Optical genome mapping reveals maternal mosaicism in two Sibling cases of Early-Onset Facioscapulohumeral muscular dystrophy type 1

Abstract

Background

Facioscapulohumeral muscular dystrophy (FSHD) is an autosomal dominant condition caused by shortened D4Z4 repeat units in the subtelomeric region of 4q35, always on the 4qA haplotype, or due to variants in the SMCHD1 gene leading to hypomethylation of the D4Z4 macrosatellite DNA repeats.

Methods

To explore the potential genetic basis for suspected FSHD presenting with early onset in two siblings without evident family history of the disorder, whole genome sequencing (WGS) and optical genome mapping (OGM) were conducted on the affected individuals and their parents.

Results

The two siblings manifested severe and early-onset clinical features consistent with FSHD, initiating with facial muscle weakness that progressively spread downward since the age of four months. OGM disclosed a reduced number of D4Z4 repeat units within the subtelomeric region of 4q35 in both affected siblings. This finding was pivotal in establishing the diagnosis of FSHD1 in the two brothers. The analysis also revealed that their clinically asymptomatic mother harbored the pathogenic D4Z4 repeat configuration (4qA) at a 50% frequency, indicating her mosaic carrier status. Additionally, WGS and Sanger sequencing identified a paternal origin variant c.695_699del (p.Val232Glyfs*7) in the DNAJB6 gene in both siblings.

Conclusion

The application of advanced genomic methodologies has proven instrumental in unraveling the intricacies of genetic diseases that challenge traditional diagnostic paradigms. Specifically, this study highlights the effectiveness of OGM in diagnosing FSHD1 and confirming D4Z4 repeat reduction, particularly in cases involving parental mosaicism.