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Congenital Titinopathy: Comprehensive Characterization of the Most Severe End of the Disease Spectrum
Sandra Coppens1, Nicolas Deconinck2, Patricia Sullivan3
1Hopital Erasme, ULB Center of Human Genetics, Université Libre de Bruxelles, Brussels, Belgium.
Insights
Congenital titinopathy shows variable severity. Some individuals with titin gene variants succumb prenatally or in infancy, while others survive longer, suggesting titin expression levels influence outcomes.
Area of Science:
- Genetics
- Neuromuscular Disorders
- Molecular Biology
Background:
- Congenital titinopathy is an increasingly recognized congenital muscle disorder.
- The extreme ends of its severity spectrum remain under-characterized.
Purpose of the Study:
- To investigate the clinical presentation and needs of severely affected individuals with congenital titinopathy.
- To explore the genetic and molecular underpinnings of disease variability.
Main Methods:
- Comprehensive analysis of clinical, imaging, pathology, autopsy, and genetic data from 15 individuals across 11 families.
- Genetic variant analysis, including prediction of titin expression and splicing impact.
- Minigene assays to confirm splicing effects.
Main Results:
- Severely affected individuals exhibited prenatal hypokinesia/akinesia and growth restriction, with high rates of termination, neonatal mortality, or ongoing respiratory support.
- Most patients carried variants predicted to allow some near-normal-length titin expression.
- Two families with homozygous truncating variants showed evidence of altered splicing, leading to some near-normal-length titin expression, confirmed by minigene assay.
Conclusions:
- Congenital titinopathy exhibits significant clinical variability, with outcomes influenced by the amount and/or length of expressed titin.
- Near-normal titin expression appears crucial for early prenatal survival.
- Splicing alterations caused by disease-associated variants can contribute to titin expression, impacting clinical prediction and potential therapeutic strategies.
Abstract:
Congenital titinopathy has recently emerged as one of the most common congenital muscle disorders.
Objective:
To better understand the presentation and clinical needs of the under-characterized extreme end of the congenital titinopathy severity spectrum.
Methods:
We comprehensively analyzed the clinical, imaging, pathology, autopsy, and genetic findings in 15 severely affected individuals from 11 families.
Results:
Prenatal features included hypokinesia or akinesia and growth restriction. Six pregnancies were terminated. Nine infants were born at or near term with severe-to-profound weakness and required resuscitation. Seven died following withdrawal of life support. Two surviving children require ongoing respiratory support. Most cohort members had at least 1 disease-causing variant predicted to result in some near-normal-length titin expression. The exceptions, from 2 unrelated families, had homozygous truncating variants predicted to induce complete nonsense mediated decay. However, subsequent analyses suggested that the causative variant in each family had an additional previously unrecognized impact on splicing likely to result in some near-normal-length titin expression. This impact was confirmed by minigene assay for 1 variant.
Interpretation:
This study confirms the clinical variability of congenital titinopathy. Severely affected individuals succumb prenatally/during infancy, whereas others survive into adulthood. It is likely that this variability is because of differences in the amount and/or length of expressed titin. If confirmed, analysis of titin expression could facilitate clinical prediction and increasing expression might be an effective treatment strategy. Our findings also further-support the hypothesis that some near-normal-length titin expression is essential to early prenatal survival. Sometimes expression of normal/near-normal-length titin is due to disease-causing variants having an additional impact on splicing. ANN NEUROL 2025;97:611-628.
