Novel dominant distal titinopathy phenotype associated with copy number variation

Perrin, Aurélien; Morales, Raúl Juntas; Chapon, Françoise; Thèze, C.; Lacourt, Delphine; Pegeot, Henri; Uro‐Coste, Emmanuelle; Giovannini, Diane; Leboucq, Nicolas; Mallaret, Martial; Lagrange, É.; Rigau, Valérie; Gaudon, Karen; Richard, Pascale; Kœnig, M.; Métay, Corinne; Cossée, Mireille

doi:10.1002/acn3.51434

Cited by 3 publications

(6 citation statements)

References 18 publications

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“…Skeletal muscle titinopathies include many diseases with highly different age at onset, mode of inheritance, progression, and muscle weakness distribution [6,8,[18][19][20][21][22][23]. The Finnish founder mutation FINmaj causing TMD is the first muscle disease-causing variant identified in titin, and causes the most common single muscle disease in Finland [1].…”

Section: Discussionmentioning

confidence: 99%

Long‐term favorable prognosis in late onset dominant distal titinopathy: Tibial muscular dystrophy

Lillback

Savarese

Sandholm

et al. 2023

Euro J of Neurology

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Background and purpose Tibial muscular dystrophy (TMD) is a dominant late onset distal titinopathy. It was first described in Finnish patients 3 decades ago. TMD patients with several other TTN mutations occur in many European populations. In this retrospective study, we were able to obtain longitudinal follow‐up data of the disease progression over 15 years in 137 TMD patients. Methods We retrieved clinical data retrospectively from three examinations spanning a period of 15 years. The data were analyzed in R. Frequencies, percentages, and median values were used to describe data. Probability values were determined with the chi‐squared test. Results In the cohort, the first symptoms were walking difficulties (97.8%) and weakness in distal lower limbs (98.5%). The progression of the weakness in distal lower limbs was moderate, and in the proximal lower limbs and proximal upper limbs it was mild. The distal upper limbs were not affected. Magnetic resonance imaging results indicated fatty degeneration preferentially in lower leg anterior muscles, gluteus minimus, and hamstring muscles. Serum creatine kinase values in the cohort were mostly normal (40.7%) or mildly elevated (53.7%). The data suggest that 50% of patients need walking aids by the age of 88 years. Conclusions Despite individual variability of severity, the overall disability due to walking difficulties and upper limb weakness remained moderate even at very advanced ages, and cardiomyopathy did not develop due to the titin defect alone. The acquired results promote the correct identification of TMD, and the obtained trajectories of disease evolution can be used as natural history data for any therapeutic intervention.

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Section: Discussionmentioning

confidence: 99%

Long‐term favorable prognosis in late onset dominant distal titinopathy: Tibial muscular dystrophy

Lillback

Savarese

Sandholm

et al. 2023

Euro J of Neurology

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“…The sequencing depth of intron retention showed a proportion of deleted transcripts close to 50%, suggesting that NMD of the deleted allele is probably absent or minimal. 6 The predicted protein translated would be 60 kDa (figure 3C).…”

Section: Families D-ementioning

confidence: 99%

“…5 We previously reported a dominant deletion of TTN exons 11-18 resulting in a 16 nucleotide long intron retention between exons 10 and 19 in skeletal muscle transcripts, in two families with a distal titinopathy. 6 The standard method for CNV detection is comparative genomic hybridisation (CGH) array,7 although the short size of the oligoprobes and the repetitive structure of TTN are possible limitations to be considered. Recently, several studies have shown that next-generation sequencing (NGS) combined with the use of powerful bioinformatics methods improves the CNV detection.…”

Section: Introductionmentioning

confidence: 99%

Titin copy number variations associated with dominant inherited phenotypes

Perrin,

Métay,

Savarese

et al. 2023

J Med Genet

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BackgroundTitinopathies are caused by mutations in the titin gene (TTN). Titin is the largest known human protein; its gene has the longest coding phase with 364 exons. Titinopathies are very complex neuromuscular pathologies due to the variable age of onset of symptoms, the great diversity of pathological and muscular impairment patterns (cardiac, skeletal muscle or mixed) and both autosomal dominant and recessive modes of transmission. Until now, only few CNVs inTTNhave been reported without clear genotype–phenotype associations.MethodsOur study includes eight families with dominant titinopathies. We performed next-generation sequencing or comparative genomic hybridisation array analyses and found CNVs in theTTNgene. We characterised these CNVs by RNA sequencing (RNAseq) analyses in six patients’ muscles and performed genotype–phenotype inheritance association study by combining the clinical and biological data of these eight families.ResultsSeven deletion-type CNVs in theTTNgene were identified among these families. Genotype and RNAseq results showed that five deletions do not alter the reading frame and one is out-of-reading frame. The main phenotype identified was distal myopathy associated with contractures. The analysis of morphological, clinical and genetic data and imaging let us draw new genotype–phenotype associations of titinopathies.ConclusionIdentifyingTTNCNVs will further increase diagnostic sensitivity in these complex neuromuscular pathologies. Our cohort of patients enabled us to identify new deletion-type CNVs in theTTNgene, with unexpected autosomal dominant transmission. This is valuable in establishing new genotype–phenotype associations of titinopathies, mainly distal myopathy in most of the patients.

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“…Biallelic mutations, mainly TTNtv with few non‐truncating variants, cause skeletal muscle diseases with or without a cardiac involvement 5,12–19 . The increasing number of patients diagnosed with a recessive titinopathies is facilitating the delineation of genotype–phenotype correlations 20,21 .…”

Section: Introductionmentioning

confidence: 99%

“…10,11 Biallelic mutations, mainly TTNtv with few non-truncating variants, cause skeletal muscle diseases with or without a cardiac involvement. 5,[12][13][14][15][16][17][18][19] The increasing number of patients diagnosed with a recessive titinopathies is facilitating the delineation of genotypephenotype correlations. 20,21 Finally, non-truncating variants in two specific exons (344 and 364) cause distinct, well-characterized, phenotypes (HMERF and TMD/LGMD2, respectively).…”

Section: Introductionmentioning

confidence: 99%

Use of animal models to understand titin physiology and pathology

Marcello

Cetrangolo

Savarese

et al. 2022

J Cellular Molecular Medi

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In recent years, increasing attention has been paid to titin ( TTN ) and its mutations. Heterozygous TTN truncating variants (TTNtv) increase the risk of a cardiomyopathy. At the same time, TTNtv and few missense variants have been identified in patients with mainly recessive skeletal muscle diseases. The pathogenic mechanisms underlying titin‐related diseases are still partly unknown. Similarly, the titin mechanical and functional role in the muscle contraction are far from being exhaustively clarified. In the last few years, several animal models carrying variants in the titin gene have been developed and characterized to study the structural and mechanical properties of specific titin domains or to mimic patients' mutations. This review describes the main animal models so far characterized, including eight mice models and three fish models (Medaka and Zebrafish) and discusses the useful insights provided by a thorough characterization of the cell‐, tissue‐ and organism‐phenotypes in these models.

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Novel dominant distal titinopathy phenotype associated with copy number variation

Cited by 3 publications

References 18 publications

Long‐term favorable prognosis in late onset dominant distal titinopathy: Tibial muscular dystrophy

Long‐term favorable prognosis in late onset dominant distal titinopathy: Tibial muscular dystrophy

Titin copy number variations associated with dominant inherited phenotypes

Use of animal models to understand titin physiology and pathology

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