Large scale population screening for Duchenne muscular dystrophy—Predictable and unpredictable challenges. (5th July 2022)

• Record Type: Journal Article
• Authors: Cohen, Gal; Shtorch‐Asor, Atalia; Ben‐Shachar, Shay; Goldfarb‐Yaacobi, Racheli; Kaiser, Meirav; Rosenfeld, Revital; Vinovezky, Mika; Irge, Dana; Furman, Yael; Reiss, Dafni; Litz‐Philipsborn, Shira; Sukenik‐Halevy, Rivka
• Is Part Of: Prenatal diagnosis. Volume 42:Number 9(2022)
• Page Start: 1162
• Page End: 1172
• Publication Date: 2022-07-05
• Subjects: Prenatal diagnosis -- Periodicals; Fetus -- Diseases -- Diagnosis -- Periodicals; Electronic journals; 618.32075
• DOI: 10.1002/pd.6201
• Languages: English
• ISSNs: 0197-3851

Abstract

Abstract: 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. Key points: What's already known about this topic? Deletions and duplications account for 65%–80% of pathogenic Duchenne muscular dystrophy (DMD) variants. About two‐thirds of DMD pathogenic variants are inherited from a female carrier. A nationwide carrier screening for DMD was initiated in Israel in 2020. What does this study add? The carrier rate among 12, 362 women tested for deletions and duplications in the DMD gene was 1:1374. Screening should be adjusted for methodological limitations and may require extensive genetic counseling and work‐up.