Mosaic FMR1 deletion causes fragile X syndrome and can lead to molecular misdiagnosis: a case report and review of the literature

Abstract

The most common cause of fragile X syndrome is expansion of a CGG trinucleotide repeat in the 5'UTR of FMR1. This expansion leads to transcriptional silencing of the gene. However, other mutational mechanisms, such as deletions of FMR1, also cause fragile X syndrome. The result is the same for both the expansion mediated silencing and deletion, absence of the gene product, FMRP. We report here on an 11-year-old boy with a cognitive and behavioral profile with features compatible with, but not specific to, fragile X syndrome. A mosaic deletion of 1,013,395 bp was found using high-density X chromosome microarray analysis followed by sequencing of the deletion breakpoints. We review the literature of FMR1 deletions and present this case in the context of other FMR1 deletions having mental retardation that may or may not have the classic fragile X phenotype.

Fig. 1

Photograph of the patient with mosaic deletion of FMR1. He shows some (e.g., prominent jaw, thickening of nasal bridge) but not all (e.g., normal size ears) of the distinctive facial features of fragile X syndrome.

Fig. 2

Clinical laboratory findings by standard fragile X testing. A: PCR amplification of the FMR1 CGG repeat of DNA isolated from the patient and a normal male with 23 CGG repeats. B: Southern analysis of DNA isolated from this patient with atypical fragile X syndrome. Lane 1, normal female; lane 2, the patient being tested; lane 3, normal male; lane 4, male with typical CGG expansion and methylation; lane 5, molecular weight marker.

Fig. 3

High-density X chromosome array analysis of the patient and sequencing of the junction fragment. A: View of entire X chromosome. Arrow indicates deleted region. B: View of X chromosome from coordinates 145,400,000 to 147,800,000. The top track graphs individual probes while the bottom track depicts 15,000 bp windows of average signal. Deleted region can be seen as reduced signal extending from 146,047,696 to 147,061,090.

Fig. 4

Sequence of the junction fragment (bottom portion of panel) and corresponding breakpoints in the Ensembl genome browser (top portion of the panel). The proximal break is 146,047,696 and the distal breakpoint is 147,061,090 resulting in the deletion of 1,013,395 nucleotides. The 4 bp AATG homologous sequence between the two LINE1 elements is indicated by the yellow boxed sequence.