G.P.35: Analysis of a large patient cohort with recessive truncating TTN mutations reveals novel clinical features and a diverse range of muscle pathologies

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TTN encodes titin, the largest human protein. In striated muscle two titin molecules align “head to head” to span the full length of the sarcomere, providing a scaffold for sarcomere organisation, a sensing and signalling hub, and both passive and active modulation of muscle contraction. Dominant mutations in TTN are established causes of cardiomyopathy, tibial muscular dystrophy, and hereditary myopathy with early respiratory failure. More recently, several individuals with two truncating mutations have been described with increased internalised nuclei (CNM) with or without multi-minicores (MMC). Using next generation sequencing, we identified 14 individuals from 11 families with compound heterozygous or homozygous truncating TTN mutations. Presentation was in utero or during infancy in all cases. Weakness of truncal and respiratory muscles was often prominent, and early-onset scoliosis and respiratory failure were common complications. Three affected individuals had dilated cardiomyopathy (DCM) or left ventricular dysfunction, and one carrier parent developed DCM in later life. Two individuals had congenital aortic abnormalities (coarctation and stenosis). Many affected individuals had distinctive clinical features which are unusual for congenital myopathies, including congenital or early-onset hand and foot deformities, congenital scoliosis, spinal rigidity, cleft palate, distal hypermobility and short stature. The most common histological abnormality was a mixed CNM-MMC pattern. Novel histological patterns included typical congenital fibre-type disproportion (CFTD) and CNM-MMC with caps and nemaline rods. The presence of palatal clefts, facial dysmorphology, and cardiac malformations in several individuals with TTN mutations suggests that titin plays a role in foetal development. Mutations in TTN should be considered in any individual with predominant truncal and respiratory weakness, and CNM, MMC, CFTD, caps, rods, or any combination of these, on muscle biopsy.