Recurrent nonsense p.Trp3416* variant in the DMD gene identified in healthy Lebanese individuals: Implications for variant classification and genotype-phenotype correlations.

BACKGROUND

Duchenne muscular dystrophy (DMD) is a severe X-linked neuromuscular disorder caused by pathogenic variants in the DMD gene, leading to dystrophin deficiency and progressive muscle degeneration. Thousands of variants with diverse types have been reported in DMD, contributing to a broad clinical spectrum. While typically associated with severe phenotypes, pathogenic DMD variants may also cause Becker muscular dystrophy (BMD), a milder form with later-onset muscle weakness, or isolated dilated cardiomyopathy with minimal skeletal muscle involvement. Rarely, asymptomatic individuals carry putative pathogenic variants, challenging established genotype-phenotype correlations.

METHODS

This study includes five unrelated Lebanese families who presented for genetic counseling or pre-marital screening and subsequently underwent genetic testing.

RESULTS

Exome sequencing revealed a predicted protein-truncating variant in exon 71 of DMD p.(Trp3416*) in multiple individuals, including three hemizygous healthy males aged 35, 65 and 67. Despite being classified as pathogenic, the variant's presence in asymptomatic males raises questions about its actual pathogenicity. In silico tools (e.g., Franklin, Varsome, CADD score: 52.0) predicted a strong deleterious effect. The variant is extremely rare in population databases and has conflicting interpretations in ClinVar, previously associated with DMD, BMD, and cardiomyopathy. Although other truncating variants in exon 71 are known to cause DMD, the identification of p.(Trp3416*) in healthy individuals with normal neuromuscular and cardiac function suggests the possibility of alternative splicing, modifier genes, or compensatory mechanisms mitigating the effect of dystrophin loss.

CONCLUSION

This study underscores the importance of functional validation and long-term clinical monitoring to refine variant classification and guide accurate genetic counseling.