Developmental Disabilities, Staten Island, New York.
Department of Human Genetics, Emory University School of Medicine, Atlanta, Georgia.
Wessex Regional Genetics Laboratory, Salisbury NHS District Hospital, Salisbury, United Kingdom.
Biochemical and Molecular Genetics, Hospital Clinic de Barcelona, IDIBAPS and CIBERER, Barcelona, Spain.
Department of Genetics and Evolutionary Biology, Institute of Biosciences, Universidade de São Paulo, São Paulo, Brazil.
Asuragen, Inc., Austin, Texas.


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.


FMR1; fragile X; trinucleotide repeat instability

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