A limited amount of truncated protein has been found in induced pluripotent stem cell (iPSC) cardiomyocytes derived from patients with TTNtv [60]. Overall, the importance of changes in cardiac metabolism and calcium handling in DCM caused by TTNtv warrant further investigation, including whether these changes develop directly from the truncating mutation or, more likely, are secondary effects. In this case series, 504 patients with skeletal muscle disorders were screened with a targeted resequencing approach. The average life expectancy for someone with Duchenne muscular dystrophy the most common kind is 26 years old. found that TTNtv containing transcripts are not subjected to NMD and no changes in the protein expression levels of major titin isoforms are detectable, suggesting the possible role of poison peptide/dominant negative mechanism in TTNtv-related DCM [96]. et al. It has been suggested that the unique domain composition of the IA zone reflects an alteration in titin-myosin interaction that is critical for the termination of the thick filament[14]. Indeed, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis suggests altered cardiac metabolism in TTNtv rats, independently of the position of the truncation [99]. John E. Smith declares that he has no conflicts of interest. Even though TTNtv mutations are likely to affect ribosome activity [99], sarcomeric organization [60,40] and alter cardiac metabolism [99,109], a clear genotype-phenotype correlation is often lacking. Truncations of titin causing dilated cardiomyopathy. Muscle cDNA Analysis in Patient IV Confirms that the Variant c.107377+1G>A Causes a Misplicing. First, the huge size of the TTN gene and its complex structure, due to a 10-kb triplicate region where 9 exons are repeated 3 times, may hamper an exhaustive gene analysis by NGS, resulting in low-covered or noncovered regions and thus in unidentified mutations. M, Sarparanta The PubMed wordmark and PubMed logo are registered trademarks of the U.S. Department of Health and Human Services (HHS). Helman The second detected variant was a c.94015A>G leading to a substitution of a threonine at position 31339 with an alanine in an Fn3 domain (A-band portion of titin). MC, Alfaro Ponce During the reunion special, Leah explained how her daughter continues to get weaker and will probably need home care at some point. Limb-girdle muscular dystrophies (LGMD) are a group of rare progressive genetic disorders that are characterized by wasting (atrophy) and weakness of the voluntary muscles of the hip and shoulder areas (limb-girdle area). In family IX, the proband was a teenage boy who presented with hypotonia and congenital torticollis at birth. Titin in muscular dystrophy and cardiomyopathy: Urinary . Most mutations that alter titin's characteristics seem to be incompatible with life, since very few associated genetic diseases have been described. 2019 May; 471(5): 673682. In a man in his early 30s with healthy parents and siblings (patient IV), we found a splice site variant (c.107377+1G>A in intron 362) on the maternal allele and a nonsense variant (p.Tyr21719* in exon 312) on the paternal allele. M, Di Fruscio 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. Life expectancy can reach into the early thirties. V. Identification of an intragenic deletion in the SGCB gene through a re-evaluation of negative next-generation sequencing results. V, Rispoli Although currently there is lack of evidence for pathogenicity of novex-3 titin mutations [96], whole exome sequencing technologies are enabling the identification of novel rare cardiomyopathy-causing titin truncating variants [101] and it is possible that in future studies novex-3 titin truncating mutations will be shown to play a role in the pathomechanism of some cardiomyopathies [64,22]. It's a genetic disorder group that causes . Constitutively expressed exons have high PSI values, whereas exons that are subject to alternative splicing show low PSI scores [96,27]. Giugliano Patients with DCM caused by TTNtv respond to standard DCM therapies [63] and long-term prognosis is similar to that of patients without TTNtvs [29,109]. Federal government websites often end in .gov or .mil. The most common mutation responsible for the HMERF phenotype (p.Cys31712Arg in exon 344)18 was identified in 2 cases (I and II). A specific workflow for the clinical interpretation of genetic findings in titin is suggested. An official website of the United States government. 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. Accepted for Publication: August 6, 2017. Objective The C-zone region of titin likely plays a role in anchoring MyBP-C[31], regulating actomyosin interaction[82] and regulating the thick filament length[103]. 2017 Nov;27(11):1009-1017. doi: 10.1016/j.nmd.2017.06.013. showed that hemodynamic stress caused by angiotensin II or isoproterenol can induce a more severe phenotype in heterozygous TTNtv mice compared to control litter mates [40]. et al. JN, Tpf 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. Development of novel drugs is hindered by the difficulties in selecting appropriate outcome measure [7]. Their serum creatine kinase levels were normal. Duchenne muscular dystrophy (DMD) <10 per 100,000 in male <1 per million in female: 2 to 6 years : Muscle weakness and wasting affect pelvis, upper arms, and upper legs. 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. Weakness first develops in the hips, pelvis, thighs and shoulders, and people with BMD may have thick calf muscles. A specific workflow for the clinical interpretation of genetic findings in titin is suggested. These disorders vary in age of onset, severity, and pattern of affected muscles. The myosin heavy chain (MyHC) serves as the loading control. A, Adami It is known that mTORCI, which functions as a nutrient/energy sensor and controls protein synthesis, is activated in DCM patients [99,122]. All images were made in DeepView/Swiss-PdbViewer, version 4.1.0 (GlaxoSmithKline R&D and Swiss Institute of Bioinformatics). Genet. et al. DCM is the most common indication for heart transplantation and is associated with TTNtv in ~20% of DCM cases [57,56,96,99]. Cardiomyopathies are diseases that cause primary abnormalities in the heart muscle [57]. Moreover TTNtv+ zebrafish show electrophysiological defects that could potentially develop into arrhythmia [3]. J, Vihola Overall, these animal studies suggest a need to further investigate the haploinsufficiency mechanism in DCM patients with TTNtvs. Unlike full-length titin isoforms, novex-3 is too short to reach the A-band region [11,96]. 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. Now, an expert who has never treated Ali is weighing in on her condition. Therefore, alcohol is an additional environmental risk that can contribute to a more severe outcome of TTNtv-associated DCM. Although further studies are needed to attribute causality to missense changes, reporting possible causative variants is an effective strategy to improve consistency in the interpretation of molecular findings in titin. The change from threonine to alanine is predicted in a loop and will probably not interfere with the structure. 2019;90:1-23. doi: 10.1016/bs.acc.2019.01.001. 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Extensive mRNA splicing results in distinct titin isoforms [11,70] (Figure 1). Hereditary myopathy with early respiratory failure: occurrence in various populations. Muscle weakness and atrophy are progressive and may spread to affect other muscles of the body. 1,2 DMD is caused by mutations in the DMD gene located on the short arm of the X chromosome. Some people can live longer if the disease starts later or if complications of the condition like cardiomyopathy are not severe. The disease worsened and the patient has required a cane to walk for the last 5 years. 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). Many of the DCM-causing TTN mutations are heterozygous truncating variants (TTNtv) that include frameshift, nonsense, and essential splice site mutations and are over-represented in the A-band segment of titin [56,96], see Figure 1. J, Vihola 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]. 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]. Before Deficiency in RBM20 is leading to increased expression of large N2BA-type titin isoforms in the adult heart[61,50,79,80]. 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. 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). A single heterozygous protein truncating variant is not sufficient for a diagnosis of titinopathy. Homozygous truncating mutation in prenatally expressed skeletal isoform of TTN gene results in arthrogryposis multiplex congenita and myopathy without cardiac involvement. Adv Clin Chem. . M, Savarese The patient, as well as his similarly affected sibling, harbored a single-nucleotide duplication (p.Arg26562Thrfs*12) on the maternal allele. He presented with a progressive distal weakness in the lower limbs (onset at 40 years) and a restrictive respiratory insufficiency due to respiratory muscle weakness. Chauveau Richards PMC A segregation study confirmed that none of the 3 unaffected siblings were compound heterozygous for these TTN missense variants. First, we enrolled, in a multicenter study, patients with clinically and genetically heterogenous conditions and specific clinical studies (magnetic resonance imaging or cardiac tests) were unavailable or not performed for some patients. Recently, an alternative start site has been identified in the titin gene that is predicted to results in expression of cronos titin, a ~2000 kDa isoform that lacks the Z-disk and most of the I-band domains but contains the A-band and M-line domains [123]. P, Udd PYK, Bouquiaux [1] The disorders differ as to which muscles are primarily affected, the degree of weakness, how fast they worsen, and when symptoms begin. Krger M, Ktter Front Physiol. Savarese Consequently, I-band exons with TTNtv, can be excluded from the transcript without resulting in a frameshift, acting as a natural exon skipping mechanism [96,77]. Because of this, Alis doctor, Dr. Tsao, wanted Alis twin sister Aleeah (aka Gracie) to be checked but thankfully, she got a great bill of health. ML, Centner S, Aziz Next-generation sequencing libraries were prepared using MotorPlex, as previously described.25,26 An in-house pipeline25-27 was used to analyze the raw data. Recessive truncating titin gene, TTN, mutations presenting as centronuclear myopathy. Mimicking natural skipping of exons with low PSI scores [96,77] , exon skipping with antisense oligonucleotides could provide a more specific treatment option for patients with DCM caused by TTNtv. Interestingly, recent whole-exome sequencing studies by Ahlberg et al. Udd M, 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]. V, Savarese These diseases include Duchenne's muscular dystrophy (DMD) and centronuclear myopathy (CNM). M, Labeit . They have traditionally been classified by clinical presentation, mode of inheritance, age of onset, and overall progression. 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. A. MC. MeSH 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]. M, Udd Correction: This article was corrected online August 8, 2018, to correct Ms Ruggieris degree. This site needs JavaScript to work properly. All Rights Reserved. Not all individuals that carry a TTNtv develop DCM and a multifactorial disease model has been proposed where multiple factors contribute to the development of a TTNtv - based phenotype [99,27]. Symptoms of the most common variety begin in childhood, mostly in boys. et al. Both siblings harbored 2 compound heterozygous missense variants: p.Asn32797Ser and p.Trp33529Arg. observed more severely impaired left ventricular (LV) function, lower stroke volumes and more sustained ventricular tachycardia in TTNtv+ patients[96]. P, generated a conditional KO mouse model with progressive postnatal loss of the complete titin protein achieved by removing exon 2 (E2-KO)[94]. Thompson Echocardiography results in her early 50s showed mild left ventricular hypokinesia and a mildly reduced ejection fraction (43%). A, Haravuori M, However, Alis parents have made sure that they wont let her condition slow her down, and on countless occasions, theyve praised her for being an inspiration. 2002 Sep. 71(3):492-500. et al. The site is secure. There's no cure for DM, but certain treatments and therapies can help manage symptoms and improve quality of life. A 'second truncation' in TTN causes early onset recessive muscular dystrophy. It is of interest therefore to determine whether distinct molecular pathways are associated with TTNtv-based DCM. Currently, many strategies to treat DMD are in clinical trials [5], [6]. The muscular dystrophies (MD) are a group of inherited genetic conditions that gradually cause the muscles to weaken, leading to an increasing level of disability. FOIA F, and transmitted securely. The functions of novex-3 and cronos titin have not been established. PPCM can also be a manifestation of familial DCM and TTNtv in PPCM patients is a possible prognostic factor for low recovery rate [108,112]. B, Hackman Second, additional elusive mutations may be deep intronic or structural variants. Finally, Gramlich et al. Fattori Novel heterozygous truncating titin variants affecting the A-band are associated with cardiomyopathy and myopathy/muscular dystrophy. However, a primary cardiac involvement is often seen and peculiar imaging findings seem to characterize congenital or early onset titinopathies. identified TTNtv as a major genetic contributor to atrial fibrillation [3]. Median life expectancy with ventilatory support, introduced in most settings in the 1990s, ranged between 21.0 and 39.6 years (pooled median: 29.9 years, 26.5-30.8; weighted pooled median: 31.8 years, 29.3-36.2). All Rights Reserved, Challenges in Clinical Electrocardiography, Clinical Implications of Basic Neuroscience, Health Care Economics, Insurance, Payment, Scientific Discovery and the Future of Medicine, 2018;75(5):557-565. doi:10.1001/jamaneurol.2017.4899. M, Piluso Some children with severe muscular dystrophy may die in infancy or childhood, while adults who have forms that progress slowly can live a normal lifespan. Clearly it is important to focus on the underlying mechanisms of TTNtv-induced DCM. However, these statistics range greatly depending on the kind of MD the . 2023 American Medical Association. C-terminal titin deletions cause a novel early-onset myopathy with fatal cardiomyopathy. We propose a specific workflow for the clinical interpretation of genetic findings in titin. G, Dionisi Muscular dystrophy is a progressive condition that eventually leads to disability. 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]. The mutated residue is shown as CPK. Titin, encoded by the gene TTN, is the largest human protein, and plays central roles in sarcomeric structures and functions in skeletal and cardiac muscles. The A-band segment contains the so-named I/A zone, D-zone, C-zone and M-band regions (supplemental Table S1). We performed an evaluation of putative causative variants in the TTN gene, combining genetic, clinical, and imaging data with messenger RNA and/or protein studies. No signs of respiratory or cardiac involvement were detected at a recent follow-up (2016). also demonstrates defects in sarcomere assembly in patient-derived iPSC cardiomyocytes [100]. Here we review what is known about TTN mutations in muscle disease, with a major focus on DCM. An exon-skipping therapeutic strategy has already been approved by the Food and Drug Administration (FDA) for use in Duchenne muscular dystrophy [1,110], and the hope is that similar exon skipping approaches are feasible and be beneficial in TTNtv patients as well. The aim of this study was to correlate the D4Z4 repeat array fragment size to the orofacial muscle weakening exhibited in a group of patients with a genetically supported diagnosis of FSHD. In this model a second genetic variant and/or environmental stressor is needed, as a second or third hit, to uncover the effects of the TTNtv. The patient had presented with difficulties in running and Achilles tendon contractures since the preteen years. Although, Verdonschot et al. et al; ACMG Laboratory Quality Assurance Committee. Tibial muscular dystrophy. Since childhood, the patient had shown a slowly progressive generalized muscular weakness and gait abnormalities with frequent falling. Max was diagnosed 11 years ago at age 4; Rowen and Charlie were diagnosed in the months following at ages 2 years and 7 months. M, Piluso Importance Titin missense mutations are also likely to contribute to a small fraction of DCM [13,38] and they are a rare cause of hypertrophic cardiomyopathy (HCM) and of arrhythmogenic right ventricular dysplasia [56,75,16,102,9] (Figure 1). The amino acid change probably affects the folding of the domain (Figure 2). 219th ENMC International Workshop Titinopathies International database of titin mutations and phenotypes, Heemskerk, The Netherlands, 29 April-1 May 2016. PubMedGoogle ScholarCrossref 3. HHS Vulnerability Disclosure, Help The weakness in the lower extremities worsened in the early 30s. In the presence of monoallelic truncating variants, as well as of missense variants, the possible causative effect of mutations in genes other than titin has to be ruled out and the presence of the aforementioned key clinical points has to be assessed by deep phenotyping. Epub 2017 Jun 22. This article does not contain any primary studies with human participants or animals performed by any of the authors. M. Next-generation sequencing approaches for the diagnosis of skeletal muscle disorders. The mutated amino acid is located on the external surface of a strand in an Ig-domain in the I-band region, probably affecting the stability (Figure 2A). late adult-onset distal myopathy in 66 Finnish patients. & research is showing a life expectancy of around 70 years, as long as there are no signs of heart or lung failure. An increasing number of rare, ultrarare, and private variants in the titin gene is detected in any sequencing approach, and NGS has dramatically expanded the spectrum of skeletal muscle disorders associated with causative mutations in TTN.5 Our workflow results in a greater understanding and more consistent interpretation of titin variants by neurologists, pediatricians, and geneticists less familiar with the titin gene and titinopathies. Tibial muscular dystrophy in a Belgian family. et al. Most of the identified mutations were previously unreported. 2016 Aug 30;3(3):293-308. doi: 10.3233/JND-160158. G, Mutarelli The natural history of limb-girdle muscular dystrophy is one of gradual progression over years, with life expectancy beyond the fifth and sixth decades of life. Although TTNtv+ patients present more life-threatening arrhythmias associated with enhanced interstitial myocardial fibrosis, the survival rate is similar between TTNtv+ and TTNtv patients at long-term follow-up [109,29]. Biallelic truncating mutations have been so far associated with a wide range of phenotypes, showing heterogeneous clinical and histological features. Meaning M, Di Fruscio Most studies are currently focused on TTNtv that cause dilated cardiomyopathy [56,96,99]. Although the onset of TTNtv-induced DCM is ~40 years [56], environmental insults, such as chemotherapy can induce pediatric-onset DCM cases [28]. The muscular dystrophies (MDs) are a heterogeneous group of inherited disorders characterized by progressive weakness and degeneration of skeletal muscles ( Table ). Conclusions and Relevance The hardest part is her physically deteriorating and knowing these things are happening to her, the 26-year-old explained. H, Muscular dystrophy is a genetic health disease that affects the body's muscles. Ali was diagnosed with Titin Myotonic muscular dystrophy in 2014, a rare form of progressive weakness disease that had existed in less than 20 cases around the world at the time of her diagnosis. Motor chip: a comparative genomic hybridization microarray for copy-number mutations in 245 neuromuscular disorders. et al. Tibial muscular dystrophy Patients with tibial muscular dystrophy usually begin developing symptoms between the ages of 40 and 60. 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Alanine is predicted in a loop and will probably not interfere with the structure of TTNtv-induced.... 1,2 DMD is caused by mutations in 245 neuromuscular disorders these TTN missense variants titinopathies!, Titins M-band region contains the so-named I/A zone, D-zone, C-zone M-band... Involvement were detected at a recent follow-up ( 2016 ) hips, pelvis, and! Rbm20 is leading to increased expression of large N2BA-type titin isoforms [ 11,70 ] ( Figure 1 ) compound... Major genetic contributor to atrial fibrillation [ 3 ]:1009-1017. doi: 10.1016/j.nmd.2017.06.013 images were made in,! Eventually leads to disability acid change probably affects the folding of the condition like cardiomyopathy are not severe are with. With Human participants or animals performed by any of the condition like cardiomyopathy are not severe diseases that cause cardiomyopathy... Series, 504 patients with tibial muscular dystrophy usually begin developing symptoms between the ages of 40 and.. 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To disability IX, the 26-year-old explained titin isoforms, novex-3 is short... Without cardiac involvement were detected at a recent follow-up ( 2016 ) %...