Hypertrophic cardiomyopathy

Gene: TTR

Green List (high evidence)

Submitted on behalf of the GMS Cardiology specialist group. The group has agreed that this gene should be Green on this panel.

Created: 2 Dec 2019, 11:26 a.m. | Last Modified: 2 Dec 2019, 11:26 a.m.

Panel Version: 1.81

Green List (high evidence)

On CGGL Royal Brompton diagnostic panel. Associated with Hereditary amyloidosis, which is phenocopy of HCM, patients can present with LVH, therefore appropriate for overlapping phenotypes

Created: 18 Sep 2019, 12:56 p.m. | Last Modified: 18 Sep 2019, 12:56 p.m.

Panel Version: 1.74

Phenotypes
Amyloidosis, hereditary, transthyretin-related OMIM 105210

Publications

• 28475415

Variants in this GENE are reported as part of current diagnostic practice

I don't know

Amyloidosis, hereditary, transthyretin-related (105210 )

Created: 25 Mar 2019, 4:30 p.m.

29567486 /28369730: HCM phenocopy. OMIM 105210 - hereditary, transthyretin-related Amyloidosis: cardiomyopathy associated with phenotype. Few DM variants on HGMD associated with cardiomyopathy, HCM only are VUS. 28635949: specific cardiac variants in this gene.

Created: 25 Mar 2019, 4:27 p.m.

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Variants in this GENE are reported as part of current diagnostic practice

Comment on list classification: Promoted to green following discussion with NHS GMS cardiology specialist group. Cardiac amyloidosis is associated with thickening of the ventricular wall which can resemble hypertrophic cardiomyopathy.

Created: 4 Feb 2019, 7:19 a.m.

I don't know

The 'treatable' tag has been added due to new therapies available that target this gene. Inotersen is an antisense oligonucleotide inhibitor of mutant and wild-type human transthyretin (TTR), developed and approved by NICE for the treatment of hereditary transthyretin amyloidosis (hATTR) (PMID: 30120737, https://www.nice.org.uk/guidance/hst9/chapter/1-Recommendations) Patisiran is a small interfering RNA (siRNA) molecule that targets the transthyretin gene (TTR) messenger mRNA (mRNA), to suppress both mutant and wild-type amyloid transthyretin (ATTR) protein production. This drug has been approved by NHSE for treatment of transthyretin-mediated amyloidosis (https://www.bbc.co.uk/news/health-48907976)

Created: 9 Jul 2019, 12:36 p.m. | Last Modified: 9 Jul 2019, 12:36 p.m.

Panel Version: 1.55

This gene was part of an initial gene list collated by Matthew Edwards Royal Brompton Hospital sent 16th Jan 2019 on behalf of the London South GLH for review by the GMS Cardiology Specialist Group. Only gene symbol from the Royal Brompton gene panel was provided - suggested initial gene rating and evidence for inclusion not provided with the list.

Created: 20 Feb 2019, 2:17 p.m.

Comment on list classification: Promoted from Red to Amber due to new review and discussion with the NHSE GMS Cardiology specialist group.

Created: 17 Jan 2019, 5:14 p.m.

Publications

• 30878017
• 31131842
• 31118583
• 31111153
• 30120737

Green List (high evidence)

pathogenic variants in this gene cause Hereditary TTR amyloidosis. Affected individuals can present with left ventricular hypertrophy (LVH) that can mimic HCM. Recent study (PMID:28475415) found pathogenic varaint in this gene in 0.6% individuals in HCM cohort (n=697)

Created: 17 Jan 2019, 5:06 p.m.

TTR mutations cause amyloidosis which can manifest as polyneuropathy and / or cardiac amyloidosis (can be misdiagnosed as HCM). 3-4% of black Africans have p.Val142Ile mutation, which can cause cardiomyopathy at >65 years of age. Damy et al. 2015 suggest ~11% of black African HCM patients (>65 years) may have TTR mutation. Other rarer mutations throughout the gene.

Created: 6 Jan 2016, 5:11 p.m.

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Publications

• Publications supporting role of this gene in HCM - PMID: 28475415
• PMID:16115295
• PMID:16194874
• PMID:26537620
• PMID:1626570
• PMID:1570831

Variants in this GENE are reported as part of current diagnostic practice