2023 ACMG Annual Clinical Genetics Meeting Digital Edition: Poster Gallery-Two Distinct Rearrangements in One Family within the Duchenne Muscular Dystrophy Gene

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In this study, the researchers investigated two distinct deletions in the DMD gene that were present within one nuclear family. The DMD gene is associated with Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD). Exonic rearrangements in the DMD gene account for the molecular defects in 50-70% of DMD/BMD cases. The researchers characterized the junction points of the large genomic deletions in order to better understand the genotype-phenotype correlation and the molecular mechanism underlying DMD gene instability.<br /><br />The smaller deletion in the mother and sister was completely contained within the larger deletion in the son. Through STR marker analysis, the researchers found that the different sized deletions likely occurred on the same maternally inherited allele. It is proposed that the mother's smaller deletion predisposed the son's larger deletion.<br /><br />The analysis of the deletion breakpoint sequences suggested that the two distinct but overlapping rearrangements in this family likely occurred through a mechanism involving extended microhomology mediated end joining (MMEJ). This suggests that genomic rearrangements do not occur randomly, but instead may arise due to local features in the genome that promote DNA instability.<br /><br />This study provides new insights that could be relevant for exon-skipping therapies and genetic counseling. It also contributes to the understanding of the molecular mechanisms underlying DMD rearrangements. Further analysis of STR markers is still pending.<br /><br />In summary, this study identified and characterized two distinct deletions in the DMD gene within one nuclear family, providing insights into the genotype-phenotype correlation and the molecular mechanism underlying DMD gene instability. The findings have implications for patient management, genetic counseling, and potential therapies for DMD.

Asset Subtitle

Presenting Author - Xuemei Shi, PhD; Co-Author - Daniel Moats, BS; Co-Author - Daniel B. Magner, PhD; Co-Author - Anna Childers, MS; Co-Author - Meg Keating, MS; Co-Author - R Curtis Rogers, MD; Co-Author - Jennifer A. Lee, PhD, FACMG;

Meta Tag

Variant Detection

Molecular Pathophysiology

Genotype-Phenotype Correlations

Genomic Structure

Genomic Methodologies

Genetic Testing

Counseling

Congenital Anomaly

Clinical Applications of Molecular Cytogenetics

Chromosomal Abnormalities

Co-Author Jennifer A. Lee, PhD, FACMG

Co-Author R Curtis Rogers, MD

Co-Author Meg Keating, MS

Co-Author Anna Childers, MS

Co-Author Daniel B. Magner, PhD

Co-Author Daniel Moats, BS

Presenting Author Xuemei Shi, PhD

Keywords

DMD gene

deletions

Duchenne muscular dystrophy

Becker muscular dystrophy

exonic rearrangements

genotype-phenotype correlation

molecular mechanism

DNA instability

exon-skipping therapies

genetic counseling