Holm Graessner | PubMed Health

PubMed2026

Individualized antisense oligonucleotide treatment eligibility of patients living with neurodevelopmental diseases.

With advances in genetic diagnostic tools, pathogenic variants in patients with genetic diseases are being identified at an accelerated pace. For a subset of these patients, individualized genetic interventions such as antisense oligonucleotides (ASOs) would address the disease cause. These individualized, or n-of-1, ASOs are currently being clinically applied in dozens of cases but mainly in patients with neurodegenerative diseases. For neurodevelopmental disorders, however, several questions arise: (1) Are they treatable? (2) What is the appropriate time window? (3) Does the treatment effect justify the burden and risks of treatment? In this consensus statement, we argue for the case to consider the development of individualized ASO treatment for individuals living with neurodevelopmental diseases and discuss which aspects need to be taken into consideration.

Humans↗

PubMed2025

The burden of TTN variants in the genomic era: Analysis of 18,462 individuals from the Solve-RD consortium and general recommendations.

PURPOSE: Titin, the largest protein in the human body, has been associated with several disease phenotypes caused by variants in the TTN gene. With around 20% of the population carrying a rare TTN variant and over 60 million genomes expected to have been sequenced worldwide by 2025, interpreting these findings presents major challenges. This study analyzed TTN variants in the Solve-RD cohort, the European network for unsolved rare disease cases. METHODS: We collected data from 11,072 individuals with suspected rare diseases and 7390 healthy relatives from the Solve-RD consortium, checking and manually reviewing TTN variants. We then used a filtering approach focused on clinical relevance, and we provided updated recommendations based on recent literature. RESULTS: Among the cohort, 240 individuals (1.3%) carried at least one heterozygous TTN truncating variant (TTNtv), with a 3.8% prevalence in the neuromuscular subgroup, primarily composed of unsolved cases. Four individuals received a titinopathy diagnosis. Additionally, 99 participants (0.5%) had a TTNtv in a high cardiac percent spliced in exon (>80%), and 4 had an overt cardiomyopathy. CONCLUSION: This study highlights the need for standardized approach to TTN variants, and investigation of missing heritability in individuals with skeletal myopathy with het TTNtv. Establishing consensus on percent spliced in-based thresholds will be essential for assessing cardiac risk and guiding the management of asymptomatic individuals.

Humans↗