Review of source material:
James CA et al PMID: 33831308
ClinGen: https://search.clinicalgenome.org/kb/genes/HGNC:28472
The relationship between TMEM43 and arrhythmogenic right ventricular dysplasia (autosomal dominant) was evaluated using the ClinGen Clinical Validity Framework as of July 10th, 2019. Variants in TMEM43 were first reported in humans with this disease as early as 2008 (Merner et al., PMID 18313022). At least 9 variants (mostly missense) have been reported in humans. However, the pathogenicity of most of the variants is unknown. The majority of genetic evidence comes from case-level data and segregation data for one founder variant, p.Ser358Leu, which has been reported in more than 20 families with ARVC and occurred de novo in one individual (Merner et al., 2008, PMID 18313022; Christensen et al. 2011, PMID 21214875; Baskin et al., 2013, PMID 23812740; Hodgkinson et al., 2013, PMID 22725725; Milting et al., 2014, PMID 24598986). This gene-disease relationship is also supported by an animal model, expression stuies, and in vitro assays. In summary, TMEM43 is definitively associated with autosomal dominant arrhythmogenic right ventricular dysplasia . This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Arrythmogenic Right Ventricular Cardiomyopathy Gene Curation Expert Panel on October 26, 2018 (SOP Version 6).
ClinGen Evidence for Haploinsufficiency
Only heterozygous point mutations within the gene have been described in families with arrhythmogenic right ventricular cardiomyopathy (ARVC)(PMID:21214875, 23812740, 24598986,18313022). Gene function is unknown. PMID 21391237 described two patients with TMEM43 heterozygous missense mutations in Emery Dreifuss Muscular Dystrophy Related Myophathy. No familial follow-up was available. Functional studies suggest that mutant TMEM43 may be involved in the nuclear localization of emrin and SUN2.
Literature review:
A rare form of ARVC is caused by a missense mutation within the gene of transmembrane protein 43 (TMEM43) on chromosome 3p25 (ARVC-5). In a total of 15 Canadian families, a heterozygous amino acid substitution (p.S358L) in TMEM43 fully cosegregated with autosomal dominant ARVC and was proposed to be a founder mutation on the island of Newfoundland (Canada).TMEM43-p.S358L is a fully penetrant mutation.
However, of most variants the molecular disease mechanism is not yet known and the pathogenic role of some missense variants is still a matter of debate.
Milting H et al 2015 Apr 7 (PMID:24598986)
we find that the TMEM43 S358L mutation hyperactivated NF-κB signal as expected. However, this activation does not promote typically inflammatory responses. Instead, it induces another signal TGFβ in fibrosis progress
Zheng G et al. 2019 Feb (PMID:29980933)
In 83 affected individuals with arrhythmogenic right ventricular dysplasia-5 from 15 unrelated Newfoundland families, [Merner et al.(2008)PubMed: 18313022] identified heterozygosity for a missense mutation (S358L) in the TMEM43 gene that was not found in 47 spouses or 161 controls.
In an analysis of the TMEM43 gene in 55 Danish probands who fulfilled the criteria for ARVD and 10 patients with only some features of ARVD, Christensen et al. (2011) identified 1 woman fulfilling the criteria who carried the S358L variant.
In DNA samples from 195 unrelated individuals with suspected ARVD, [Baskin et al. (2013)]PubMed: 23812740] identified 6 patients who carried the S358L 'Newfoundland' mutation in TMEM43, including a 43-year-old New Zealand man who was not of Newfoundland descent. In addition, 5 patients carried 5 different rare sequence variants in the TMEM43 (see, e.g., 612048.0004), 2 of whom also carried a variant in the PKP2 and DSP genes, respectively.
Omim https://www.omim.org/entry/612048 Baskin et al.(2013)]PubMed: 23812740; Merner et al. (2008)PubMed: 18313022
One putative pathogenic variant, the missense change p.Ser358Leu, was identified in a number of families, the majority of which were of Newfoundland ancestry [Merner et al 2008, Christensen et al 2011, Baskin et al 2013]. This variant may relocate proteins essential for cardiac conduction, thereby altering gap junction function to reduce cardiac conduction velocity [Siragam et al 2014]. TMEM43 interacts with emerin and lamins A and B and may be a binding partner in the LINC complex (linker of the nucleoskeleton and cytoskeleton). The pathogenic mechanism of the abnormal gene product is unknown.
Gene reviews https://www.ncbi.nlm.nih.gov/books/NBK1131/
Inheritance:
Autosomal dominant
Optional modifiers:
Allelic requirement:
Monoallelic_autosomal
Crosscutting modifiers:
Disease associated variant consequences:
Altered gene product structure
Narrative summary of molecular mechanisms:
The majority of genetic evidence comes from one founder missense mutation, S358L. Molecular mechanism is largely unknown but a proposed mechanism is hyperactivation of NF-kB signal due to altered gene product structure. Although ARVC is known to display variable penetrance, this particular founder mutation has been described as fully penetrant. Other missense mutations have been reported but their pathogenicity is debated. There is no evidence currently for haploinsufficiency as a mechanism.
List variant classes in this gene proven to cause this disease
- Missense
Potential novel variant classes based on predicted functional consequence:
???
Perhaps if evidence is only robust for one missense variant, then all other variants should be treated with caution even other missense variants.??