Titin copy number variations associated with dominant inherited phenotypes

Area of Science:

• Genetics and Molecular Biology
• Neuromuscular Disorders

Background:

• Titinopathies result from mutations in the titin gene (TTN), the largest known human gene.
• These neuromuscular pathologies are complex, exhibiting variable onset, diverse impairment patterns (cardiac, skeletal, mixed), and both dominant and recessive inheritance.
• Previously, few TTN copy number variations (CNVs) were reported with unclear genotype-phenotype correlations.

Purpose of the Study:

• To identify and characterize CNVs in the TTN gene in families with dominant titinopathies.
• To establish genotype-phenotype associations for TTN-related disorders.
• To improve diagnostic sensitivity for complex neuromuscular pathologies.

Main Methods:

• Analysis of eight families with dominant titinopathies using next-generation sequencing or array comparative genomic hybridization.
• Identification and characterization of TTN CNVs via RNA sequencing (RNAseq) in patient muscle samples.
• Genotype-phenotype inheritance association study integrating clinical, biological, and imaging data.

Main Results:

• Seven deletion-type CNVs in the TTN gene were identified.
• Five deletions were in-frame, and one was out-of-frame, as confirmed by genotype and RNAseq.
• The primary phenotype observed was distal myopathy with contractures, enabling new genotype-phenotype associations.

Conclusions:

• The identification of novel TTN CNVs, including those with unexpected autosomal dominant transmission, enhances diagnostic capabilities for titinopathies.
• New genotype-phenotype associations were established, highlighting distal myopathy as a key phenotype.
• Characterizing TTN CNVs is crucial for understanding and diagnosing these complex neuromuscular conditions.