Submission Details

The TTR gene has been associated with amyloidosis, an autosomal dominant syndromic disorder characterized by deposition of extracellular transthyretin amyloid deposits throughout the body. Of note, autosomal recessive inheritance has been reported. Being a syndrome, individuals with TTR- related amyloidosis can present with multi-systemic phenotypes including, polyneuropathy, carpal tunnel syndrome, cardiomyopathy, gastrointestinal features, autonomic insufficiency, and renal insufficiency. Familial amyloidosis was first described in 1952 (Andrade et al.; PMID 12978172), but it was not until 1984 (Saraiva et al.; PMID 6736244) that TTR was discovered as the causative gene responsible for this initial report of familial amyloidosis. There are >100 known mutations in TTR reported in humans world-wide as documented in Mutations in Hereditary Amyloidosis Registry (http://www.amyloidosismutations.com) and the Indiana University- Purdue University Indianapolis (IUPUI), USA Amyloidosis Research group site at (http://www.iupui.edu/~amyloid/home.html). All reported mutations are missense (Rowczenio et al., 2014). Multiple cases are reported in the literature but the maximum score for genetic evidence (12 pts) has been reached. The mechanism for disease is gain of function, as mutation causes either tetramer dissociation or monomer denaturation, which both contribute to the formation of amyloid fibrils in tissue (Sekijima, 2015; PMID 25604431). Note, wild-type ATTR (wtATTR), the protein product of the TTR gene, can cause amyloidosis (senile cardiac amyloidosis) on its own, but this form is age-dependent, and often occurs at a much greater age of onset than individuals who harbor a pathogenic variant in TTR. This gene-disease association is supported by the function of the gene product, decreased myocyte functional activity in non-patient cells treated with fibril forming TTR, multiple animal models, rescue experiments, and studies of the clinical impact of anti-sense-oligonucleotides (ASOs) for the treatment of amyloidosis in humans (http://ttrstudy.com). In summary, TTR is definitively associated with Amyloidosis. This association has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time.

Lumping and Splitting: Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found that no difference in molecular mechanism underlies the two disease entities: (1) Amyloidosis, hereditary, transthyretin-related (MIM:105210), and (2) Carpal tunnel syndrome, familial (MIM:115430). Furthermore, carpal tunnel syndrome is often a presenting phenotype that occurs in hereditary amyloidosis (MIM:105210). Therefore, the two entities (MIM:105210 and MIM:115430) have been lumped into one disease entity, Hereditary ATTR amyloidosis.

Data on the occurrence of hypertrophic cardiomyopathy (HCM) in individuals with Hereditary ATTR amyloidosis was collected by the Hypertrophic Cardiomyopathy Gene Curation Committee (subgroup of the Cardiovascular Working Group). Some individuals with Hereditary ATTR amyloidosis present with features of hypertrophic cardiomyopathy (HCM) and/or restrictive cardiomyopathy (RCM). The prevalence of HCM and/or RCM in Hereditary ATTR amyloidosis is high but exact percentages have not been accurately defined due the high prevalence of HCM and RCM (~25%) development in senile cardiac amyloidosis, which occurs due to accumulation of wildtype TTR accumulation in the heart with age (Galant et al., 2017 PMID 28213611; Meier-Ewert et al., 2011 PMID 21989745; Perlini et al, 2016 PMID 27900617; Ruberg and Berk, 2012 PMID 22949539). Several variants including TTR-V30M, TTR-T60A, and TTR-V122L are the most commonly associated with cardiac amyloidosis (Siddiqi and Ruberg, 2017 PMID 28739313). Additionally, the Charcot-Marie-Tooth Gene Curation Working Group reviewed the subtype of individuals that present with features of polyneuropathy, those individuals typically developing an axonal, length-dependent, predominantly sensory and autonomic neuropathy or small fiber neuropathy in the early course, which rapidly progresses involving motor nerves as well. For the neuropathy sub-phenotype, the current literature provides additional evidence including further neuropathy cases associated to various TTR mutations such as p.Val50Met (PMIDs: 8071954, 19180884, 24101130) and p.Leu75Pro (1351039, 7910950, 31319424) with variant-based functional studies ranging from urea-assays (PMID: 12351683) to mouse models (PMIDs: 9095004, 12351683). Functional evidence further supports the gene-disease relationship for neuropathy, including expression studies (PMID: 28335735), nerve tissue based cell cultures (PMIDs: 11567048, 18983977, 14981241), and rescue experiments including three successful phase 3 clinical trials (PMIDs: 22843282, 30145929, 29972753)