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The crucial role of titin in fetal development: recurrent miscarriages and bone, heart and muscle anomalies characterise the severe end of titinopathies spectrum
  1. Maria Francesca Di Feo1,
  2. Victoria Lillback2,3,
  3. Manu Jokela4,5,
  4. Meriel McEntagart6,
  5. Tessa Homfray7,
  6. Elisa Giorgio8,9,
  7. Guido C Casalis Cavalchini10,
  8. Alfredo Brusco11,
  9. Maria Iascone12,
  10. Luigina Spaccini13,
  11. Patrizia D'Oria14,
  12. Marco Savarese2,15,
  13. Bjarne Udd2,16
  1. 1Department of Neuroscience, Rehabilitation, Ophthalmology, Genetics, and Maternal and Child Health (DINOGMI), University of Genoa, Genova, Italy
  2. 2Folkhälsan Research Center, Helsinki, Uusimaa, Finland
  3. 3University of Helsinki Department of Medical and Clinical Genetics, Helsinki, Uusimaa, Finland
  4. 4Tampere University Hospital, Tampere, Pirkanmaa, Finland
  5. 5TYKS Turku University Hospital, Turku, Varsinais-Suomi, Finland
  6. 6Department of Medical Genetics, St George's University of London, London, London, UK
  7. 7St George's University of London, London, London, UK
  8. 8Department of Molecular Medicine, University of Pavia, Pavia, Lombardia, Italy
  9. 9Fondazione Istituto Neurologico Nazionale C Mondino Istituto di Ricovero e Cura a Carattere Scientifico, Pavia, Lombardia, Italy
  10. 10Medical Genetics Unit, Azienda Ospedaliero Universitaria Città della Salute e della Scienza di Torino, Torino, Piemonte, Italy
  11. 11Department of Medical Sciences, University of Turin School of Medicine, Torino, Piemonte, Italy
  12. 12Laboratorio di Genetica Medica, ASST Papa Giovanni XXIII, Bergamo, BG, Italy
  13. 13Unità di Genetica Medica, UOC Ostetricia e Ginecologia, Ospedale dei Bambini Vittore Buzzi, Milano, Lombardia, Italy
  14. 14UOC Ostetrica e Ginecologia, Ospedale Bolognini di Seriate, Seriate, Lombardia, Italy
  15. 15Department of Medical Genetics, University of Helsinki, Helsinki, Uusimaa, Finland
  16. 16Tampere University Hospital Department of Musculoskeletal Diseases, Tampere, Pirkanmaa, Finland
  1. Correspondence to Dr Maria Francesca Di Feo, Department of Neuroscience, Rehabilitation, Ophthalmology, Genetics, and Maternal and Child Health (DINOGMI), University of Genoa, Genova, Italy; mfrancesca.difeo{at}


Background Titin truncating variants (TTNtvs) have been associated with several forms of myopathies and/or cardiomyopathies. In homozygosity or in compound heterozygosity, they cause a wide spectrum of recessive phenotypes with a congenital or childhood onset. Most recessive phenotypes showing a congenital or childhood onset have been described in subjects carrying biallelic TTNtv in specific exons. Often karyotype or chromosomal microarray analyses are the only tests performed when prenatal anomalies are identified. Thereby, many cases caused by TTN defects might be missed in the diagnostic evaluations. In this study, we aimed to dissect the most severe end of the titinopathies spectrum.

Methods We performed a retrospective study analysing an international cohort of 93 published and 10 unpublished cases carrying biallelic TTNtv.

Results We identified recurrent clinical features showing a significant correlation with the genotype, including fetal akinesia (up to 62%), arthrogryposis (up to 85%), facial dysmorphisms (up to 73%), joint (up to 17%), bone (up to 22%) and heart anomalies (up to 27%) resembling complex, syndromic phenotypes.

Conclusion We suggest TTN to be carefully evaluated in any diagnostic process involving patients with these prenatal signs. This step will be essential to improve diagnostic performance, expand our knowledge and optimise prenatal genetic counselling.

  • genetics, medical
  • pediatrics
  • neuromuscular diseases
  • reproductive medicine

Data availability statement

All data relevant to the study are included in the article or uploaded as supplementary information.

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Data availability statement

All data relevant to the study are included in the article or uploaded as supplementary information.

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  • MS and BU contributed equally.

  • Contributors Conceptualisation: MS and MFDF; data curation: MFDF; data analysis and writing (original draft): MFDF and VL; patient recruitment and phenotypical characterisation: EG, AB, TH, MM, MJ, MI, LS, PD'O, GCCC and BU; supervision and writing (review and editing): MS and BU. MFDF and MS are also the guarantors.

  • Funding MS received funding from the Academy of Finland and Sydantutkimussaatio. BU received funding from the Academy of Finland and the European Joint Programme for Rare Disease.

  • 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.