Making sense of missense variants in TTN-related congenital myopathies

Martin Rees, Roksana Nikoopour, Atsushi Fukuzawa, Ay Lin Kho, Miguel Fernandez-Garcia, Elizabeth Wraige, Istvan Bodi, Charu Deshpande, Özkan Özdemir, Hülya-Sevcan Daimagüler, Mark Pfuhl, Mark Holt, Birgit Brandmeier, Sarah Grover, Cheryl Longman, Maria Elena Farrugia, Joël Fluss, Emma Matthews, Michael Hanna, Francesco MuntoniAnna Sarkozy, Rahul Phadke, Rosaline Quinlivan, Emily Oates, Rolf Schröder, Christian Thiel, Jens Reimann, Nicol Voermans, Corrie Erasmus, Erik-Jan Kamsteeg, Chaminda Konersman, Carla Grosmann, Shane Mckee, Sandya Tirupathi, Steven A Moore, Ekkehard Wilichowski, Elke Hobbiebrunken, Gabriele Dekomien, Isabelle Richard, Peter van den Bergh, Cristina Domínguez-González, Sebahattin Cirak, Ana Ferreiro, Heinz Jungbluth, Mathias Gautel

Research output: Contribution to journalArticlepeer-review


Mutations in the sarcomeric protein titin, encoded by TTN, are emerging as a common cause of myopathies. The diagnosis of a TTN-related myopathy is however often not straightforward due to clinico-pathological overlap with other myopathies and the prevalence of TTN variants in control populations. Here, we present a combined clinico-pathological, genetic and biophysical approach to the diagnosis of TTN-related myopathies and the pathogenicity ascertainment of TTN missense variants. We identified 30 patients with a primary TTN-related congenital myopathy (CM) and two truncating variants, or one truncating and one missense TTN variant, or homozygous for one TTN missense variant. TTN-related myopathies show considerable overlap with other myopathies but are strongly suggested by a combination of clinico-pathological features. Presentation was typically at birth with the clinical course characterized by variable progression of weakness, contractures, scoliosis and respiratory symptoms but sparing of extraocular muscles. Cardiac involvement depended on the variant position. Our biophysical analyses demonstrated that missense mutations associated with CMs are strongly destabilizing and exert their effect when expressed on a truncating background or in homozygosity. We hypothesise that destabilizing TTN missense mutations phenocopy truncating variants and are a key pathogenic feature of recessive titinopathies that might be amenable to therapeutic intervention.
Original languageEnglish
JournalActa Neuropathologica
Publication statusAccepted/In press - 20 Dec 2020


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