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Neuromuscular and cardiovascular phenotypes in paediatric titinopathies: a multisite retrospective study
  1. Alayne P Meyer1,2,
  2. Cara L Barnett3,
  3. Katherine Myers1,4,
  4. Carly E Siskind5,
  5. Tia Moscarello6,
  6. Rachel Logan7,
  7. Jennifer Roggenbuck8,9,
  8. Kelly A Rich8
  1. 1 Division of Genetic and Genomic Medicine, Nationwide Children's Hospital, Columbus, Ohio, USA
  2. 2 Center for Gene Therapy, Abigail Wexner Research Institute, Nationwide Children's Hospital, Columbus, Ohio, USA
  3. 3 Heart Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA
  4. 4 Center for Cardiovascular Research and The Heart Center, Nationwide Children's Hospital, Columbus, Ohio, USA
  5. 5 Department of Neurology, Stanford Health Care, Stanford, California, USA
  6. 6 Stanford Center for Inherited Cardiovascular Disease, Stanford Health Care, Stanford, California, USA
  7. 7 Division of Neurosciences, Children's Healthcare of Atlanta Inc, Atlanta, Georgia, USA
  8. 8 Department of Neurology, The Ohio State University Wexner Medical Center, Columbus, Ohio, USA
  9. 9 Division of Human Genetics, The Ohio State University Wexner Medical Center, Columbus, Ohio, USA
  1. Correspondence to Alayne P Meyer, Division of Genetic and Genomic Medicine, Nationwide Children's Hospital, Columbus, Ohio, USA; alayne.meyer{at}nationwidechildrens.org; Cara L Barnett; Cara.Barnett{at}cchmc.org

Abstract

Background Pathogenic variants in TTN cause a spectrum of autosomal dominant and recessive cardiovascular, skeletal muscle and cardioskeletal disease with symptom onset across the lifespan. The aim of this study was to characterise the genotypes and phenotypes in a cohort of TTN+paediatric patients.

Methods Retrospective chart review was performed at four academic medical centres. Patients with pathogenic or truncating variant(s) in TTN and paediatric-onset cardiovascular and/or neuromuscular disease were eligible.

Results 31 patients from 29 families were included. Seventeen patients had skeletal muscle disease, often with proximal weakness and joint contractures, with average symptom onset of 2.2 years. Creatine kinase levels were normal or mildly elevated; electrodiagnostic studies (9/11) and muscle biopsies (11/11) were myopathic. Variants were most commonly identified in the A-band (14/32) or I-band (13/32). Most variants were predicted to be frameshift truncating, nonsense or splice-site (25/32). Seventeen patients had cardiovascular disease (14 isolated cardiovascular, three cardioskeletal) with average symptom onset of 12.9 years. Twelve had dilated cardiomyopathy (four undergoing heart transplant), two presented with ventricular fibrillation arrest, one had restrictive cardiomyopathy and two had other types of arrhythmias. Variants commonly localised to the A-band (8/15) or I-band (6/15) and were predominately frameshift truncating, nonsense or splice-site (14/15).

Conclusion Our cohort demonstrates the genotype–phenotype spectrum of paediatric-onset titinopathies identified in clinical practice and highlights the risk of life-threatening cardiovascular complications. We show the difficulties of obtaining a molecular diagnosis, particularly in neuromuscular patients, and bring awareness to the complexities of genetic counselling in this population.

  • Cardiomyopathies
  • Neuromuscular Diseases
  • Genotype
  • Phenotype
  • Pediatrics

Data availability statement

Data are available upon reasonable request.

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Data availability statement

Data are available upon reasonable request.

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Footnotes

  • Twitter @carbar31

  • APM and CLB contributed equally.

  • Contributors APM, JR, KM and KAR were involved in the design of this study. APM, CLB, JR, KM, TM, RL and CES completed patient chart review and data entry. APM, CLB, JR, KM, TM, RL and CES drafted and reviewed the final publication. APM is the study guarantor.

  • Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.

  • Competing interests None declared.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.