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Reclassification of DMD Duplications as Benign: Recommendations for Cautious Interpretation of Variants Identified in
Wenbin He1,2,3, Guiquan Meng1, Xiao Hu3
1Institute of Reproductive and Stem Cell Engineering, NHC Key Laboratory of Human Stem Cell and Reproductive Engineering, School of Basic Medical Science, Central South University, Changsha 410008, China.
Abstract:
Duplications are the main type of dystrophin gene (DMD) variants, which typically cause dystrophinopathies such as Duchenne muscular dystrophy and Becker muscular dystrophy. Maternally inherited exon duplication in DMD in fetuses is a relatively common finding of genetic screening in clinical practice. However, there is no standard strategy for interpretation of the pathogenicity of DMD duplications during prenatal screening, especially for male fetuses, in which maternally inherited pathogenic DMD variants more frequently cause dystrophinopathies. Here, we report three non-contiguous DMD duplications identified in a woman and her male fetus during prenatal screening. Multiplex ligation probe amplification and long-read sequencing were performed on the woman and her family members to verify the presence of DMD duplications. Structural rearrangements in the DMD gene were mapped by long-read sequencing, and the breakpoint junction sequences were validated using Sanger sequencing. The woman and her father carried three non-contiguous DMD duplications. Long-read and Sanger sequencing revealed that the woman's father carried an intact DMD copy and a complex structural rearrangement of the DMD gene. Therefore, we reclassified these three non-contiguous DMD duplications, one of which is listed as pathogenic, as benign. We postulate that breakpoint analysis should be performed on identified DMD duplication variants, and the pathogenicity of the duplications found during prenatal screening should be interpreted cautiously for clinical prediction and genetic/reproductive counseling.
Insights
Maternally inherited dystrophin gene (DMD) duplications in fetuses require careful interpretation. Breakpoint analysis is crucial for accurate pathogenicity assessment, especially during prenatal screening for muscular dystrophies.
Area of Science:
- Genetics
- Molecular Biology
- Clinical Diagnostics
Background:
- Dystrophin gene (DMD) duplications are common variants causing dystrophinopathies like Duchenne and Becker muscular dystrophies.
- Maternally inherited DMD duplications are frequently detected during prenatal genetic screening, particularly in male fetuses.
- Current strategies lack standardization for interpreting the pathogenicity of DMD duplications found during prenatal diagnosis.
Purpose of the Study:
- To investigate and accurately classify three non-contiguous DMD duplications identified in a woman and her male fetus.
- To evaluate the clinical significance of DMD duplications detected during prenatal screening.
- To emphasize the need for refined interpretation methods for DMD variants in genetic counseling.
Main Methods:
- Multiplex ligation probe amplification (MLPA) and long-read sequencing were employed to detect and verify DMD duplications.
- Long-read sequencing was used to map structural rearrangements within the DMD gene.
- Sanger sequencing validated breakpoint junction sequences for precise structural analysis.
Main Results:
- Three non-contiguous DMD duplications were identified in the maternal lineage.
- Detailed structural analysis revealed a complex rearrangement in the paternal lineage, reclassifying previously identified pathogenic duplications as benign.
- The woman and her father carried these non-contiguous DMD duplications, with one initially considered pathogenic but later reclassified.
Conclusions:
- Breakpoint analysis is essential for accurate pathogenicity interpretation of DMD duplication variants.
- Caution is advised when interpreting the clinical significance of DMD duplications during prenatal screening.
- Findings support the need for comprehensive structural analysis and careful genetic counseling for families with DMD variants.
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