Large scale population screening for Duchenne muscular dystrophy-Predictable and unpredictable challenges.

OBJECTIVE

Large deletions and duplications account for 65%-80% of pathogenic Duchenne muscular dystrophy (DMD) variants. A nationwide carrier screening for DMD was initiated in Israel in 2020. We assessed the carrier rate and spectrum of variants detected in a cohort of women screened for DMD carrier status and analyzed screening efficacy and challenges related to DMD population screening.

METHODS

A cohort of 12,362 women were tested at a single institute using multiplex ligation-dependent probe amplification based copy number analysis of the 79 DMD exons. Consecutive sequencing of the primer region was performed when a single exon deletion was suspected.

RESULTS

Deletions involving multiple exons were detected in seven cases and duplications involving multiple exons were found in four. Of these, nine were pathogenic based on previous reports and familial segregation testing, translating to a carrier rate of 1:1374. A family history was reported in three cases. Single exon deletions were suspected in 81 cases; further sequencing detected a single nucleotide variant affecting probe hybridization. These cases clustered according to ethnic origin.

DISCUSSION

Population screening for DMD has a significant yield. Most carriers did not report a family history of dystrophinopathies. Screening should be adjusted for methodological limitations. Some cases may require extensive genetic counseling and work-up.