Making sense of missense variants in TTN-related congenital myopathies

<jats:title>Abstract</jats:title><jats:p>Mutations in the sarcomeric protein titin, encoded by<jats:italic>TTN</jats:italic>, are emerging as a common cause of myopathies. The diagnosis of a<jats:italic>TTN</jats:italic>-related myopathy is, however, often not straightforward due to clinico-pathological overlap with other myopathies and the prevalence of<jats:italic>TTN</jats:italic>variants in control populations. Here, we present a combined clinico-pathological, genetic and biophysical approach to the diagnosis of<jats:italic>TTN</jats:italic>-related myopathies and the pathogenicity ascertainment of<jats:italic>TTN</jats:italic>missense variants. We identified 30 patients with a primary<jats:italic>TTN</jats:italic>-related congenital myopathy (CM) and two truncating variants, or one truncating and one missense<jats:italic>TTN</jats:italic>variant, or homozygous for one<jats:italic>TTN</jats:italic>missense variant. We found that <jats:italic>TTN</jats:italic>-related myopathies show considerable overlap with other myopathies but are strongly suggested by a combination of certain 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<jats:italic>TTN</jats:italic>missense mutations phenocopy truncating variants and are a key pathogenic feature of recessive titinopathies that might be amenable to therapeutic intervention.</jats:p>