Prenatal-Onset Recessive Titinopathies: Clinical Spectrum, Genotype-Phenotype Correlations, and Outcomes

Area of Science:

• Genetics
• Molecular Biology
• Clinical Medicine

Background:

• Recessive titinopathies caused by biallelic TTN truncating variants (TTNtvs) exhibit a wide clinical spectrum.
• Prognostic counseling is complicated by the TTN gene's size, complex splicing, and differential expression.

Purpose of the Study:

• To delineate regional genotype patterns and clinical characteristics of recessive titinopathies from prenatal onset.
• To inform genotype-phenotype associations and improve genetic counseling for TTN-related disorders.

Main Methods:

• Analysis of clinical and genetic data from 96 prenatal-onset TTNtv cases.
• Utilized a 2D scatter plot to map variants onto 10 biological regions and 55 analytical units.
• Performed Fisher's exact tests to associate variant combinations with severe clinical endpoints.

Main Results:

• Decreased fetal movement, arthrogryposis, and amniotic fluid abnormalities were common prenatal symptoms.
• High rates of termination, intrauterine demise, and severe postnatal morbidity (respiratory failure, early death) were observed.
• Biallelic TTNtvs in A-band and metatranscript-only regions were most common; variants on low-PSI exons were frequent.
• Biallelic changes affecting high-PSI exons correlated with severe outcomes, while metatranscript-only plus I-band variants showed lower lethality risk.

Conclusions:

• TTNtvs on low PSI exons or metatranscript-only regions are common in prenatal-onset recessive titinopathy.
• Findings support genotype-phenotype correlations for TTN-related disorders.
• Health surveillance for heterozygous carriers is recommended due to risks of adult-onset and peripartum cardiomyopathy.