Homozygous truncating mutation in prenatally expressed skeletal isoform of TTN gene results in arthrogryposis multiplex congenita and myopathy without cardiac involvement

Fernández–Marmiesse, Ana; Carrascosa-Romero, M.C.; Ponce, Blanca Alfaro; Nascimento, A.; Ortez, C.; Romero, Norma B.; Palacios, Lourdes; Jiménez‐Mallebrera, Cecilia; Jou, Cristina; Gouveia, Sofía; Couce, María L.

doi:10.1016/j.nmd.2016.11.002

Cited by 34 publications

(49 citation statements)

References 15 publications

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“…Features included fetal hypokinesia, distal arthrogryposis, delayed motor milestones, high-arched palate and weak suction. Muscle biopsy showed persistent amyoplasia 76. A later cohort study of 30 patients with recessive congenital titinopathy showed 10 also had a mutation within TTN metatranscript-only exons 78.…”

Section: Genes Encoding Fetally Expressed Myostructural Proteinsmentioning

confidence: 97%

“…TTN (MIM 188840) encodes the giant muscle protein titin, spanning from Z-disc to M-line and playing a crucial role in cardiac and skeletal muscle sarcomere assembly, structure and force transmission 76. Chauveau and colleagues77 first described TTN -related fetal akinesia caused by recessive TTN mutations.…”

Section: Genes Encoding Fetally Expressed Myostructural Proteinsmentioning

confidence: 99%

“…Terminal heart failure required a transplant at age 4. Fernández-Marmiesse et al described fetal hypokinesia caused by a homozygous truncating mutation in exon 197 76. This exon is absent from adult TTN isoforms, but present in the fetal 364-exon inferred complete isoform, also known as the TTN ‘metatranscript’ (reference sequence NM_001267550.2) 76 78.…”

Section: Genes Encoding Fetally Expressed Myostructural Proteinsmentioning

confidence: 99%

“…This exon is absent from adult TTN isoforms, but present in the fetal 364-exon inferred complete isoform, also known as the TTN ‘metatranscript’ (reference sequence NM_001267550.2) 76 78. The authors suggest cardiac muscle was spared because exon 197 is absent from the cardiac titin isoforms 76. Features included fetal hypokinesia, distal arthrogryposis, delayed motor milestones, high-arched palate and weak suction.…”

Section: Genes Encoding Fetally Expressed Myostructural Proteinsmentioning

confidence: 99%

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Genetics of neuromuscular fetal akinesia in the genomics era

et al. 2018

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Fetal hypokinesia or akinesia encompasses a broad spectrum of disorders, united by impaired movement in utero. Often, the underlying aetiology is genetic in origin, affecting part of the neuromuscular system. The affordable and high-throughput nature of next-generation DNA sequencing has led to an explosion in disease gene discovery across rare diseases, including fetal akinesias. A genetic diagnosis has clinical utility as it may affect management and prognosis and informs recurrence risk, facilitating family planning decisions. More broadly, knowledge of disease genes increasingly allows population-based preconception carrier screening, which has reduced the incidence of recessive diseases in several populations. Despite gains in knowledge of the genetics of fetal akinesia, many families lack a genetic diagnosis. In this review, we describe the developments in Mendelian genetics of neuromuscular fetal akinesia in the genomics era. We examine genetic diagnoses with neuromuscular causes, specifically including the lower motor neuron, peripheral nerve, neuromuscular junction and muscle.

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Section: Genes Encoding Fetally Expressed Myostructural Proteinsmentioning

confidence: 97%

Section: Genes Encoding Fetally Expressed Myostructural Proteinsmentioning

confidence: 99%

Section: Genes Encoding Fetally Expressed Myostructural Proteinsmentioning

confidence: 99%

Section: Genes Encoding Fetally Expressed Myostructural Proteinsmentioning

confidence: 99%

See 2 more Smart Citations

Genetics of neuromuscular fetal akinesia in the genomics era

et al. 2018

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“…Although, in the context of a myopathy, typically only variants in exons described in the skeletal muscle isoform N2A (NM_133378.4) are considered. However, six pathogenic variants in TTN exons not included within the described skeletal muscle isoform N2A (NM_133378.4) are recently reported affecting 10 different families with recessive congenital titinopathies (Chervinsky et al, ; Fernández‐Marmiesse et al, ; Oates et al, ). These pathogenic variants in TTN metatranscript‐only exons support emerging evidence that there are numerous developmental TTN transcripts isoforms yet to be formally described (Savarese et al, ).…”

Section: Introductionmentioning

confidence: 99%

Recurrent TTN metatranscript‐only c.39974–11T>G splice variant associated with autosomal recessive arthrogryposis multiplex congenita and myopathy

et al. 2019

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We present eight families with arthrogryposis multiplex congenita and myopathy bearing a TTN intron 213 extended splice-site variant (NM_001267550.1:c.39974-11T>G), inherited in trans with a second pathogenic TTN variant. Muscle-derived RNA studies of three individuals confirmed mis-splicing induced by the c.39974-11T>G variant; in-frame exon 214 skipping or use of a cryptic 3′ splice-site effecting a frameshift. Confounding interpretation of pathogenicity is the absence of exons 213-217 within the described skeletal muscle TTN N2A isoform. However, RNAsequencing from 365 adult human gastrocnemius samples revealed that 56% specimens predominantly include exons 213-217 in TTN transcripts (inclusion rate ≥66%). Further, RNA-sequencing of five fetal muscle samples confirmed that 4/5 specimens predominantly include exons 213-217 (fifth sample inclusion rate 57%). Contractures improved significantly with age for four individuals, which may be linked to decreased expression of pathogenic fetal transcripts. Our study extends emerging evidence supporting a vital developmental role for TTN isoforms containing metatranscript-only exons. K E Y W O R D S alternative splicing, arthrogryposis, congenital titinopathies, intronic splice variant, TTN metatranscript-only

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Interpreting Genetic Variants in Titin in Patients With Muscle Disorders

Savarese

Maggi²,

Vihola

et al. 2018

JAMA Neurol

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IMPORTANCE Mutations in the titin gene (TTN) cause a wide spectrum of genetic diseases. The interpretation of the numerous rare variants identified in TTN is a difficult challenge given its large size. OBJECTIVE To identify genetic variants in titin in a cohort of patients with muscle disorders. DESIGN, SETTING, AND PARTICIPANTS In this case series, 9 patients with titinopathy and 4 other patients with possibly disease-causing variants in TTN were identified. Titin mutations were detected through targeted resequencing performed on DNA from 504 patients with muscular dystrophy, congenital myopathy, or other skeletal muscle disorders. Patients were enrolled from 10 clinical centers in April 2012 to December 2013. All of them had not received a diagnosis after undergoing an extensive investigation, including Sanger sequencing of candidate genes. The data analysis was performed between September 2013 and January 2017. Sequencing data were analyzed using an internal custom bioinformatics pipeline. MAIN OUTCOMES AND MEASURES The identification of novel mutations in the TTN gene and novel patients with titinopathy. 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. RESULTS Of the 9 novel patients with titinopathy, 5 (55.5%) were men and the mean (SD) age at onset was 25 (15.8) years (range, 0-46 years). Of the 4 other patients (3 men and 1 woman) with possibly disease-causing TTN variants, 2 (50%) had a congenital myopathy and 2 (50%) had a slowly progressive distal myopathy with onset in the second decade. Most of the identified mutations were previously unreported. However, all the variants, even the already described mutations, require careful clinical and molecular evaluation of probands and relatives. Heterozygous truncating variants or unique missense changes are not sufficient to make a diagnosis of titinopathy. CONCLUSIONS AND RELEVANCE The interpretation of TTN variants often requires further analyses, including a comprehensive evaluation of the clinical phenotype (deep phenotyping) as well as messenger RNA and protein studies. We propose a specific workflow for the clinical interpretation of genetic findings in titin.

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Homozygous truncating mutation in prenatally expressed skeletal isoform of TTN gene results in arthrogryposis multiplex congenita and myopathy without cardiac involvement

Cited by 34 publications

References 15 publications

Genetics of neuromuscular fetal akinesia in the genomics era

Genetics of neuromuscular fetal akinesia in the genomics era

Recurrent TTN metatranscript‐only c.39974–11T>G splice variant associated with autosomal recessive arthrogryposis multiplex congenita and myopathy

Interpreting Genetic Variants in Titin in Patients With Muscle Disorders

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