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Front. Genet. | doi: 10.3389/fgene.2018.00150

Detecting AGG Interruptions in Females with a FMR1 Premutation by Long-Read Single-Molecule Sequencing: a One Year Clinical Experience

 Simon Ardui1, Valerie Race1,  Thomy de Ravel1, Hilde Van Esch1, Koenraad Devriendt1, Gert Matthijs1 and Joris R. Vermeesch1*
  • 1Department of Human Genetics, Faculty of Medicine, KU Leuven, Belgium

The fragile X syndrome arises from the FMR1 CGG expansion of a premutation [55-200 repeats] to a full mutation allele [> 200 repeats] and is the most frequent cause of inherited X-linked intellectual disability. The risk for a premutation to expand to a full mutation allele depends on the repeat length and AGG triplets interrupting this repeat. In genetic counseling it is important to have information on both these parameters to provide an accurate risk estimate to women carrying a premutation allele and weighing up having children. For example, in case of a small risk a woman might opt for a natural pregnancy followed up by prenatal diagnosis while she might choose for preimplantation genetic diagnosis if the risk is high. Unfortunately, the detection of AGG interruptions was previously hampered by technical difficulties complicating their use in diagnostics. Therefore we recently developed, validated and implemented a new methodology which uses long-read single-molecule sequencing to identify AGG interruptions in females with a FMR1 premutation. Here we report on the assets of AGG interruption detection by sequencing and the impact of implementing the assay on genetic counseling.

Keywords: AGG interruptions, Fragile X Syndrome, single-molecule real-time sequencing, Fragile X premutation, Genetic Counseling, FMR1, CGG repeat

Received: 07 Feb 2018; Accepted: 10 Apr 2018.

Edited by:

Shai E. Elizur, Sheba Medical Center, Israel

Reviewed by:

Maria P. Lombardi, University of Amsterdam, Netherlands
Sarah L. Nolin, NYS Institute for Basic Research  

Copyright: © 2018 Ardui, Race, de Ravel, Van Esch, Devriendt, Matthijs and Vermeesch. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: Prof. Joris R. Vermeesch, Faculty of Medicine, KU Leuven, Department of Human Genetics, Leuven, 3000, Belgium, joris.vermeesch@kuleuven.be