FMR2 gene deletion as a cause of non-specific mental retardation and autistic behavior in two brothers

Background: Silencing of the Fragile X Mental Retardation 2 gene (FMR2, Xq28) as a consequence of CCG trinucleotide repeat expansion located upstream of the gene is the cause of non-specific X-linked mental retardation (MRX) in 1/50.000 newborn males. This condition, also known as FRAXE, represents a mild to borderline form of mental retardation (MR) associated with communication deficits, attention problems, hyperactivity, and autistic behavior. Little is known about FMR2 deletions as potential cause of FRAXE in the absence of trinucleotide expansion. Several reports on large deletions including FMR1, FMR2 and other adjacent genes exist. However, reports on alterations affecting only FMR2 are to our knowledge limited to descriptions of a balanced translocation having the breakpoint within the FMR2 gene and two submicroscopic deletions which originally led to the cloning of the FMR2 gene.

Case report: The patients are two brothers, 10 and 11 years old at time of referral. Pregnancy, delivery and neonatal history were normal in both cases. The boys became symptomatic in their second year of life with delayed language development and increasing behavioral problems (e.g. aggression, agitation and ADHD like symptoms). In addition, autistic features like hand flapping, restricted interests, repetitive behavior, and impaired social interaction and communication became obvious with increasing age. The clinical assessment indicated mild mental retardation in both boys. However, performance of IQ tests was impossible due to the severe behavioral disorder. No obvious dysmorphic features were noticed. The history was free from seizures.

Genetic testing: Following inconclusive results from our standardized laboratory, metabolic and genetic workup for patients with MR an array comparative genomic hybridization (aCGH) was performed. This method revealed a deletion of 121 to 145 kb within the FMR2 gene in our patients. The mother does not show clinical signs and was identified as a carrier of the deletion. An unaffected elder brother does not carry the deletion.

Conclusion: The prevalence of FMR2 alterations other than CCG trinucleotide repeat expansion causative for FRAXE is largely unknown. However, results from our patients demonstrate that FMR2 deletions may contribute to the FRAXE phenotype. Screening for FMR2 deletions therefore may be helpful to unveil the genetic cause of CCG expansion blank non-specific MRX.