Genotype-phenotype correlations in recessive titinopathies.

Area of Science:

• Genetics
• Neuromuscular Disorders
• Molecular Biology

Background:

• High-throughput sequencing enables comprehensive analysis of the titin (TTN) gene.
• Recessive titinopathies are a growing group of genetic muscle disorders.
• Understanding TTN variants is crucial for diagnosing and managing titinopathies.

Purpose of the Study:

• To characterize genetic variants and clinical features in the largest cohort of recessive titinopathy patients.
• To evaluate genotype-phenotype correlations in recessive titinopathy.
• To identify potential links between TTN variant location and disease presentation.

Main Methods:

• Analysis of clinical and genetic data from a cohort of 123 patients with biallelic pathogenic or likely pathogenic TTN variants.
• Inclusion of both previously reported and new patient cases.
• Identification and characterization of 132 causative TTN variants.

Main Results:

• Congenital myopathy (hypotonia, delayed motor development) was observed in over half of patients, with variants distributed across the TTN gene.
• Non-congenital phenotypes (distal or proximal) with later onset were associated with pathogenic variants in the final three TTN exons (362-364).
• A total of 132 causative variants were identified in the cohort.

Conclusions:

• The location of TTN variants, particularly nonsense variants, is associated with clinical severity and disease onset.
• Findings suggest distinct genotype-phenotype correlations based on TTN variant location.
• This study expands the understanding of recessive titinopathies and their genetic underpinnings.