Homozygous truncating mutation in prenatally expressed skeletal isoform of TTN gene results in arthrogryposis multiplex congenita and myopathy without cardiac involvement. Mutations in the titin (TTN) gene on chromosome 2q31 most often produce autosomal dominant tibial muscular dystrophy, a distal muscular dystrophy of mid-adult life with prominent involvement of the tibialis anterior and toe extensor muscles. Truncating mutations in C-terminal titin may cause more severe tibial muscular dystrophy (TMD). Muscular Dystrophy Is a Titinopathy Caused by Mutations in TTN, the Gene Encoding the Giant Skeletal-Muscle Protein Titin. Bethesda, MD 20894, Web Policies But recent technological advances have made it possible to improve treatment. al developed 2 rat strains and modeled a proximal and distal TTNtv mutation and their RNA-seq study revealed a profound nonsense mediated mRNA decay (NMD) of the allele with TTNtv, indicating haploinsufficiency[99]. Life expectancy can reach into the early thirties. The most common type is dilated cardiomyopathy (DCM) with a prevalence of up to ~1:250 [57,99]. PYK, Bouquiaux and transmitted securely. Schematic Representation of Mutations Identified and Algorithm for the Clinical Interpretation of Genetic Findings in Titin, Table 1. Additionally, research groups are focusing on exon skipping approaches to cure TTNtv-associated DCM. Drs Udd and Nigro contributed equally to this work. Have a tip? Muscle cDNA Analysis in Patient IV Confirms that the Variant c.107377+1G>A Causes a Misplicing. The position-dependent effect might be explained by TTN exon usage in left ventricular tissue, characterized by the relative incorporation of exons into titin transcripts, termed proportion spliced-in (PSI) [96]. The possible role of titin variants as modifiers or within a digenic or multigenic disease is not discussed here. M. Next-generation sequencing approaches for the diagnosis of skeletal muscle disorders. Epub 2019 Mar 5. PMC Carmignac Titin is a giant myofilament that extends from the Z-disk (N-terminus) to the M-band (C-terminus) region of the sarcomere and is encoded by the TTN gene [37,69,11,46,47]. In an extensive study of 504 mainly adult, patients who had not received a genetic diagnosis and were presenting with clinical signs of muscular dystrophy, congenital myopathy, or other skeletal muscle disorders, we identified 9 novel patients (1.8%) with titinopathy and 4 patients (0.8%) with very likely disease-causing TTN mutations. V. Limb-girdle muscular dystrophiesinternational collaborations for translational research. 2002 Sep. 71(3):492-500. Cardiac problems can be a feature. Tasca Hence, it has been suggested that TTNtv can be tolerated in the healthy population because the majority of the mutations fall in I-band exons that are subject to alternative splicing [96,60]. Familial adenomatous polyposis (FAP) is an autosomal dominant inherited condition in which numerous adenomatous polyps form mainly in the epithelium of the large intestine.While these polyps start out benign, malignant transformation into colon cancer occurs when they are left untreated. In addition, women carrying TTNtv mutations have a better prognosis than men [56,30]. Constitutively expressed exons have high PSI values, whereas exons that are subject to alternative splicing show low PSI scores [96,27]. Schafer et. Obtained funding: Savarese, Angelini, Udd, Nigro. TTNtv have also been linked to peripartum cardiomyopathy (PPCM) where the distribution of truncating variants in PPCM is similar to that found in DCM [108,112]. et al. This article does not contain any primary studies with human participants or animals performed by any of the authors. National Library of Medicine Dystrophin acts like a shock absorber when muscles contract. 219th ENMC International Workshop Titinopathies International database of titin mutations and phenotypes, Heemskerk, The Netherlands, 29 April-1 May 2016. C, Muscular dystrophy is a genetic health disease that affects the body's muscles. B, p.Thr31339Ala modeled using the structure 2NZI of titin domains A168-A170. Sequencing data were analyzed using an internal custom bioinformatics pipeline. Practical Aspects in Genetic Testing for Cardiomyopathies and Channelopathies. The site is secure. Supervision: Savarese, Hackman, Udd, Nigro. Two further biallelic PTVs were identified in patient VI (p.Val26358Phefs*4 and p.Gln35879*, the latter recently reported as a BalkanMiddle East founder mutation34,35) and in 2 siblings (cases VIIa and VIIb) (p.Cys9322* and p.Arg35800Glnfs*10). et al; ACMG Laboratory Quality Assurance Committee. J, Vihola This site needs JavaScript to work properly. Interestingly, mutated iPSC cardiomyocytes, derived from DCM patients with TTNtv, show attenuated response to isoproterenol, [Ca2+]out and angiotensin-ll. Guex Patient VI was a woman in her mid-50s presenting in her early 30s with frequent tripping. The change from threonine to alanine is predicted in a loop and will probably not interfere with the structure. Next-generation sequencing for molecular diagnosis of neuromuscular diseases. et al. Detection of genomic structural variants from next-generation sequencing data. Immunohistochemicaldystrophin tests can indicate a decrease in dystrophin detected in sarcoglycanopathies. Savarese Sequence variants in TTN are described according to the coding DNA reference sequence (LRG_391t1), covering transcript variant-IC (NM_001267550.1). Dubowitz FOIA A 34-year-old Belgian patient (patient V) with an unremarkable family history harbored the p.Glu11945Argfs*6 variant in exon 164 and the c.25063+1G>A variant in intron 87 in compound heterozygosity. You dont know what to expect or when to expect whats going to happen, but you know something is going to happen. Learn more details about the disease below. found that all components of the mitochondrial electron transport chain are significantly upregulated in patients with TTNtv, leading to pronounced cardiac lterations in mitochondrial function [109]. PubMedGoogle ScholarCrossref 3. The underlying mechanisms by which titin mutations induce disease are poorly understood and targeted therapies are not available. Vasli Novex-3 titin, a ~700 kDa titin isoform is found in cardiac and skeletal muscle [11,42,64]. Accessibility The age of onset of the disease varies from childhood to adult life. et al. Muscular dystrophies ( MD) are a genetically and clinically heterogeneous group of rare neuromuscular diseases that cause progressive weakness and breakdown of skeletal muscles over time. Udd G, Bonkowsky Moreover TTNtv+ zebrafish show electrophysiological defects that could potentially develop into arrhythmia [3]. Clinical Summary of Index Patients, Table 2. The distal myopathies belong to a larger group of disorders known as the muscular dystrophies. Background and Objectives Duchenne muscular dystrophy (DMD) is a rare progressive disease that is often diagnosed in early childhood and leads to considerably reduced life expectancy; because of its rarity, research literature and patient numbers are limited. A, Chapon If previously reported disease-causing mutations are identified, they may easily address the diagnosis of a titinopathy; however, segregation studies and a deep phenotyping are mandatory for a correct genotype-phenotype correlation and for proper genetic counselling. Epub 2018 Jun 2. Extensive mRNA splicing results in distinct titin isoforms [11,70] (Figure 1). Titin serine kinase phosphorylates telethonin, the protein implicated in LGMD2G. With early treatment, it can reach 30 years. The computed molecular surface is semitransparent gray and the secondary structure is shown with yellow strands and red helices. Tibial muscular dystrophy Patients with tibial muscular dystrophy usually begin developing symptoms between the ages of 40 and 60. A new titinopathy: childhood-juvenile onset Emery-Dreifusslike phenotype without cardiomyopathy. The former is located in an Fn3 domain in the A-band portion of titin, and in silico studies predicted that the amino acid is located on the external surface of the domain, possibly affecting the binding to the interactors. Features of Titin-Related Skeletal Musical Disorders. Concept and design: Savarese, Maggi, Vihola, Jonson, Politano, Angelini, Comi, Hackman, Udd, Nigro. In Touch Weekly is part of the a360media Entertainment Group.Copyright a360media 2023. J, Vihola Often additional rare truncating variants or other pathogenic cardiomyopathy genes are present in TTNtv carriers that can increase the severity of DCM or can be associated with an earlier onset of the disease [56,86,97,51]. sharing sensitive information, make sure youre on a federal MeSH In addition to providing elasticity, these segments also interact with signaling proteins and have been proposed to function as mechanosensor complexes [114,95,67,88,46,81,77] with mouse models that genetically target individual spring elements supporting such roles [93,48,61,94,23,15]. In addition, TTNtv-associated DCM patients respond well to standard DCM therapies [63]. Charton Messenger RNA analyses confirmed the splicing effect of the intronic variant (eFigure in the Supplement). MD is a progressive condition, which means it gets worse over time. Furthermore, TTNtv can be associated with a more severe form of chemotherapy-induced cardiomyopathy (CCMP). C, Bonnemann It is now well established that TTN is a major human disease gene that causes multiple neuromuscular and cardiac diseases [56,96,99,13,98,26,75,89,20,74]. Increasing evidence is indicating that titin truncating variants cause recessive skeletal muscle disorders.9,15,16,34 In the presence of monoallelic PTVs, we suggest performing a WB analysis that represents the most valuable and potentially conclusive test, as it is the only available tool able to predict the presence of further elusive truncating variants in trans (as seen in patient VIII and in a previously reported patient9). Since childhood, the patient had shown mildly progressive generalized muscular weakness. et al. Urinary N-terminal fragment of titin is a marker to diagnose muscular dystrophy in patients with cardiomyopathy. Mutations in the titin gene (TTN) cause a wide spectrum of genetic diseases. In silico predictions confirmed that c.25063+1G>A would result in a splicing defect. Patient VIIb, a sibling, showed similar clinical and histological features. Titins M-band region contains the serine/threonine kinase (TK) domain and is involved in numerous signaling pathways [83,116,115,91,90,39,19]. Limb-girdle muscular dystrophy type 2G is caused by mutations in the gene encoding the sarcomeric protein telethonin. VSC, Oldfors B, Patient Xa with missense mutations showed a normal titin C-terminal pattern, while patient IXa with a single protein truncating variant and 2 missense variants showed a reduction of the small (<20 kDa) titin C-terminal fragments in particular. Results showed that titin deficiency leads to sarcomere disassembly and atrophy in striated muscle and eventually DCM. Mrosek The clinical details of each patient are summarized in Table 1 and described in the eAppendix in the Supplement. Titin provides passive stiffness to the striated muscle sarcomere and modulates active contractile force [45,16,104,18,36,34,33,35,79,4,10,73,50]. Due to alternative splicing, adult full-length cardiac isoforms differ in the length of their tandem and PEVK segments in the I-band and their stiffness varies accordingly [11,17,118] [32]. Further messenger RNA and WB analyses were not performed because of the unavailability of muscle tissue. The patients had not received diagnoses despite extensive diagnostic investigations performed according to the observed phenotype. Clipboard, Search History, and several other advanced features are temporarily unavailable. Next-generation sequencing is rapidly being implemented into routine clinical practice, improving the diagnostic rate for patients with neuromuscular diseases.21-23 Almost all NGS screenings reveal many rare and private titin variants and their clinical interpretation is particularly challenging.5,19,24-26 By using MotorPlex (Agilent Technologies), a targeted NGS panel, we screened TTN and the other muscle disease genes in 504 patients with skeletal muscle disorders.25,26 Here, we describe the approach used for the NGS data interpretation and we propose a workflow for a more straightforward and reproducible interpretation of the clinical meaning of titin variants. Our study has limitations. et al. Missense variants were explicitly studied in a single large recessive family only (family X). There are many kinds of muscular dystrophy. 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