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

• Published in: Journal of medical genetics Vol. 60; no. 9; pp. 866 - 873
• Main Authors: Di Feo, Maria Francesca, Lillback, Victoria, Jokela, Manu, McEntagart, Meriel, Homfray, Tessa, Giorgio, Elisa, Casalis Cavalchini, Guido C, Brusco, Alfredo, Iascone, Maria, Spaccini, Luigina, D'Oria, Patrizia, Savarese, Marco, Udd, Bjarne
• Format: Journal Article
• Language: English
• Published: England BMJ Publishing Group Ltd 01.09.2023; BMJ Publishing Group LTD
• Subjects: Abortion; Akinesia; Arthrogryposis; Cardiac muscle; Cardiomyopathy; Children; Connectin; Exons; Fetuses; Genetic counseling; genetics, medical; Genotype & phenotype; Genotype-phenotype correlations; Genotypes; Heterozygosity; Karyotypes; Maternal & child health; Muscular dystrophy; Musculoskeletal system; neuromuscular diseases; pediatrics; Phenotypes; Proteins; reproductive medicine; genetics, medical; neuromuscular diseases; reproductive medicine; pediatrics
• ISSN: 0022-2593; 1468-6244; 1468-6244
• DOI: 10.1136/jmg-2022-109018

BackgroundTitin 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spectrum.MethodsWe performed a retrospective study analysing an international cohort of 93 published and 10 unpublished cases carrying biallelic TTNtv.ResultsWe identified recurrent clinical features showing a significant correlation with the genotype, including fetal akinesia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.ConclusionWe 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.