Long-read sequencing resolves compound heterozygosity arising from a de novo and a maternally mosaic HSPG2 variant in Schwartz-Jampel syndrome type 1

Schwartz-Jampel Syndrome Type 1 (SJS1) is a rare autosomal recessive disorder characterized by myotonia and distinctive facial features, such as blepharospasm and pursed lips. The condition results from biallelic variants in HSPG2 , which are usually inherited from both parents. So far, de novo or mosaic HSPG2 variants have not been reported. An 11-year-old boy with no family history presented with myotonia and gait instability. Laboratory tests showed elevated creatine kinase levels, and electromyography revealed neurogenic myotonic discharges. Whole-exome sequencing trio was performed, and identified three HSPG2 variants in the patient: c.7438 C > T (p.Arg2480Trp), c.9145del (p.Ala3049GlnfsTer56), and c.12899G > T (p.Arg4300Leu). Long-read sequencing of the patient confirmed that c.7438 C > T and c.12899G > T were in cis on one allele, while c.9145del was on the other allele, establishing a compound heterozygous genotype. Retrospective analysis detected low-level maternal mosaicism for c.9145del, which explained the initial segregation discrepancy. This case is the first documentation of a de novo and a potential mosaic variant in HSPG2 . It highlights the limitations of conventional sequencing in detecting mosaic variants and the utility of long-read sequencing in resolving challenging inheritance patterns, underscoring the growing value of advanced sequencing technologies in rare disease diagnostics.