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

TTN gene encodes for titin, the largest protein in the human body, with a crucial role in the development and functioning of the sarcomere. Here, we collected clinical and molecular data from a cohort of early-onset recessive titinopathy cases, and we proved that biallelic titin pathogenic variants cause recognizable fetal and developmental defects. Also, we found that the clinical signs may vary according to the combination of variants. Severe recessive titinopathies, mainly caused by truncating variants in metatranscript-only exons or in exon 359, have antenatal signs resembling a syndromic phenotype, not only affecting the muscular systems but also bone, heart, and other organs, with a quite high rate of dysmorphisms and a significant rate of fetal and neonatal death. (By Dr Maria Francesca Di Feo, https://jmg.bmj.com/content/early/2023/03/28/jmg-2022-109018 )

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