To report a novel large-scale tandem quadruplication within the DMD gene and characterize the phenotype-genotype correlation in an Algerian family with Duchenne muscular dystrophy (DMD).

Dystrophinopathies result from a spectrum of pathogenic structural variants in the DMD gene, primarily deletions, duplications, and point mutations. While complex genomic rearrangements such as triplications are rare, symptomatic large-scale tandem quadruplications have not been previously reported, and their expressivity remains to be determined.

Clinical evaluation included neurological examination, biochemical analysis, and genetic testing using Next-Generation Sequencing (NGS) with sequencing-depth analysis for copy number variation, in a family presenting with DMD phenotype.

We identified a family consisting of three siblings (two boys and one girl). The proband, an 8-year-old boy presented with progressive proximal lower limb weakness since the age of 3. Both the proband and his 6-year-old brother exhibited a classic DMD phenotype including waddling gait, Gowers’ sign, calf muscles hypertrophy and significant pelvic girdle muscle weakness with a low North-Star Ambulatory Assessment (NSAA) score (17/34).

Biochemical tests in both boys showed markedly increased creatine-kinase (CK) levels (>10,000 IU/L) and liver enzymes (AST, ALT, LDH). The one-year-old sister is still too young for conclusive clinical examination but showed significantly elevated levels of CK consistent with possible symptomatic status. The carrier mother’s CK levels and cardiac examination were normal.

NGS with sequencing-depth analysis identified an out-of-frame quadruplication of 33 contiguous exons (8-40) in the DMD gene. This pathogenic structural variant correlates with classic, severe DMD phenotype observed in the affected males.

This case-report documents the first detailed characterization of a large-scale tandem quadruplication in the DMD gene, a novel class of structural variant expanding the mutational spectrum of dystrophinopathies, and highlighting the importance of genetic analysis in elucidating the pathophysiology, guiding therapeutic considerations and informing genetic counselling.