“DMD gene pathogenic variations cause a spectrum of phenotypes, including intermediate or very mild muscle phenotypes, and ultrarare fully asymptomatic cases. To review these atypical cases, we performed a horizon scan on public datasets and consulted our internal database including 1200 diagnoses.
We inventoried 81 males and proposed the following clinical categorization: fully asymptomatic males aged >43 years (A, N=22); isolated hyperCKemia (CK, N=35); mild weakness (any age) with or without high CK (WCK, N=24).
Deletions were in-frame, apart from the known exception-to-the-rule of exon 2 and exon 78. In all cases, deleted intervals clustered between exons 2 to 55, and no downstream exons were involved, apart from an exon 78 deletion in a WCK patient. Consequently, domains downstream exon 55 resulted intact in the A, CK and WCK phenotypes and preserved EFH1, EFH2, WW and ZZ domains, and the C-terminus translation; these data also imply that the DMD 3′ Dp71 isoform was always preserved in these categories.
We also correlated the identified phenotypes to deleted exons, intronic breakpoints, exon-exon junctions, DMD 3′ isoforms rule, and protein epitopes. Interestingly, some genetic profiles have been exclusively/mainly observed in A/CK phenotypes, suggesting their compatibility with a quasi-normal muscular function.
Atypical phenotypes may also provide insights in understanding DMD etiopathogenesis, in elucidating dystrophin protein transcription, translation, and regulatory pathways, and in possibly refining therapy design. Finally, some deletions should be carefully considered when identified as incidental findings and genetic counseling must be always proposed to interpret these rare DMD genotypes.”