Amino Acid-Level Signal-to-Noise Analysis Aids in Pathogenicity Prediction of Incidentally Identified TTN-Encoded Titin Truncating Variants.
Abstract
<h4>Background</h4>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.<h4>Methods</h4>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.<h4>Results</h4>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.<h4>Conclusions</h4>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.
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https://hdl.handle.net/10161/23423Published Version (Please cite this version)
10.1161/circgen.120.003131Publication Info
Connell, Patrick S; Berkman, Amy M; Souder, BriAnna M; Pirozzi, Elisa J; Lovin, Julia
J; Rosenfeld, Jill A; ... Landstrom, Andrew P (2021). Amino Acid-Level Signal-to-Noise Analysis Aids in Pathogenicity Prediction of Incidentally
Identified TTN-Encoded Titin Truncating Variants. Circulation. Genomic and precision medicine, 14(1). pp. e003131. 10.1161/circgen.120.003131. Retrieved from https://hdl.handle.net/10161/23423.This is constructed from limited available data and may be imprecise. To cite this
article, please review & use the official citation provided by the journal.
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Show full item recordScholars@Duke
Andrew Paul Landstrom
Associate Professor of Pediatrics
Dr. Landstrom is a physician scientist who specializes in the care of children and
young adults with arrhythmias, heritable cardiovascular diseases, and sudden unexplained
death syndromes. As a clinician, he is trained in pediatric cardiology with a focus
on arrhythmias and genetic diseases of the heart. He specializes in caring for patients
with heritable arrhythmia (channelopathies) such as long QT syndrome, Brugada syndrome,
catecholaminergic polymorphic ventricular tachycardia,

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