Genomic Screening for Pathogenic Transthyretin Variants Finds Evidence of Underdiagnosed Amyloid Cardiomyopathy From Health Records

Carry, Brendan; Young, Katelyn; Fielden, Samuel W.; Kelly, Melissa; Sturm, Amy C.; Avila, Jose David; Martin, Christa Lese; Kirchner, H. Lester; Fornwalt, Brandon K.; Haggerty, Christopher M.

doi:10.1016/j.jaccao.2021.07.002

Cited by 7 publications

(2 citation statements)

References 38 publications

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“…More than 120 mutations of the TTR gene have been described, and as of December 2021 there are 68 pathogenic/likely pathogenic variants of the TTR gene listed in the National Center for Biotechnology Information ClinVar database (6)(7)(8). Some genotype-phenotype variability has been reported.…”

Section: Introductionmentioning

confidence: 99%

Clinical Profile and Prognosis of Hereditary Transthyretin Amyloid Cardiomyopathy: A Single-Center Study in South China

Wang

Peng

Pang

et al. 2022

Front. Cardiovasc. Med.

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BackgroundHereditary transthyretin amyloid cardiomyopathy (ATTR-CM) is a genotypically heterogeneous disorder with a poor prognosis. There is limited literature describing the variants responsible for ATTRv in areas outside the United State, the United Kingdom and Europe. This study was performed to describe the clinical characteristics and genotypic profiles of this disease in South China.MethodsThis was a single-center retrospective study that evaluated 29 patients with a confirmed diagnosis of hereditary transthyretin amyloid cardiomyopathy enrolled from January 2016 to November 2021.Results93.1% patients were male and the median age of symptom onset was 53 (46, 62.5) years old. The initial manifestations of ATTR-CM were cardiovascular symptoms (55.2%), neuropathy (41.4%) and vitreous opacity (3.4%). Phenotypes at diagnosis were mixed (82.8%), predominant cardiac (6.9%), neurological (6.9%) and ophthalmic (3.4%). Poor R-wave progression (41%), pseudo-infarct (31%) and low-voltage (31%) patterns were common findings on electrocardiogram. Unexplained increased wall thickness was observed in all 29 patients, with mean septal and posterior wall thicknesses of 14.25 ± 6.26 mm and 15.34 ± 2.84 mm, respectively. Diastolic dysfunction was also seen in all 29 patients, and 17 (58%) had a restrictive fill pattern at diagnosis. Nine different missense mutations of the TTR gene were found in 29 patients from 23 families, with c.349G>T (p.Ala117Ser) the most common mutation. The median survival time after diagnosis was 47.6 (95% CI 37.9-57.4) months, with 1, 3 and 5-year survival rates of 91.2%, 74% and 38% respectively. Patients with advanced heart failure (National Amyloidosis Staging stage II/III) had worse survival than stage I [Breslow (Generalized Wilcoxon), χ2 = 4.693, P = 0.03)].ConclusionsATTR amyloidosis genotypes and phenotypes are highly heterogeneous. Advanced heart failure predicts a poor prognosis. Understanding the different clinical profiles of ATTR cardiac amyloidosis with different genotype is important to its early recognition.

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Section: Introductionmentioning

confidence: 99%

Clinical Profile and Prognosis of Hereditary Transthyretin Amyloid Cardiomyopathy: A Single-Center Study in South China

Wang

Peng

Pang

et al. 2022

Front. Cardiovasc. Med.

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“…Typically, genomic DNA for this type of analysis originates from whole blood, and the genomic DNA can be analyzed by various molecular strategies, not only through direct sequencing, but also using RFLP, southern blot, or other methods, depending on the type and the site of the mutation under analysis. Other tissues, such as buccal cells or hair bulb cells, could be used to obtain genomic DNA, avoiding the more invasive method of blood withdrawal and improving the availability of the patients [ 14 , 15 , 16 , 17 , 18 , 19 , 20 ]. The analysis of DNA from tissue other than the blood cells should be performed with caution, as it is possible that somatic mosaicism of the analyzed genomic region can be present in subjects with hATTR [ 14 ].…”

Section: Introductionmentioning

confidence: 99%

Hereditary Transthyretin-Related Amyloidosis: Genetic Heterogeneity and Early Personalized Gene Therapy

et al. 2022

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Point mutations of the transthyretin (TTR) gene are related with hereditary amyloidosis (hATTR). The number of people affected by this rare disease is only partially estimated. The real impact of somatic mosaicism and other genetic factors on expressivity, complexity, progression, and transmission of the disease should be better investigated. The relevance of this rare disease is increasing and many efforts have been made to improve the time to diagnosis and to estimate the real number of cases in endemic and non-endemic areas. In this context, somatic mosaicism should be better investigated to explain the complexity of the heterogeneity of the hATTR clinical features, to better estimate the number of new cases, and to focus on early and personalized gene therapy. Gene therapy can potentially improve the living conditions of affected individuals and is one of the central goals in research on amyloidosis related to the TTR gene, with the advantage of overcoming liver transplantation as the sole treatment for hATTR disease.

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Prevalence of Pathogenic Transthyretin Gene Variants in the Rocky Mountain Region

Jacoby,

Quan,

Todd

et al. 2024

Muscle and Nerve

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Introduction/AimsHereditary transthyretin amyloidosis (ATTRv) is a genetic condition caused by pathogenic variants in the transthyretin (TTR) gene resulting in multisystem amyloid deposition, especially in peripheral nerve and heart. Information on the prevalence of ATTRv in the United States is limited. The objective of this study was to understand the prevalence and genetic ancestry in the Val142Ile population in a large regional US population.MethodsColorado Center for Personalized Medicine (CCPM) biobank collects specimens from consenting adults seen throughout the University of Colorado Health System, a large tertiary healthcare system within the Rocky Mountain Region (RMR). Single nucleotide polymorphism (SNP) array genotyping and whole exome sequencing (WES) were performed for genetic research. Prevalence of TTR variants was studied.ResultsA total of 73,346 participants had genetic testing; 151 (0.21%) individuals had a pathogenic or likely pathogenic TTR variant. The most common variant was Val142Ile, making up 82.61% of TTR variants found. Over four percent of people with African non‐Hispanic ancestry had a Val142Ile variant.DiscussionThe most common TTR variant in our study was Val142Ile, the most common variant in the United States (US). Similar to other US‐based studies, affected individuals were predominantly of African, non‐Hispanic ancestry. The availability of treatments for symptomatic ATTRv patients raises opportunities and challenges for biobanks as the identification of at‐risk individuals places pressure on highly specialized centers and providers to see patients for screening and follow‐up.

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Genomic Screening for Pathogenic Transthyretin Variants Finds Evidence of Underdiagnosed Amyloid Cardiomyopathy From Health Records

Cited by 7 publications

References 38 publications

Clinical Profile and Prognosis of Hereditary Transthyretin Amyloid Cardiomyopathy: A Single-Center Study in South China

Clinical Profile and Prognosis of Hereditary Transthyretin Amyloid Cardiomyopathy: A Single-Center Study in South China

Hereditary Transthyretin-Related Amyloidosis: Genetic Heterogeneity and Early Personalized Gene Therapy

Prevalence of Pathogenic Transthyretin Gene Variants in the Rocky Mountain Region

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