The crucial role of titin in fetal development: Recurrent miscarriages and bone, heart and muscle anomalies characterise the severe end of titinopathies spectrum

Maria Francesca Di Feo, Victoria Lillback, Manu Jokela, Meriel McEntagart, Tessa Homfray, Elisa Giorgio, Guido C. Casalis Cavalchini, Alfredo Brusco, Maria Iascone, Luigina Spaccini, Patrizia D'Oria, Marco Savarese, Bjarne Udd

Research output: Contribution to journalArticleScientificpeer-review

Abstract

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 Methods: We performed a retrospective study analysing an international cohort of 93 published and 10 unpublished cases carrying biallelic TTNtv.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

Original languageEnglish
Number of pages8
JournalJOURNAL OF MEDICAL GENETICS
DOIs
Publication statusE-pub ahead of print - 2023
Publication typeA1 Journal article-refereed

Keywords

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

Publication forum classification

  • Publication forum level 2

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

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