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

Abstract

Background Titin truncating variants (TTNtv) 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. However, TTN is not yet included in many NGS panels for congenital musculoskeletal anomalies and dysmorphisms, and karyotype or chromosomal microarray analyses are often 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 Methods We analyzed an international cohort of 93 published and 10 unpublished cases carrying biallelic TTNtv. Results We identified recurrent clinical features in antenatal and congenital recessive titinopathies, including fetal akinesia, arthrogryposis, facial dysmorphisms, joint, bone, and heart anomalies resembling complex, syndromic phenotypes. Conclusion We suggest TTN to be carefully evaluated in any diagnostic process involving patients with the mentioned signs. This step will be essential to improve diagnostic performance, expand our knowledge, and optimize prenatal genetic counseling.

Biallelic truncating TTN variants in M‐band encoding exons cause a fetal lethal titinopathy

“…analyzed clinical and molecular data from a cohort of novel and previously described recessive titinopathy cases with congenital anomalies or dysmorphisms and showed that biallelic pathogenic titin variants caused recognizable fetal and developmental defects. All newly reported patients present with a severe prenatal or congenital phenotype leading to fetal, perinatal, or infantile death, thus describe the most severe end of the titinopathies 22 . Compared with previous reports (Table 1), the clinical phenotype of rare hydrops, polyhydramnios, and paucity of fetal movements in fetus II3 in this study is indicative of a lethal recessive titinopathy 24 .…”

Novel TTN Mutation Causing Severe Congenital Myopathy and Uncertain Association with Infantile Hydrocephalus

“…Several recent reports have documented autosomal recessive congenital titinopathies associated with proteintruncating variants occurring exclusively in meta-transcript-only exons [10,[12][13][14][15][16]. Fetuses harboring metatranscript-only variants exhibit a severe phenotype characterized by developmental anomalies such as dysgenesis of the corpus callosum, congenital bone fractures, and hypoplastic heart, resulting in the highest rate of fetal lethality [17]. Homozygous recessive mutations within the Nterminal domain of the TTN gene lead to a lethal outcome and biallelic TTN variations are also associated with severe congenital titinopathy [6,15].…”