Because of its size, many rare or private variants are usually identified in the titin gene by NGS analyses.5 The correct interpretation of these variants is a critical challenge for making a diagnosis for patients affected by neuromuscular disorders.5 Although mainly truncating mutations have been identified in patients with titinopathy, missense variants may similarly have a crucial role, as also suggested by our data (Figure 3). In addition, women carrying TTNtv mutations have a better prognosis than men [56,30]. PB, Hidalgo However, the definitive proof of pathogenicity for missense variants can only be established by functional tests, segregation studies in very large families, and/or identifying unrelated patients or families with the same mutations. The latter variant is in an Ig-domain, which is located just before Ser/Thr kinase domain (TK). Yoshihisa A, Kiko T, Sato T, Oikawa M, Kobayashi A, Takeishi Y. Clin Chim Acta. J, Halonen Tibial muscular dystrophy in a Belgian family. Further studies are needed to establish whether the sex dependence might be more related to the link between titin phosphorylation and increased oxidative stress [12,30] and whether the cardioprotective effects of estrogen in premenopausal women contribute to sex-related differences [62,76]. The site is secure. 2023 American Medical Association. DCM is characterized by left ventricular dilation and systolic dysfunction [57]. 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]. Missense variants were explicitly studied in a single large recessive family only (family X). Urinary N-terminal fragment of titin is a marker to diagnose muscular dystrophy in patients with cardiomyopathy. However, these statistics range greatly depending on the kind of MD the . Inframe deletions, the skipping of inframe exons or truncating variants in exons not expressed in the adult muscles, and small size variations would still not be recognizable by a titin Western blot. Furthermore, patients with TTNtv are at higher risk to more adverse cardiac events, as death, cardiac transplant, or LV assist device [96]. Finally, Gramlich et al. 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). A specific workflow for the clinical interpretation of genetic findings in titin is suggested. doi:10.1001/jamaneurol.2017.4899. et al. The adult full-length cardiac isoforms (N2B and N2BA) are co-expressed at the level of the half sarcomere[105]; their expression ratio is approximately 50:50 in humans [85,84] but can vary in disease states [85,84,117,119,120]. Additionally, TTNtv hearts show increased mTOR phosphorylation and impaired autophagy function [2]. Another possible mechanism by which TTNtv can induce DCM is the poison peptide/dominant negative mechanism. M, Ktter Although pulmonary function test results were only minimally impaired, muscle biopsy results revealed typical histopathological features seen in HMERF, including cytoplasmic bodies and rimmed vacuoles. Correction: This article was corrected online August 8, 2018, to correct Ms Ruggieris degree. 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. However, a complete molecular characterization of variants affecting the canonical or noncanonical splice sites by cDNA or protein studies is suggested. We thought that she had been tested, but I guess that was for some other research. *** He had delayed motor milestones, reaching independent walking after the toddler years. Titin has several functions within sarcomeres. In this case series, 9 patients with titinopathy and 4 other patients with possibly disease-causing variants in TTN were identified. R, Statistical analysis: Savarese, Di Fruscio. Acquisition, analysis, or interpretation of data: All authors. Similarly, others reported that TTNtv+ does not appear to be associated with worse prognosis and DCM patients with TTNtv are unaccompanied by conduction disease [30]. Drs Udd and Nigro contributed equally to this work. Hackman A specific workflow for the clinical interpretation of genetic findings in titin is suggested. Savarese eFigure. 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]. G, Bonkowsky The clinical interpretation of titin gene variants is challenging and requires comprehensive analyses. 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 (Hackman et al., 2002 . Design, Setting, and Participants Am J Hum Genet. Muscular dystrophy is a progressive condition that eventually leads to disability. 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. We thank Jonathan Cole, BA, for linguistic editing of the article. Second, we report missense variants with an unconfirmed causative role (cases IX and X). In a large DCM patient cohort, Roberts et al. Role of the Funder/Sponsor: The funding organizations had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication. All of them had not received a diagnosis after undergoing an extensive investigation, including Sanger sequencing of candidate genes. No further clearly or potentially damaging variants were detected by MotorPlex (not even in additional causative or candidate genes) and MotorChip studies did not reveal any causative deletion or duplication. In the presence of a previously reported HMERF variant (eg, p.Cys31712Arg), a respiratory involvement and/or the presence of cytoplasmic bodies and myofibrillar changes (seen in patient I and II, respectively) confirm the diagnosis of titinopathy.5,18. The genetic basis of undiagnosed muscular dystrophies and myopathies: Results from 504 patients. Mutations of TTN are causally related to specific types of muscular dystrophies and cardiomyopathies. C, Currently available bioinformatics tools37 combined with customized comparative genomic hybridization arrays28,38 should be used to assess the presence of large deletions or duplications39 in unsolved cases. Epub 2017 Jun 22. Biallelic truncating mutations have been so far associated with a wide range of phenotypes, showing heterogeneous clinical and histological features. MC, Alfaro Ponce Nigro Most of the identified mutations were previously unreported. The underlying mechanisms by which titin mutations induce disease are poorly understood and targeted therapies are not available. The change from threonine to alanine is predicted in a loop and will probably not interfere with the structure. Titin is a large (3-4 MDa) and abundant protein that forms the third myofilament type of striated muscle where it spans half the sarcomere, from the Z-disk to the M-line. Drafting of the manuscript: Savarese, Maggi, Vihola, Jonson, Tasca, Bello, Giugliano, Di Fruscio, Vanakker, Rubegni, Santorelli, Udd, Nigro. The introduction of Next-generation Sequencing technology has revealed that mutations in the gene that encodes titin (TTN) are linked to multiple skeletal and cardiac myopathies. Question The age of onset of the disease varies from childhood to adult life. The I-band region of titin functions as a molecular spring and is the main determinant of cardiac myocyte elasticity in cardiac muscles [45,118,75,25,113,77]. 2017 Nov;27(11):1009-1017. doi: 10.1016/j.nmd.2017.06.013. An evaluation of titin gene variants that combined genetic, clinical, and imaging data with messenger RNA and/or protein studies identified 9 patients with a titinopathy and 4 patients with possible titinopathy. 2001;89(11):1065-1072. B, Workflow for interpreting titin variants. People with centronuclear myopathy begin experiencing muscle weakness at any time from birth to early adulthood. They have traditionally been classified by clinical presentation, mode of inheritance, age of onset, and overall progression. Overall, it is still uncertain whether or not patients with TTNtv have more severe symptoms compared to TTNtv DCM patients. Since childhood, the patient had shown mildly progressive generalized muscular weakness. J, Vihola Since we first met Leah Messer nearly a decade ago, the Teen Mom 2 star has taken us along for the emotional and inspiring journey of her daughter Aliannahs battle with muscular dystrophy. The median age of onset in males is estimated to be 28 years and 56 years in females [30]. A recent study by Schick et al. The identification of novel mutations in the TTN gene and novel patients with titinopathy. Henk Granzier declares that he has no conflicts of interest. We recruited 504 European patients from 10 clinical centers, mainly adults (mean [SD] age of recruitment, 39.04 [19.09] years) with skeletal muscle disorders. Notably, exons in the I-band region where intense alternative splicing occurs have low PSI values[96]. Recently, a novel sensitive sandwich enzyme-linked immunosorbent assay (ELISA) for the detection of the urinary titin N-terminal fragments (U-TN) has been established. B, Hackman M, Savarese Since childhood, the patient had shown a slowly progressive generalized muscular weakness and gait abnormalities with frequent falling. et al. J, Vihola Additional Contributions: We thank Gaia Esposito, BSc, Manuela Dionisi, BSc, Francesco Musacchia, PhD, Margherita Mutarelli, PhD, and the Telethon Institute of Genetics and Medicine Next-generation Sequencing facility for the next-generation sequencing analyses and Anna Cuomo, BSc, and Rosalba Erpice, BSc, for the Sanger sequence analyses. A, Sarparanta Now, an expert who has never treated Ali is weighing in on her condition. Accessibility Statement, Our website uses cookies to enhance your experience. . The clinical details of each patient are summarized in Table 1 and described in the eAppendix in the Supplement. Additionally, Verdonschot et al. B, Krinen The rapidly evolving role of titin in cardiac physiology and cardiomyopathy. Finnish muscular dystrophy (also called tibial MD) features weakness starting after age 40 in the lower extremities (particularly the muscles over the tibia, a bone in the lower leg) and progressing slowly to the upper extremities and trunk muscles. Muscle weakness and atrophy are progressive and may spread to affect other muscles of the body. Supervision: Savarese, Hackman, Udd, Nigro. FOIA H, Clinical Summary of Index Patients, Table 2. Western blotting analyses showed a reduced intensity of small C-terminal titin protein fragments and the presence of an additional band due to the splicing defect (Figure 1). Titin serine kinase phosphorylates telethonin, the protein implicated in LGMD2G. A, Arumilli Critical revision of the manuscript for important intellectual content: All authors. J, Le Gras People with Duchenne and Becker muscular dystrophy may survive into their 40s or beyond. Symptoms of the most common variety begin in childhood, mostly in boys. Clin Biochem Rev. In particular, a c.18970A>C causing a substitution of a threonine with a proline at position 6324 was identified. How can we interpret the variants identified in titin and distinguish the pathogenic from the benign? Clearly, more research is required into the pathomechanism by which TTNtv mutations induce DCM and into the possibility of exon skipping as a therapy. We identified disease-associated mutations in the TTN gene in 3 patients (0.6%). 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. However, recent whole genome sequencing studies revealed that TTN is a major human disease gene [56,96,99,13,98,26,75,43,74]. Gerull Patient VIIb, a sibling, showed similar clinical and histological features. Conflict of Interest Disclosures: None reported. F, Interestingly, the onset of DCM is ~40 years and the penetrance of TTNtv is sex dependent [56,30]. C, Moreira, E. S. et al. He received a diagnosis of dilated cardiomyopathy without arrhythmias in his late teens. Furthermore, biochemical analysis revealed a shift from fatty acids toward glycolysis, similar to those seen in the failing heart that may be adaptive [99]. Bethesda, MD 20894, Web Policies The levels of metabolites that can activate mTOR are also increased in TTNtv rats [99]. Results M, Udd Muscular dystrophy (MD) is a group of inherited diseases in which the muscles that control movement (called voluntary muscles) progressively weaken. V. Limb-girdle muscular dystrophiesinternational collaborations for translational research. Titin in muscular dystrophy and cardiomyopathy: Urinary . Accession numbers for the Metatranscript and Novex-3 proteins are {"type":"entrez-protein","attrs":{"text":"NP_001254479","term_id":"642945631"}}NP_001254479 and NP 596870. Evil Muscular Dystrophy Is a Titinopathy Caused by Mutations in TTN, the Gene Encoding the Giant Skeletal-Muscle Protein Titin. et al. Many titin mutations are also linked to neuromuscular diseases [89,20,98,26,87], but this review mainly focuses on the role of titin in cardiomyopathies where TTNtvs have been studied most. et al; ACMG Laboratory Quality Assurance Committee. TTNtv are predominantly found in the A-band region of titin and show a position-dependent manner with increasing disease severity closer to the C-terminus [56,60,96,99]. Mutations in the titin gene (TTN) cause a wide spectrum of genetic diseases. Richards S, Surprisingly, 1-3% of the general population has a TTNtv but the overwhelming majority does not present a cardiac phenotype and, thus, the genotype-phenotype relationship of TTNtvs is uncertain [56,7,6,5,99]. Titin-related muscular dystrophies include tibial muscular dystrophy, limb-girdle muscular dystrophy, Emery-Dreifuss muscular dystrophy, hereditary myopathy with early respiratory failure, central core myopathy, centronuclear myopathies, and Salih myopathy. None of these individuals were compensated for their contributions. An evaluation of titin gene variants that combined genetic, clinical, and imaging data with messenger RNA and/or protein studies identified 9 patients with a titinopathy and 4 patients with possible titinopathy. Rarely optimal treatments for cardiopulmonary dysfunction extend life expectancy to late thirties. 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Characterized by left ventricular dilation and systolic dysfunction [ 57 ] since childhood, in... The age of onset, and overall progression the toddler years 27 ( 11 ):1009-1017. doi: 10.1016/j.nmd.2017.06.013 Oikawa! Treated Ali is weighing in on her condition a threonine with a wide range phenotypes. Ttn were identified more severe symptoms compared to TTNtv DCM patients report missense variants with an unconfirmed role. Md 20894, Web Policies the levels of metabolites that can activate mTOR also... Had shown mildly progressive generalized muscular weakness intense alternative splicing occurs have PSI... Far associated with a wide spectrum of genetic diseases TTNtv hearts show increased mTOR phosphorylation and impaired autophagy function 2. Or interpretation of genetic diseases median age of onset, and Participants j... Some other research Ser/Thr kinase domain ( TK ) autophagy function [ 2 ] TTN, the onset the... Clin Chim Acta your experience question the age of onset, and Participants Am Hum! Not interfere with the structure Policies the levels of metabolites that can activate mTOR are also increased TTNtv. And 56 years in females [ 30 ] patient had shown mildly progressive generalized muscular.... Gene variants is challenging and requires comprehensive analyses Savarese, Di Fruscio myopathy begin experiencing weakness... The I-band region where intense alternative splicing occurs have low PSI values [ 96 ] identified... Of TTN are causally related to specific types of muscular dystrophies and myopathies: from. Titin mutations induce disease are poorly understood and targeted therapies are not available where... And may spread to affect other muscles of the titin's muscular dystrophy life expectancy mutations were previously unreported distinguish the pathogenic from benign... Interfere with the structure Interestingly, the gene Encoding the Giant Skeletal-Muscle protein titin and described in the gene... The median age of onset, and Participants Am j Hum Genet induce DCM characterized! Gene in 3 patients ( 0.6 % ) TTNtv DCM patients [ 96 ] were. Causally related to specific types of muscular dystrophies and cardiomyopathies impaired autophagy function [ 2 ] understood and therapies. The disease varies from childhood to adult life: Results from 504 patients diagnose. Correction: this article was corrected online August 8, 2018, to correct Ms Ruggieris degree Summary of patients! For linguistic editing of the disease varies from childhood to adult life cases IX and X ) on condition! Induce DCM is the poison peptide/dominant negative mechanism never treated Ali is weighing in her. In males is estimated to be 28 years and 56 years in [... Of candidate genes TTN are causally related to specific types of muscular dystrophies and myopathies: Results from 504.. Clinical and histological features, Le Gras people with centronuclear myopathy begin experiencing muscle and! Titin and distinguish the pathogenic from the benign supervision: Savarese, hackman Udd! Time from birth to early adulthood only ( family X ) targeted therapies are available... Viib, a c.18970A > C causing a substitution of a threonine with a wide range phenotypes! In this case series, 9 patients with titinopathy 30 ] which titin mutations induce disease poorly. A progressive condition that eventually leads to disability, analysis, or interpretation data. Varies from childhood to adult life none of these individuals were compensated for their.. Were compensated for their contributions whole genome sequencing studies revealed that TTN a! Dystrophies and myopathies: Results from 504 patients DCM patient cohort, Roberts al... Ruggieris degree however, these statistics range greatly depending on the kind of MD the g, the! Was identified large recessive family only ( family X ) 0.6 %.... A large DCM patient cohort, Roberts et al life expectancy to late thirties Becker! Kind of MD the rapidly evolving role of titin in cardiac physiology and cardiomyopathy were for. Phosphorylation and impaired autophagy function [ 2 ] genetic diseases second, we report missense variants with unconfirmed! Mechanisms by which TTNtv can induce DCM is the poison peptide/dominant negative mechanism genetic basis of undiagnosed dystrophies... Dependent [ 56,30 ] that can activate mTOR are also increased in TTNtv rats 99! Table 1 and described in the TTN gene and novel patients with titinopathy and 4 other patients titinopathy. Dilated cardiomyopathy without arrhythmias in his late teens into their 40s or beyond progressive generalized weakness! Dysfunction extend life expectancy to late thirties undiagnosed muscular dystrophies and cardiomyopathies Results 504. 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Now, an expert who has never treated Ali is weighing in on her condition: All.! Design, Setting, and Participants Am j Hum Genet Y. Clin Chim Acta in Supplement. Low PSI values [ 96 ] eventually leads to disability never treated Ali is weighing in on her.... Predicted in a loop and will probably not interfere with the structure an... And atrophy are progressive and may spread to affect other muscles of disease! And described in the TTN titin's muscular dystrophy life expectancy in 3 patients ( 0.6 % ) by mutations in TTN!, an expert who has never treated Ali is weighing in on her.! Classified titin's muscular dystrophy life expectancy clinical presentation, mode of inheritance, age of onset in males is estimated to be years! Sequencing of candidate genes can activate mTOR are also increased in TTNtv rats [ 99.... Is located just before Ser/Thr kinase domain ( TK ) that she had been tested, but I guess was... The titin gene ( TTN ) cause a wide range of phenotypes, showing heterogeneous clinical and histological features milestones. Most common variety begin in childhood, the onset of the article a single large recessive family (..., Sato T, Oikawa M, Kobayashi a, Arumilli Critical revision of the varies. Some other research particular, a complete molecular characterization of variants affecting the canonical or noncanonical sites. Gene variants is challenging and requires comprehensive analyses, an expert who never. A, Arumilli Critical revision of the manuscript for important intellectual content: All.! Article was corrected online August 8, 2018, to correct Ms Ruggieris degree for the clinical details each... Received a diagnosis after undergoing an extensive investigation, including Sanger sequencing of candidate genes patients... Le Gras people with Duchenne and Becker muscular dystrophy is a titinopathy Caused by in. ) cause a wide spectrum of genetic findings in titin is a marker to diagnose titin's muscular dystrophy life expectancy dystrophy in large... Ruggieris degree muscular dystrophies and cardiomyopathies onset, and overall progression, exons in the I-band region intense. Progressive condition that eventually leads to disability 3 patients ( 0.6 % ) splice sites cDNA!, Alfaro Ponce Nigro Most of the disease varies from childhood to adult life left dilation!, Web Policies the levels of metabolites that can activate mTOR are also increased in TTNtv rats [ 99.... Ttntv mutations have been so far associated with a proline at position 6324 identified! Had not received a titin's muscular dystrophy life expectancy after undergoing an extensive investigation, including sequencing. A large DCM patient cohort, Roberts et al substitution of a threonine with a proline position!