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000329274 041__ $$aEnglish
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000329274 1001_ $$aHastings, Robert$$b0
000329274 245__ $$aCombination of Whole Genome Sequencing, Linkage, and Functional Studies Implicates a Missense Mutation in Titin as a Cause of Autosomal Dominant Cardiomyopathy With Features of Left Ventricular NoncompactionCLINICAL PERSPECTIVE
000329274 260__ $$aPhiladelphia, Pa.$$bLippincott, Williams & Wilkins$$c2016
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000329274 520__ $$aBackground — High throughput next-generation sequencing techniques have made whole genome sequencing accessible in clinical practice; however, the abundance of variation in the human genomes makes the identification of a disease-causing mutation on a background of benign rare variants challenging. Methods and Results — Here we combine whole genome sequencing with linkage analysis in a 3-generation family affected by cardiomyopathy with features of autosomal dominant left ventricular noncompaction cardiomyopathy. A missense mutation in the giant protein titin is the only plausible disease-causing variant that segregates with disease among the 7 surviving affected individuals, with interrogation of the entire genome excluding other potential causes. This A178D missense mutation, affecting a conserved residue in the second immunoglobulin-like domain of titin, was introduced in a bacterially expressed recombinant protein fragment and biophysically characterized in comparison to its wild-type counterpart. Multiple experiments, including size exclusion chromatography, small-angle x ray scattering, and circular dichroism spectroscopy suggest partial unfolding and domain destabilization in the presence of the mutation. Moreover, binding experiments in mammalian cells show that the mutation markedly impairs binding to the titin ligand telethonin.Conclusions — Here we present genetic and functional evidence implicating the novel A178D missense mutation in titin as the cause of a highly penetrant familial cardiomyopathy with features of left ventricular noncompaction. This expands the spectrum of titin’s roles in cardiomyopathies. It furthermore highlights that rare titin missense variants, currently often ignored or left uninterpreted, should be considered to be relevant for cardiomyopathies and can be identified by the approach presented here.
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000329274 7001_ $$ade Villiers, Carin P.$$b1
000329274 7001_ $$aHooper, Charlotte$$b2
000329274 7001_ $$aOrmondroyd, Liz$$b3
000329274 7001_ $$aPagnamenta, Alistair$$b4
000329274 7001_ $$aLise, Stefano$$b5
000329274 7001_ $$aSalatino, Silvia$$b6
000329274 7001_ $$aKnight, Samantha J. L.$$b7
000329274 7001_ $$aTaylor, Jenny C.$$b8
000329274 7001_ $$aThomson, Kate L.$$b9
000329274 7001_ $$aArnold, Linda$$b10
000329274 7001_ $$0P:(DE-H253)PIP1094717$$aChatziefthymiou, Spyridon$$b11$$udesy
000329274 7001_ $$0P:(DE-H253)PIP1010121$$aKonarev, Petr$$b12
000329274 7001_ $$0P:(DE-H253)PIP1001283$$aWilmanns, Matthias$$b13
000329274 7001_ $$aEhler, Elisabeth$$b14
000329274 7001_ $$aGhisleni, Andrea$$b15
000329274 7001_ $$aGautel, Mathias$$b16
000329274 7001_ $$aBlair, Edward$$b17
000329274 7001_ $$aWatkins, Hugh$$b18
000329274 7001_ $$0P:(DE-HGF)0$$aGehmlich, Katja$$b19$$eCorresponding author
000329274 773__ $$0PERI:(DE-600)2457085-0$$a10.1161/CIRCGENETICS.116.001431$$gVol. 9, no. 5, p. 426 - 435$$n5$$p426 - 435$$tCirculation / Cardiovascular genetics$$v9$$x1942-3268$$y2016
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