De novo microduplication of the FMR1 gene in a patient with developmental delay, epilepsy and hyperactivity
Jaime Vengoechea1, Aditi S Parikh, Shulin Zhang
1Center for Human Genetics, University Hospitals Case Medical Center, Cleveland, OH 44106, USA. jaimevengoechea@gmail.com
Abstract:
Loss-of-function due to expansion of a CGG repeat located in the 5'UTR of the FMR1 gene is the most frequent cause of fragile X syndrome. Less than 1% of individuals with fragile X syndrome have been reported to have a partial or full deletion or point mutation of the FMR1 gene. However, whether a copy number gain of the FMR1 gene could result in certain clinical phenotypes has not been fully investigated. Here, we report the case of a child who presented with developmental delay starting at 9 months of age, fine motor and speech delay, progressive seizures since 18 months of age and hyperactivity. Molecular workup identified a de novo microduplication in the Xq27.3 region, including the FMR1 gene and the ASFMR1 gene. The expression level of the FMR1 gene in peripheral blood did not differ from that of the controls. In addition, an inherited 363-kb duplication on the chromosome 1q44 region and an inherited deletion of 168 kb on the chromosome 4p15.31 region were detected. It is not clear whether these inherited copy number variations (CNVs) also have a modifying role in the clinical phenotype of this patient.
Insights
A microduplication including the FMR1 gene caused developmental delays and seizures in a child. This finding expands understanding of fragile X syndrome genetics beyond repeat expansions.
Area of Science:
- Genetics
- Neurodevelopmental Disorders
- Molecular Biology
Background:
- Fragile X syndrome is primarily caused by CGG repeat expansions in the FMR1 gene.
- FMR1 gene deletions or point mutations are rare causes of fragile X syndrome.
- The impact of FMR1 gene copy number gains on clinical phenotypes remains under-investigated.
Observation:
- A child presented with developmental delay, speech and fine motor deficits, progressive seizures, and hyperactivity.
- Molecular analysis revealed a de novo microduplication in Xq27.3 encompassing the FMR1 and ASFMR1 genes.
- No significant difference in FMR1 gene expression was observed in peripheral blood compared to controls.
Findings:
- A de novo microduplication of the FMR1 gene region was identified in a patient with developmental delays and seizures.
- Inherited copy number variations (CNVs) on chromosomes 1q44 and 4p15.31 were also detected, but their role is unclear.
- This case suggests that FMR1 gene microduplications may contribute to neurodevelopmental phenotypes.
Implications:
- This case broadens the genetic understanding of fragile X syndrome and related disorders.
- Further research is needed to explore the role of FMR1 gene copy number variations in neurodevelopment.
- Identifying novel genetic mechanisms is crucial for accurate diagnosis and potential therapeutic strategies.
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