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Unraveling MECP2 structural variants in previously elusive Rett syndrome cases through IGV interpretation
Tomer Poleg1, Noam Hadar1, Gali Heimer2,3
1Faculty of Health Sciences, Ben-Gurion University of the Negev, Be'er Sheva, Israel.
NPJ Genomic Medicine
|March 14, 2025
Summary
Structural variants (SVs) in the MECP2 gene may explain previously undiagnosed Rett syndrome (RTT) cases. Detecting these elusive SVs through genetic testing can improve diagnosis rates for RTT.
Area of Science:
- Genetics
- Neurodevelopmental Disorders
Background:
- Rett syndrome (RTT) is a severe neurodevelopmental disorder.
- Mutations in the MECP2 gene cause the majority of RTT cases, but some patients remain undiagnosed.
- The role of small-to-intermediate structural variants (SVs) in MECP2 has not been fully explored.
Purpose of the Study:
- To investigate the potential role of novel de novo SVs in MECP2-negative RTT cases.
- To improve diagnostic rates for RTT by identifying previously elusive genetic causes.
Main Methods:
- Standard short-read whole genome sequencing was used.
- Bioinformatic analysis and manual review using IGV were employed to detect SVs.
Main Results:
- Novel de novo SVs were identified in three previously unresolved RTT cases.
- Identified SVs included complex deletions, an inversion, a translocation, and a small deletion.
- These findings suggest SVs are a potential cause of "MECP2-negative" RTT.
Conclusions:
- Elusive SVs in MECP2 may be a common cause of undiagnosed RTT.
- Integrating SV detection into genetic testing can enhance RTT diagnosis.
- This approach can broaden the understanding of RTT and related disorders.
