Inferring disease course from differential exon usage in the wide titinopathy spectrum

Area of Science:

• Genetics
• Molecular Biology
• Clinical Medicine

Background:

• Biallelic titin truncating variants (TTNtv) present a broad spectrum of phenotypes, from prenatal muscle diseases to adult limb-girdle muscular dystrophy.
• The large size and complexity of the TTN gene pose challenges for accurate molecular diagnosis and prognosis.

Purpose of the Study:

• To investigate the utility of TTN exon usage analysis for genotype-phenotype correlations in patients with TTNtv.
• To explore the potential of exon usage data in improving diagnostic accuracy and prognostic predictions for titinopathies.

Main Methods:

• A case series of 13 patients with biallelic TTNtv was analyzed.
• Exome or genome sequencing was used to detect TTN mutations.
• RNA sequencing and TTN exon usage analysis were performed on patient samples and public datasets.

Main Results:

• Genotype-phenotype correlations were identified using percentage spliced in (PSI) data for TTN exons.
• Exon usage analysis provided prognostic implications, indicating disease worsening or improvement.
• A prenatal titinopathy diagnosis was ruled out in one case based on exon usage findings.

Conclusions:

• TTN exon usage analysis offers valuable insights for interpreting TTNtv.
• This method can enhance clinical diagnosis and prognosis for titinopathies.
• The approach serves as a model for personalized medicine in other genetic diseases with alternative splicing.