Genomic Unity® 2.0 Case Study
Overview
Patient:
66-year-old female
Clinical presentation:
Proximal muscle weakness and amyotrophy, myopathy, rhabdomyolysis, abnormal gait
Testing strategy:
Variantyx whole genome testing with combined short and long-read sequencing
Key finding:
Compound heterozygous splicing and deep intronic SNVs in the GYG1 gene
Clinical outcome:
Diagnosis established
Why Genomic Unity® 2.0 was the right choice
Despite prior non-diagnostic targeted testing, the patient’s progressive proximal amyotrophy and muscle weakness, combined with a muscle biopsy positive for glycogen, was strongly suggestive of adult onset polyglucosan body myopathy.
Genomic Unity® 2.0 was selected because it delivers the most comprehensive genomic insight from the start while:
- Reducing time to diagnosis
- Avoiding unnecessary testing
- Supporting the highest standard of patient care
Diagnostic finding: Polyglucosan body myopathy 2
Variantyx Genomic Unity® 2.0 testing identified a heterozygous, pathogenic, splicing variant and a heterozygous, likely pathogenic, deep intronic variant in the GYG1 gene. The deep intronic variant has been demonstrated to result in aberrant splicing.
The variants are in trans.
Long-read sequencing provides individual, continuous reads that span both variant locations – approximately 1,600 nucleotides apart. The continuous reads clearly demonstrate that the variants reside on different DNA strands and are therefore in trans.
Impact on clinical care
Established an elusive diagnosis.
Variant spotlight: Phasing
Detection challenges:
Short-read technologies like exome and standard genome sequencing generate short reads that are assembled into a contiguous stretch of DNA using overlapping sequences. The breaks between individual reads makes it impossible to determine whether variants located thousands of nucleotides apart occur on the same or different alleles – a key criteria for definitive diagnosis of autosomal recessive disorders.
Why Genomic Unity® 2.0
- Sequences a patient’s genome twice: once with short-read genome sequencing and once with long-read genome sequencing
- Individual, continuous reads thousands of nucleotides in length enable direct phasing of variants at kilobase-scale distances
Additional similar cases
Genomic Unity® 2.0 – Phasing of KDM5B SNV and deletion explains intellectual disability
Genomic Unity® 2.0 – Phasing determines indel parent of origin providing Angelman syndrome diagnosis