Ann Lab Med.  2024 Sep;44(5):437-445. 10.3343/alm.2023.0437.

Clinical Application of Optical Genome Mapping for Molecular Diagnosis of Facioscapulohumeral Muscular Dystrophy

• Shim Y
• Seo J
• Lee ST
• Choi JR
• Choi YC
• Shin S
• Park HJ

• KMID: 2559150
• DOI: http://doi.org/10.3343/alm.2023.0437

Abstract

Background
Facioscapulohumeral muscular dystrophy (FSHD) is a common form of muscular dystrophy that mainly affects skeletal muscle. FSHD1 accounts for 95% of all FSHD cases and can be diagnosed based on the pathogenic contraction of the D4Z4-repeat array on chromosome 4q35. Genetic diagnosis of FSHD1 is challenging because of the large size and repetitive nature of the D4Z4 region. We evaluated the clinical applicability of optical genome mapping (OGM) for the genetic diagnosis of FSHD1.
Methods
We included 25 individuals with clinically confirmed or suspected/probable FSHD and their families. Ultra-high-molecular-weight DNA from peripheral blood was labeled, stained, and imaged using a single-molecule OGM platform (Bionano Genomics Saphyr system). D4Z4 repeat size and haplotype information were analyzed using the manufacturer’s dedicated pipeline. We also compared the workflow and test time between Southern blot analysis and OGM.
Results
We obtained concordant OGM and Southern blot results with 10 samples from patients with clinically confirmed FSHD. The D4Z4 repeat size differed within 1 unit between the Southern blot analysis and OGM. Among nine patients with clinically suspected or probable FSHD, six patients were confirmed to have pathogenic contractions by OGM. In our cohort, one de novo mosaic FSHD1 patient was successfully diagnosed with OGM. Moreover, OGM has a more straightforward and less time-consuming workflow than Southern blot analysis.
Conclusions
OGM enables accurate and reliable detection of pathogenic contraction of the D4Z4-repeat array and is a valuable tool for the genetic diagnosis of FSHD1.

Keyword

D4Z4 repeat; Facioscapulohumeral muscular dystrophy; FSHD1; Optical mapping

Figure

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  Fig. 1 Pedigrees of four families and their OGM results. Abbreviation: OGM, optical genome mapping.

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  Fig. 2 Representative OGM results from patients with clinically probable/suspected FSHD. (A, B) No pathogenic contraction was identified in a patient with clinically suspected FSHD (P8). (C, D) A pathogenic contraction was identified in a patient with clinically probable FSHD (P9). Abbreviations: OGM, optical genome mapping; FSHD, facioscapulohumeral muscular dystrophy.

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  Fig. 3 Correlation between the D4Z4-repeat size and (A) age at symptom onset (r=0.364, R2=0.072, P=0.1654) and (B) age at diagnosis (r=0.020, R2=0.001, P=0.9424) based on OGM for patients with FSHD. Abbreviations: OGM, optical genome mapping; FSHD, facioscapulohumeral muscular dystrophy.

Reference

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