The genetic causes of Dilated Cardiomyopathy: TTN missense and NFS-INDEL variants should be classified as likely benign, study finds

March 12, 2019

The lack of enrichment of non-frameshifting insertions/deletions (NFS-INDELs) in a large primary cohort of DCM patients suggests that these variants are likely non-contributory to Dilated cardiomyopathy (DCM), says a recent study1 published in Sci Rep.

Dilated Cardiomyopathy (DCM) is a relatively common cause for heart failure and sudden cardiac death, with a prevalence of at least 1:2500. DCM is a genetically heterogeneous disorder, and variants in multiple genes have been implicated as disease causing. The giant sarcomere gene, titin (TTN) is a major human disease gene and variants in this gene are the single most common genetic cause of DCM, accounting for about 20% of cases.

“Anything that reduces the numbers of variants of uncertain significance (VUSs) helps clinical cardiologists to arrange follow-up for the index patients and their relatives in a reasonable way”, says cardiologist Tiina Heliö (MD, PhD) from Helsinki University Hospital Heart and Lung Center.

“There has been much focus on the truncating variants of TTN, but the missense and non-frameshifting insertions/deletions (NFS-INDELs) in this major human disease gene have so far been unassessed and unexplored. Consequently, these variants are difficult to assess and interpret in the clinical diagnostic workflow”, explains Blueprint Genetics’ Chief Medical Officer and Laboratory Director Juha Koskenvuo (MD, PhD).

Assessing the relevance of TTN missense variants related to DCM has been particularly difficult for two reasons: the high frequency of these variants in reference populations and DCM patients, and the absence of segregation and family studies.

“In this study, we provide data that show that TTN missense and NFS-INDEL variants are not significantly enriched in a large group of DCM patients compared to control populations and should therefore be classified as likely benign in a clinical diagnostic setting. Nevertheless, it cannot be excluded that some rare TTN missense variants might have a modifier effect on the phenotype”, says Dr. Oyediran Akinrinade from the Institute of Clinical Medicine, Helsinki University Central Hospital.

This study

  • Focused on TTN missense and non-frameshifting insertion-deletion (NFS-INDELs) variants identified in DCM patients and reference populations.
  • Analyzed 530 primary DCM patients identified with TTN missense and NFS-INDELs variants
  • Reviewed over 60,000 ExAC individuals and 123,136 gnomAD database reference individuals

DCM patients in this study were sequenced using high coverage sequencing assays yielding more uniform coverage even across difficult-to-sequence regions that may alone increase the likelihood of finding slightly higher numbers of variants in DCM cohorts as compared to population databases.

Read the study in its entirety at

Further information:

Blueprint Genetics

Juha Koskenvuo, Chief Medical Officer and Laboratory Director,
Juulia Simonen, Communication Manager, tel. +358503059018

Helsinki University Central Hospital (HUCH)

Cardiologist Tiina Heliö,


  1. Relevance of Titin Missense and Non-Frameshifting Insertions/Deletions Variants in Dilated Cardiomyopathy (2019), Sci Rep. Akinrinade, Heliö, Lekanne Deprez, Jongbloed, Boven, van den Berg, Pinto, Alastalo, Myllykangas, Spaendonck-Zwarts*, van Tintelen*, van der Zwaag*, Koskenvuo*

* equal last authorship

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