Diagnostics of short tandem repeat expansion variants using massively parallel sequencing and componential tools

Area of Science:

• Genetics
• Molecular Biology
• Medical Diagnostics

Background:

• Short tandem repeats (STRs) are common in the human genome.
• Trinucleotide repeat expansion (TRE) variants can cause heritable disorders.
• Current diagnostic methods for TRE disorders face technical limitations.

Purpose of the Study:

• To develop and validate a novel pipeline for diagnosing TRE variants.
• To improve the accuracy of molecular diagnostics for TRE disorders.
• To investigate TRE variants in Oculopharyngeal Muscular Dystrophy (OPMD) patients.

Main Methods:

• Utilized massively parallel sequencing (MPS) for high-throughput DNA analysis.
• Employed an open-source software package (FDSTools) to differentiate true STR sequences from artifacts.
• Applied the pipeline to a Dutch cohort of OPMD patients.

Main Results:

• The novel pipeline successfully distinguished true STR sequences from sequencing artifacts.
• Identified expansion variants in the PABPN1 gene, ranging from GCN[11] to GCN[16] in OPMD patients.
• Found no correlation between repeat expansion length and clinical features, but severity correlated with age and initial muscle involvement.

Conclusions:

• The combined MPS and FDSTools approach offers improved TRE variant diagnosis.
• This method enhances the molecular diagnostics for OPMD and potentially other TRE disorders.
• Aging and muscle-specific factors may modulate OPMD symptom severity.