Targeted sequencing of selected functional genes in patients with wild-type transthyretin amyloidosis.

OBJECTIVE: Wild-type transthyretin (ATTRwt) amyloidosis is caused by the misfolding and deposition of the transthyretin protein (TTR) in the absence of mutations in the TTR gene. Studies regarding the variant form of ATTR amyloidosis (ATTRv) suggest that the presence of single-nucleotide polymorphisms (SNP) in genes other than the TTR, may influence the development of the disease. However, other genetic factors involved in the aetiopathogenesis of ATTRwt are currently unknown. This work investigates the presence of sequence variants in genes selected for their possible impact on ATTRwt amyloidosis. To do so, targeted sequencing of 84 protein-coding genes was performed in a cohort of 27 patients diagnosed with ATTRwt. RESULTS: After applying quality and frequency filtering criteria, 72 rare or novel genetic variants were found. Subsequent classification according to the ACMG-AMP criteria resulted in 17 variants classified as of uncertain significance in 14 different genes. To our knowledge, this is the first report associating novel gene variants with ATTRwt amyloidosis. In conclusion, this study provides potential insights into the aetiopathogenesis of ATTRwt amyloidosis by linking novel coding-gene variants with the occurrence of the disease.

Coexistence of Positive 99mTc-DPD Scintigraphy and Monoclonal Gammopathy: A Frequent Challenge.

Background: Cardiac involvement is common in amyloidosis, and the vast majority of cases of amyloid cardiomyopathy are attributed to primary amyloidosis or transthyretin amyloidosis (ATTR). Although the coexistence of scintigraphy suggestive of ATTR with monoclonal gammopathy of undetermined significance is well documented, the correct diagnosis is still challenging in non-referral centers. Methods: We performed a retrospective study reviewing all amyloid cardiomyopathy cases diagnosed at our center over the last 5 years, and described our experience and diagnostic approach. Results: During the last 5 years, 74 patients with positive scintigraphy were identified. Of these patients, 41 were included in this study as they had all necessary tests for a complete diagnosis. Two of these 41 patients had variant ATTR and 29 had wild-type ATTR. Ten patients had monoclonal gammopathy (24.4%), and it was consequently impossible to obtain a specific diagnosis. During follow-up, 14 patients (34.1%), five of them from the monoclonal gammopathy group, died, reflecting the severity of disease. Conclusions: In patients with ATTR-suggestive scintigraphy, monoclonal gammopathy frequently occurs concomitantly, thus not allowing to establish a specific diagnosis. A biopsy could only be replaced by genetic testing in selected cases.

Interferencia analítica en la determinación de troponina por anticuerpos heterófilos / Interference in the determination of Troponin due to heterophile antibodies

Resumen Por su elevada especificidad y sensibilidad, y a raíz de la tercera definición universal de infarto estas isoformas cardiacas han sido aceptadas en el ámbito internacional como los biomarcadaores de elección en la práctica clínica para el diagnóstico de síndrome coronario agudo, preferibles a la determinación de las enzimas creatina quinasa y su isoforma MB. Se presenta el caso de un varón de ochenta años, quien, de manera persistente, tuvo valores elevados de troponinas, pese a evolución clínica no compatible con síndrome coronario agudo ni otras causas de elevación de este biomarcador.

Abstract Due to its elevated specificity and sensitivity, and on being the third universal definition of myocardial infarction, these cardiac isoforms have been accepted internationally as the biomarkers of choice in clinical practice for the diagnosis of acute coronary syndrome, and are preferable to the determinations of creatine kinase and its MB isoform. A case is presented on an eighty year-old man, who persistently had elevated Troponin values, despite a clinical course that was incompatible with an acute coronary syndrome or any other causes of elevation of this biomarker.

Estimating the prevalence of allelic variants in the transthyretin gene by analysing large-scale sequencing data.

Transthyretin amyloidosis (ATTR amyloidosis) is a rare disease characterised by extracellular deposition of amyloid fibrils composed by transthyretin. ATTR amyloidosis can be sub-classified as wild-type ATTR (ATTR-wt) or as hereditary amyloidosis (ATTR-m); the prevalence of both types are likely underestimated. There are tools that can help us to study ATTR-m, as gnomAD database. Our primary aim was to estimate prevalence of variants, especially amyloidogenic variants, in the TTR gene using gnomAD database. We analysed TTR missense variants found in gnomAD. The variables studied were classified according to their clinical significance and according to the different populations. We found 71 missense variants in the TTR gene. Eleven variants were described as affects function variants (prevalence 1:230). The most frequently detected variant were c.424G>A (p.(Val142Ile)) (prevalence 1:332, MAF 0.00151) and c.148G>A (p.(Val50Met)) (prevalence 1:4924, MAF 0.000102), which represented 88% and 5%, respectively, of all affects function variants detected. Seventeen variants were classified as probably affects function, 29 as unknown variants, 4 as probably does not affect function and 10 as does not affect function variants. In terms of different populations, c.424G>A (p.(Val142Ile)) was especially prevalent in African population (MAF 0.01602; prevalence of 1:31) and c.148G>A (p.(Val50Met)) in European population (MAF 0.000179; prevalence of 1:2792). Prevalence of amyloidogenic variants in the general population was higher than prevalence heretofore described. This difference could be explained by incomplete penetrance of the disease, but other factors contributing to this fact, fundamentally the underdiagnosis of the disease.