Phenotype and clinical outcomes of Glu89Lys hereditary transthyretin amyloidosis: a new endemic variant in Spain

The p.Glu109Lys variant (Glu89Lys) is a rare cause of hereditary transthyretin amyloidosis (ATTRv) for which clinical spectrum remains unresolved. We sought to describe the clinical characteristics and outcomes of ATTR Glu89Lys amyloidosis and assess a potential founder effect in Spain. Patients with the p.Glu109Lys ATTRv variant from 14 families were recruited at 7 centres. Demographics, complementary tests and clinical course were analysed. Haplotype analysis was performed in 7 unrelated individuals. Thirty-eight individuals (13 probands, mean age 40.4 ± 13.1 years) were studied. After median follow-up of 5.1 years (IQR 1.7–9.6), 7 patients died and 7 required heart transplantation (median age at transplantation 50.5 years). Onset of cardiac and neurological manifestations occurred at a mean age of 48.4 and 46.8 years, respectively. Median survival from birth was 61.6 years and no individual survived beyond 65 years. Patients treated with disease-modifying therapies exhibited better prognosis (p  Glu89Lys ATTRv is a TTR variant with a founder effect in Spain. It is associated with near complete penetrance, early onset and mixed cardiac and neurologic phenotype. Patients have poor prognosis, particularly if not treated with disease-modifying therapies.</p

Classification of the novel variants identified in the NGS cohort.

<p>Classification of the novel variants identified in the NGS cohort.</p

Distribution of rare variants according to gene-level supporting evidence, ACMG clinical classification and minor allele frequency filtering.

<p>Distribution of rare variants according to gene-level supporting evidence, ACMG clinical classification and minor allele frequency filtering.</p

Novel pathogenic/likely pathogenic variants found in validated sarcomere genes.

<p>Novel pathogenic/likely pathogenic variants found in validated sarcomere genes.</p

Novel variants of unknown significance in <i>TTN</i> gene that are deleterious according to multiple in silico predictors.

<p>Novel variants of unknown significance in <i>TTN</i> gene that are deleterious according to multiple in silico predictors.</p

Classification of rare variants in <i>MYBPC3</i>, <i>MYH7</i>, <i>TNNI3</i>, <i>TNNT2</i> and <i>TPM1</i> (pooled data from Sanger sequencing and NGS cohorts).

<p>Classification of rare variants in <i>MYBPC3</i>, <i>MYH7</i>, <i>TNNI3</i>, <i>TNNT2</i> and <i>TPM1</i> (pooled data from Sanger sequencing and NGS cohorts).</p

Cases with confirmed CNVs.

<p>NGS results, schematic representation of the breakpoints and precise characterization by Sanger sequencing of (<b>A</b>) the deletion of exon 27 of <i>MYBPC3</i> (P168, brown sample in the graph), (<b>B)</b> the deletion spanning from exon 4 to exon 12 of <i>MYBPC3</i> (P259, turquoise sample in the graph), and (<b>C</b>) the well-characterized <i>PLN</i> deletion (blue sample in the graph). (<b>D</b>) NGS results are shown for the non-characterized <i>PLN</i> deletion (orange sample in the graph).</p

Rare variants (MAF <0.002) in the 5 most frequent sarcomere genes, 25 genes associated with or candidate for HCM and 24 genes (same panel excluding <i>TTN</i>).

<p>Rare variants (MAF <0.002) in the 5 most frequent sarcomere genes, 25 genes associated with or candidate for HCM and 24 genes (same panel excluding <i>TTN</i>).</p

Additional file 1: Table S1. of Concept and design of a genome-wide association genotyping array tailored for transplantation-specific studies

Tagging and coverage of MHC region markers. Table S2: Tagging and coverage of Tx-specific genes. Table S3: Untranslated regions (UTRs) considered in the TxArray design. Table S4: Loss-of-function variants included in the TxArray. Table S5: Copy number polymorphisms (CNPs) and variations (CNVs) included in the TxArray. (DOCX 54 kb