Prenatal diagnosis of fragile X syndrome: Small meiotic recombination events at the FMR1 locus

• Published in: Prenatal diagnosis Vol. 39; no. 5; pp. 388 - 393
• Main Authors: Bacrot, Séverine, Monnot, Sophie, Haddad, Georges, Barcia, Giulia, Rachid, Myriam, Boisson, Marie, Pasquier, Nathalie, Rondeau, Sophie, Munnich, Arnold, Steffann, Julie, Bonnefont, Jean‐Paul, Raynaud, Martine
• Format: Journal Article
• Language: English
• Published: England Wiley Subscription Services, Inc 01.04.2019
• Subjects: Adult; Algorithms; Alleles; Coexistence; Crossovers; Diagnosis; Female; Fetuses; FMR1 protein; Fragile X Mental Retardation Protein - genetics; Fragile X syndrome; Fragile X Syndrome - diagnosis; Genetic counseling; Genetic screening; Haplotypes; Humans; Intellectual disabilities; Loci; Medical diagnosis; Meiosis; Mutation; Pregnancy; Prenatal Diagnosis; Recombination; Sizing; Stability; Yeast
• ISSN: 0197-3851; 1097-0223
• DOI: 10.1002/pd.5439

What's already known about this topic? Fragile X syndrome is caused by an expansion of more than 200 CGG repeats in the FMR1 gene. CGG repeat instability expresses almost constantly as an expansion. Significant contraction events have occasionally been reported. What does this study add? This study presents an exceptional situation, where maternal transmission of an FMR1‐expanded allele ultimately results in the presence of a normal‐sized allele in the fetus. We report here two prenatal cases of non‐crossover event at the FMR1 locus. We offer an algorithm to be used in the context of fragile X syndrome prenatal diagnosis. Objective Fragile X syndrome (FXS), the most commonly inherited cause of intellectual disability, is caused by an expansion over 200 CGG repeats (full mutation) in the FMR1 gene. Intergenerational instability of an expanded FMR1 allele is linked to the carrier's gender (female), the CGG repeat size, and the number of AGG interspersions within the CGG repeat, making genetic counseling a complex task. The objective of our work was to emphasize the importance of combining haplotype analysis with FMR1‐linked markers and CGG repeat sizing for prenatal diagnosis (PND) of FXS. Methods Two PNDs of FXS were performed using haplotype analysis and sizing of the FMR1 allele. Results We detected two cases of meiotic recombination at the FMR1 locus, ie, reciprocal double crossover or non‐crossover, resulting in coexistence of the mutant maternal haplotype and the normal‐sized maternal CGG repeat. Conclusion These rare and unexpected cases (1/120 frequency in our experience) have to be kept in mind in PND of FXS since they prohibit using polymorphic marker haplotyping as the only tool to predict the fetus status.