Rare transthyretin gene variants (p.Ala45Thr, p.Val91Ala, p.Phe53Cys, p.Ala101Val, p.Glu109Lys and p.Phe53Leu): diagnostic pitfalls and clinical characteristics of Polish patients with transthyretin cardiac amyloidosis.

The knowledge about clinical features of Polish patients with hereditary type of transthyretin cardiac amyloidosis (ATTR-CA) is scant. We present rare transthyretin (TTR) gene variants and diagnostic difficulties among patients with hereditary ATTR-CA. In 2018-2024, 252 consecutive patients with suspected cardiac amyloidosis were evaluated, including blood tests, standard 12-lead electrocardiography, transthoracic echocardiography and [99mTc]Tc-DPD scintigraphy. TTR gene sequencing was performed, if mandatory. Hereditary ATTR-CA was confirmed in 14 patients (including one female). Most of them had pathogenic or likely pathogenic TTR gene variants, which are very uncommon in the hereditary transthyretin amyloidosis population: p.Ala45Thr, p.Val91Ala, p.Phe53Cys, p.Ala101Val, p.Glu109Lys and p.Phe53Leu. Of note, patients with p.Ala101Val and p.Phe53Cys variants had inconclusive [99mTc]Tc-DPD scintigraphy results, which may be due to the low sensitivity of [99mTc]Tc-DPD bone scintigraphy for these variants. Cardiac biomarkers did not reflect the intensity of cardiac uptake on [99mTc]Tc-DPD bone scintigraphy - two patients with intense cardiac uptake of tracer had normal or borderline hs-cTnT and NT-proBNP levels. During follow-up, four patients died, two patients underwent combined heart and liver transplantation. This study enriches our knowledge regarding genotype-phenotype correlations of specific TTR variants, broadens the spectrum of identified TTR variants among Polish population, and shows limited value of [99mTc]Tc-DPD scintigraphy in some patients with hereditary ATTR-CA. In cases with strong suspicion of ATTR-CA and inconclusive [99mTc]Tc-DPD scintigraphy results, genetic testing should be considered.