Hypertrophic cardiomyopathy_HCM

Gene: TTN

I don't know

ClinGen gene curation (2017):
The TTN gene has been associated with hypertrophic cardiomyopathy (HCM) in one family with an unusual presentation including variable dilatation, hypertrophy, and trabeculations with some family members meeting criteria for LVNC (Hastings et al, 2016, PMID 27625337). A heterozygous missense variant of unknown significance was reported in affected individuals in this family. Several other variants (missense, splice-site, in frame insertion) have been reported in TTN in patients with HCM. However, upon review, none of these variants were considered to have sufficient evidence to be disease-causing. The mechanism for disease is unknown. Experimental evidence to support the gene-disease association includes its biochemical function as a sarcomere component and protein interaction studies.
In summary, there is limited evidence to support this gene-disease association. Curation Expert Panel on December 14, 2017.

PMID: 28822653 (2017): Our study suggests that TTNtv might be a genetic modifier of HCM and confer an increased risk for cardiovascular death.

PMID: 28223422(2017): suggest oligogenic etiology.

PMID: 28323875 (2017): TTN mutations common in cohort of patients with severe right ventricular hypertrophy.

PMID: 28797094 (2017): deep intronic TTN variants enriched in patients with HCM

PMID: 31628103 (2019): screened HCM cohort (MURF1 binding domain only) and found two missense variants in two unrelated families. Variants segregated with disease (3 affected members of one family, 2 affected members of the other family). Variants are located in the MURF1 binding domain and in vitro functional studies showed increased binding to MURF1 (in vivo studies using zebrafish murf1 mutants show hypertrophic heart and disrupted sarcomeric structure). Suggested to be a novel (dominant negative) mechanism underlying HCM pathogenesis. (note: didn't find variants in GnomAD - quick search)

Summary: Insufficient evidence to support HCM gene-disease association

Created: 29 Jul 2020, 2:32 a.m. | Last Modified: 29 Jul 2020, 2:32 a.m.

Panel Version: 0.89

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Publications

• PMID: 27625337
• 31628103