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First interchromosomal insertion in a patient with cerebral and spinal cavernous malformations
Robin A Pilz1, Konrad Schwefel1, Anja Weise2
1Department of Human Genetics, University Medicine Greifswald, and Interfaculty Institute of Genetics and Functional Genomics, University of Greifswald, Greifswald, Germany.
Scientific Reports
|April 15, 2020
Summary
Structural genomic rearrangements, like insertions, can cause cerebral cavernous malformations (CCM). Detecting these variations in CCM2 improves genetic diagnosis for patients with unexplained CCM disease.
Area of Science:
- Genetics
- Neurology
- Vascular Biology
Background:
- Autosomal dominant cerebral cavernous malformations (CCM) are vascular lesions causing seizures and stroke-like symptoms.
- Germline mutations in CCM1, CCM2, or CCM3 are identified in most affected individuals.
- Previous studies identified a copy number neutral inversion in CCM2, suggesting other structural variants may exist.
Observation:
- This study analyzed next-generation sequencing (NGS) gene panel data from eight patients with unexplained CCMs.
- A significant structural variation, a 294kb insertion disrupting CCM2, was identified in one patient.
- This insertion was confirmed as an inverted unbalanced rearrangement originating from chromosome 1p12-p11.2.
Findings:
- The identified insertion in CCM2 was classified as pathogenic due to disruption of exon 6.
- Two bioinformatics pipelines successfully detected the structural variation in NGS data.
- This highlights the potential for identifying complex genomic rearrangements in unsolved genetic disorders.
Implications:
- Detecting structural variations significantly increases diagnostic yield in genetic testing for CCM.
- This approach can improve the diagnosis of well-defined Mendelian disorders.
- Further investigation into structural genomic rearrangements is crucial for understanding CCM pathogenesis.
