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Prevalence of TTR variants detected by whole-exome sequencing in hypertrophic cardiomyopathy

Lopes, LR; Futema, M; Akhtar, MM; Lorenzini, M; Pittman, A; Syrris, P; Elliott, PM; (2019) Prevalence of TTR variants detected by whole-exome sequencing in hypertrophic cardiomyopathy. The Journal of Protein Folding Disorders , 26 (4) pp. 243-247. 10.1080/13506129.2019.1665996. Green open access

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Abstract

BACKGROUND: A proportion of patients with hypertrophic cardiomyopathy (HCM) have a diagnosis of cardiac amyloidosis. Hereditary transthyretin amyloid cardiomyopathy (ATTRv-CM) is caused by mutations in the TTR gene. Our aim was to study the prevalence of potentially amyloidogenic TTR variants in a whole-exome sequencing (WES) study of a large HCM cohort. METHODS AND RESULTS: 770 consecutive HCM probands underwent WES and clinical characterisation. Patients with rare or known pathogenic variants in TTR underwent 99mTechnetium labelled 3,3-diphosphono-1,2-propanodicarboxylic acid (DPD) scintigraphy and were retrospectively re-assessed for clinical features of amyloidosis. Two patients had rare TTR variants of unknown significance and four had the known pathogenic V122I (p.V142I) variant (one homozygous and also heterozygous for a likely pathogenic MYL3 variant and another double heterozygous for a likely pathogenic MYBPC3 variant). Four out of 6 patients with TTR variants underwent DPD scintigraphy; the only positive study was in the patient with the homozygous V122I (p.V142I) variant. CONCLUSIONS: Pathogenic TTR variants are rare in carefully assessed HCM patients and may occur in double heterozygosity with pathogenic sarcomere variants. The lack of evidence for an amyloidosis phenotype in all but one TTR variant carrier illustrates the importance of complete clinical evaluation of HCM patients that harbour pathogenic TTR variants.

Type: Article
Title: Prevalence of TTR variants detected by whole-exome sequencing in hypertrophic cardiomyopathy
Open access status: An open access version is available from UCL Discovery
DOI: 10.1080/13506129.2019.1665996
Publisher version: https://doi.org/10.1080/13506129.2019.1665996
Language: English
Additional information: This version is the author accepted manuscript. For information on re-use, please refer to the publisher’s terms and conditions.
Keywords: Hereditary transthyretin amyloidosis, hypertrophic cardiomyopathy, whole-exome sequencing
UCL classification: UCL
UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > Institute of Cardiovascular Science
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > Institute of Cardiovascular Science > Clinical Science
URI: https://discovery.ucl.ac.uk/id/eprint/10084483
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