Titin founder mutation is a common cause of myofibrillar myopathy with early respiratory failure

Pfeffer, Gerald; Barresi, Rita; Wilson, I. J.; Hardy, Steven A.; Griffin, Helen; Hudson, Judith A.; Elliott, Hannah R; Ramesh, Aravind; Radunović, Aleksandar; Winer, John; Vaidya, Sujit; Raman, Ashok; Busby, Mark; Farrugia, Maria Elena; Ming, Alec; Everett, C M; Emsley, Hedley; Horvath, Rita; Straub, Volker; Bushby, Kate; Lochmüller, Hanns; Chinnery, Patrick F.; Sárközy, Anna

doi:10.1136/jnnp-2012-304728

Cited by 75 publications

(123 citation statements)

References 24 publications

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“…The Mex6 deletion (c.107889delA, p.Lys35963Asnfs * 9) is present in two unrelated Spanish families [Hackman et al, 2008]; the c.95134T>C, p.Cys31712Arg (first published as p.Cys30071Arg, N2BA-TTN) change has been associated with a founder effect in a series of families of UK origin with myofibrillar myopathy [Pfeffer et al, 2014a]; and the FINmaj mutation, which is the most prevalent TTN mutation, is present in ß2/10,000 in the Finish population due to a founder effect [Udd, 2012]. The vast majority of the known TTN mutations have been identified at the heterozygous state in patients with sporadic or dominant conditions.…”

Section: Population Distribution and Mode Of Inheritancementioning

confidence: 99%

A Rising Titan:TTNReview and Mutation Update

2014

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The 364 exon TTN gene encodes titin (TTN), the largest known protein, which plays key structural, developmental, mechanical, and regulatory roles in cardiac and skeletal muscles. Prior to next-generation sequencing (NGS), routine analysis of the whole TTN gene was impossible due to its giant size and complexity. Thus, only a few TTN mutations had been reported and the general incidence and spectrum of titinopathies was significantly underestimated. In the last months, due to the widespread use of NGS, TTN is emerging as a major gene in human-inherited disease. So far, 127 TTN disease-causing mutations have been reported in patients with at least 10 different conditions, including isolated cardiomyopathies, purely skeletal muscle phenotypes, or infantile diseases affecting both types of striated muscles. However, the identification of TTN variants in virtually every individual from control populations, as well as the multiplicity of TTN isoforms and reference sequences used, stress the difficulties in assessing the relevance, inheritance, and correlation with the phenotype of TTN sequence changes. In this review, we provide the first comprehensive update of the TTN mutations reported and discuss their distribution, molecular mechanisms, associated phenotypes, transmission pattern, and phenotype-genotype correlations, alongside with their implications for basic research and for human health.

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Section: Population Distribution and Mode Of Inheritancementioning

confidence: 99%

A Rising Titan:TTNReview and Mutation Update

2014

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“…Being of German descent also favors the diagnosis of FLNC-MFM, given that the founder FLNC mutation has been reported in German patients. 3 FLNC sequencing in this patient showed a p.Trp2710X mutation. This p.Trp2710X mutation was first identified as the founder mutation in German patients and later was reported in patients from other ethnic backgrounds.…”

Section: Discussionmentioning

confidence: 99%

“…2,3 TTN-MFM patients usually develop respiratory insufficiency early in the disease course, 3 whereas FLNC-MFM patients experience respiratory compromise later with disease progression. 2 The family history of respiratory compromise developing a decade after the onset of weakness as seen in our patient is typical of FLNC-MFM.…”

Section: Discussionmentioning

confidence: 99%

“…4 Mutations in the rod domain of filamin C cause MFM, while mutations in its actinbinding domain cause early-onset distal myopathy, preferentially affecting posterior leg compartment and hand muscles without MFM pathology. [3][4][5] FLNC-MFM patients usually present only after the fourth decade of life. Respiratory muscles become affected with disease progression in 50% of patients.…”

Section: Discussionmentioning

confidence: 99%

“…Cardiac abnormalities occur in one-third of patients, albeit mild. 3 Symptomatic and supportive care, as well as cardiac and respiratory surveillance, are the mainstay treatment for patients with FLNC-MFM. Genetic counseling and the option of genetic testing should be offered to at-risk relatives.…”

Section: Discussionmentioning

confidence: 99%

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Clinical Reasoning: A 52-year-old woman with progressive proximal weakness

2014

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Fetal akinesia deformation sequence syndrome associated with recessive TTN variants

Alkhunaizi

Martin

Jelin

et al. 2022

American J of Med Genetics Pt A

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Arthrogryposis multiplex congenita (AMC) [also known as multiple joints contracture or Fetal Akinesia Deformation Sequence (FADS)] is etiologically a heterogeneous condition with an estimated incidence of approximately 1 in 3000 live births and much higher incidence when prenatally diagnosed cases are included. The condition can be acquired or secondary to fetal exposures and can also be caused by a variety of single-gene disorders affecting the brain, spinal cord, peripheral nerves, neuromuscular junction, muscle, and a variety of disorders affecting the connective tissues (Niles et al., Prenatal Diagnosis, 2019; 39:720-731). The introduction of nextgeneration gene sequencing uncovered many genes and causative variants of AMC but also identified genes that cause both dominant and recessive inherited conditions with the variability of clinical manifestations depending on the genes and variants.Molecular diagnosis in these cases is not only important for prognostication but also for the determination of recurrence risk and for providing reproductive options including preimplantation and prenatal diagnosis. TTN, the largest known gene in the human genome, has been known to be associated with autosomal dominant dilated cardiomyopathy. However, homozygote and compound heterozygote pathogenic variants with recessive inheritance have rarely been reported. We report the effect of recessive variants located within the fetal IC and/or N2BA isoforms in association with severe FADS in three families. All parents were healthy obligate carriers and none of them had cardiac or skeletal muscle abnormalities. This report solidifies FADS as an alternative phenotypic presentation associated with homozygote/ compound heterozygous pathogenic variants in the TTN.

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Titin founder mutation is a common cause of myofibrillar myopathy with early respiratory failure

Cited by 75 publications

References 24 publications

A Rising Titan:TTNReview and Mutation Update

A Rising Titan:TTNReview and Mutation Update

Clinical Reasoning: A 52-year-old woman with progressive proximal weakness

Fetal akinesia deformation sequence syndrome associated with recessive TTN variants

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