Finding FMR1 mosaicism in Fragile X syndrome

Abstract

Objective: Almost all patients with Fragile X Syndrome (FXS) exhibit a CGG repeat expansion (full mutation) in the Fragile Mental Retardation 1 gene (FMR1). Here, the authors report five unrelated males with FXS harboring a somatic full mutation/deletion mosaicism.

Methods: Mutational profiles were only elucidated by using a combination of molecular approaches (CGG-based PCR, Sanger sequencing, MS-MLPA, Southern blot and mPCR).

Results: Four patients exhibited small deletions encompassing the CGG repeats tract and flanking regions, whereas the remaining had a larger deletion comprising at least exon 1 and part of intron 1 of FMR1 gene. The presence of a 2-3 base pairs microhomology in proximal and distal non-recurrent breakpoints without scars supports the involvement of microhomology mediated induced repair (MMBIR) mechanism in three small deletions.

Conclusion: The authors data highlights the importance of using different research methods to elucidate atypical FXS mutational profiles, which are clinically undistinguishable and may have been underestimated.

Keywords: FMR1 gene; Fragile X syndrome; copy number variation; deletion; mosaicism.

Figure 1

Extension of the small FMR1 deletions (5′-3′) described in patients 1629 (1), 1033 (2), 1234 (3) and 1337 (4). Wild type sequence (NG_007529.1) with a (CGG)₁₉ repeat tract; CGG repeat sequences are boxed; 1- Patient 1629; 2- Patient 1033; 3- Patient 1234; 4- Patient 1337; Chi-like sequence (5′ GGTGGAGG 3′) previously reported to be involved in deletions comprising CGG repeats [19] is indicated in bold underlined text; The homologous simple repeat sequence (5′ GGCGGCGGCGG 3′) proposed by Mononen and colleagues [27] to play a role in repeat instability leading to duplications/deletions in FXS is in italicized and underlined.