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Fragile X syndrome with FMR1 and FMR2 deletion
S J Moore1, L Strain, G F Cole
1Department of Medical Genetics, Aberdeen Royal Hospitals Trust, Foresterhill, UK.
Insights
A rare deletion of FMR1 and FMR2 genes caused severe developmental delay and epilepsy in a young boy. This finding highlights the importance of genetic testing for fragile X syndrome when standard tests fail.
Area of Science:
- Genetics
- Neurodevelopmental Disorders
- Molecular Biology
Background:
- Fragile X syndrome (FXS) is typically caused by triplet repeat expansions in the FMR1 gene.
- Genetic deletions involving FMR1 and adjacent genes can lead to distinct phenotypes.
Observation:
- A 13-year-old boy presented with severe developmental delay, epilepsy, autistic features, epicanthic folds, and joint hypermobility.
- This patient had a de novo deletion encompassing both FMR1 and FMR2 genes, the smallest reported to date.
- Initial diagnostic tests, including cytogenetics and standard FMR1 molecular tests, were inconclusive.
Findings:
- Comparison with three other reported cases of FMR1 and FMR2 deletion revealed shared features of epilepsy and more severe intellectual disability than typical FXS.
- Three of the four patients exhibited joint laxity, and two had epicanthic folds.
- Severe developmental delay and epilepsy appear to be characteristic of the phenotype resulting from the deletion of both FMR1 and FMR2 genes.
Implications:
- The study suggests that severe developmental delay and epilepsy may be key features of the FMR1/FMR2 deletion syndrome.
- It emphasizes the need for advanced DNA studies to detect deletions in cases of suspected fragile X syndrome where routine testing yields negative results.
- This expands the understanding of the genetic basis and clinical spectrum of fragile X-associated disorders.
Abstract:
We report a 13 year old boy with fragile X syndrome resulting from a de novo deletion of the FMR1 and FMR2 genes extending from (and including) DXS7536 proximally to FMR2 distally. The patient has severe developmental delay, epilepsy, and behavioural difficulties, including autistic features. He has epicanthic folds, in addition to facial features typical of fragile X syndrome, and marked joint hypermobility. We compare our patient to the three other cases reported in which both FMR1 and FMR2 are deleted. This case has the smallest deletion reported to date. All four patients have epilepsy and a more severe degree of mental retardation than is usual in fragile X syndrome resulting from FMR1 triplet repeat expansion. Three of the patients have joint laxity and two have epicanthic folds. We suggest that these features, in particular severe developmental delay and epilepsy, may form part of the characteristic phenotype resulting from deletion of both FMR1 and FMR2 genes. The diagnosis in this case was delayed because routine cytogenetics showed no abnormality and standard molecular tests for FMR1 triplet repeat expansion (PCR and Southern blotting) failed. Further DNA studies should be undertaken to investigate for a deletion where clinical suspicion of fragile X syndrome is strong and routine laboratory tests fail.