Congenital Titinopathy: Comprehensive Characterization of the Most Severe End of the Disease Spectrum
Authors: Coppens Sandra , Deconinck Nicolas , Sullivan Patricia , Smolnikov Andrei , Clayton Joshua S. , Griffin Kaitlyn R. , Jones Kristi J. , Vilain Catheline N. , Kadhim Hazim , Bryen Samantha J. , Faiz Fathimath , Waddell Leigh B. , Evesson Frances J. , Bakshi Madhura , Pinner Jason R. , Charlton Amanda , Brammah Susan , Graf Nicole S. , Krivanek Michael , Tay Chee Geap , Foulds Nicola C. , Illingworth Marjorie A. , Thomas Neil H. , Ellard Sian , Mazanti Ingrid , Park Soo‐Mi , French Courtney E. , Brewster Jennifer , Belteki Gusztav , Hoodbhoy Shazia , Allinson Kieren , Krishnakumar Deepa , Baynam Gareth , Wood Bradley M. , Ward Michelle , Vijayakumar Kayal , Syed Amber , Murugan Archana , Majumdar Anirban , Scurr Ingrid J. , Splitt Miranda P. , Moldovan Corina , de Silva Deepthi C. , Senanayake Kumudu , Gardeitchik Thatjana , Arens Yvonne , Cooper Sandra T. , Laing Nigel G. , Raymond F. Lucy , Jungbluth Heinz , Kamsteeg Erik‐Jan , Manzur Adnan , Corley Susan M. , Ravenscroft Gianina , Wilkins Marc R. , Cowley Mark J. , Pinese Mark ,   Titin Research Consortium, Phadke Rahul , Davis Mark R. , Muntoni Francesco , Oates Emily C. 
Published: January 2025

Congenital titinopathy has recently emerged as one of the most common congenital muscle disorders.ObjectiveTo better understand the presentation and clinical needs of the under‐characterized extreme end of the congenital titinopathy severity spectrum.MethodsWe comprehensively analyzed the clinical, imaging, pathology, autopsy, and genetic findings in 15 severely affected individuals from 11 families.ResultsPrenatal 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.InterpretationThis 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