Amino Acid-Level Signal-to-Noise Analysis Aids in Pathogenicity Prediction of Incidentally Identified <i>TTN</i>-Encoded Titin Truncating Variants.

Connell, Patrick S; Berkman, Amy M; Souder, BriAnna M; Pirozzi, Elisa J; Lovin, Julia J; Rosenfeld, Jill A; Liu, Pengfei; Tunuguntla, Hari; Allen, Hugh D; Denfield, Susan W; Kim, Jeffrey J; Landstrom, Andrew P

Amino Acid-Level Signal-to-Noise Analysis Aids in Pathogenicity Prediction of Incidentally Identified <i>TTN</i>-Encoded Titin Truncating Variants.

dc.contributor.author	Connell, Patrick S
dc.contributor.author	Berkman, Amy M
dc.contributor.author	Souder, BriAnna M
dc.contributor.author	Pirozzi, Elisa J
dc.contributor.author	Lovin, Julia J
dc.contributor.author	Rosenfeld, Jill A
dc.contributor.author	Liu, Pengfei
dc.contributor.author	Tunuguntla, Hari
dc.contributor.author	Allen, Hugh D
dc.contributor.author	Denfield, Susan W
dc.contributor.author	Kim, Jeffrey J
dc.contributor.author	Landstrom, Andrew P
dc.date.accessioned	2021-07-01T18:17:34Z
dc.date.available	2021-07-01T18:17:34Z
dc.date.issued	2021-02
dc.date.updated	2021-07-01T18:17:34Z
dc.description.abstract	Background TTN, the largest gene in the human body, encodes TTN (titin), a protein that plays key structural, developmental, and regulatory roles in skeletal and cardiac muscle. Variants in TTN, particularly truncating variants (TTNtvs), have been implicated in the pathogenicity of cardiomyopathy. Despite this link, there is also a high burden of TTNtvs in the ostensibly healthy general population. This complicates the diagnostic interpretation of incidentally identified TTNtvs, which are of increasing abundance given expanding clinical exome sequencing. Methods Incidentally identified TTNtvs were obtained from a large referral database of clinical exome sequencing (Baylor Genetics) and compared with rare population variants from genome aggregation database and cardiomyopathy-associated variants from cohort studies in the literature. A subset of TTNtv-positive children evaluated for cardiomyopathy at Texas Children's Hospital was retrospectively reviewed for clinical features of cardiomyopathy. Amino acid-level signal-to-noise analysis was performed. Results Pathological hotspots were identified within the A-band and N-terminal I-band that closely correlated with regions of high percent-spliced in of exons. Incidental TTNtvs and population TTNtvs did not localize to these regions. Variants were reclassified based on current American College of Medical Genetics and Genomics criteria with incorporation of signal-to-noise analysis among Texas Children's Hospital cases. Those reclassified as likely pathogenic or pathogenic were more likely to have evidence of cardiomyopathy on echocardiography than those reclassified as variants of unknown significance. Conclusions Incidentally found TTNtvs are common among clinical exome sequencing referrals. Pathological hotspots within the A-band of TTN may be informative in determining variant pathogenicity when incorporated into current American College of Medical Genetics and Genomics guidelines.
dc.identifier.issn	2574-8300
dc.identifier.issn	2574-8300
dc.identifier.uri	https://hdl.handle.net/10161/23423
dc.language	eng
dc.publisher	Ovid Technologies (Wolters Kluwer Health)
dc.relation.ispartof	Circulation. Genomic and precision medicine
dc.relation.isversionof	10.1161/circgen.120.003131
dc.subject	cardiomyopathies
dc.subject	exome
dc.subject	genetic testing
dc.subject	incidental findings
dc.subject	population
dc.title	Amino Acid-Level Signal-to-Noise Analysis Aids in Pathogenicity Prediction of Incidentally Identified TTN-Encoded Titin Truncating Variants.
dc.type	Journal article
duke.contributor.orcid	Landstrom, Andrew P\|0000-0002-1878-9631
pubs.begin-page	e003131
pubs.issue	1
pubs.organisational-group	School of Medicine
pubs.organisational-group	Cell Biology
pubs.organisational-group	Pediatrics, Cardiology
pubs.organisational-group	Duke
pubs.organisational-group	Basic Science Departments
pubs.organisational-group	Pediatrics
pubs.organisational-group	Clinical Science Departments
pubs.publication-status	Published
pubs.volume	14