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. 2021 Aug 21;42(32):3063-3073.
doi: 10.1093/eurheartj/ehab424.

Alpha-protein kinase 3 (ALPK3) truncating variants are a cause of autosomal dominant hypertrophic cardiomyopathy

Luis R Lopes  1   2 , Soledad Garcia-Hernández  3 , Massimiliano Lorenzini  1   2 , Marta Futema  1 , Olga Chumakova  4   5 , Dmitry Zateyshchikov  6 , Maria Isidoro-Garcia  7 , Eduardo Villacorta  8 , Luis Escobar-Lopez  9   10 , Pablo Garcia-Pavia  9   10   11 , Raquel Bilbao  12 , David Dobarro  12 , Maria Sandin-Fuentes  13 , Claudio Catalli  14 , Blanca Gener Querol  14 , Ainhoa Mezcua  15   16 , Jose Garcia Pinilla  15   16 , Torsten Bloch Rasmussen  17 , Ana Ferreira-Aguar  18 , Pablo Revilla-Martí  18 , Maria Teresa Basurte Elorz  19 , Alicia Bautista Paves  20 , Juan Ramon Gimeno  10   21 , Ana Virginia Figueroa  22 , Raul Franco-Gutierrez  23 , Maria Eugenia Fuentes-Cañamero  24 , Marina Martinez Moreno  25 , Martin Ortiz-Genga  26 , Jesus Piqueras-Flores  27 , Karina Analia Ramos  28 , Ainars Rudzitis  29 , Luis Ruiz-Guerrero  30 , Ricardo Stein  31 , Mayte Triguero-Bocharán  27 , Luis de la Higuera  26 , Juan Pablo Ochoa  9   10 , Dad Abu-Bonsrah  32 , Cecilia Y T Kwok  32 , Jacob B Smith  32 , Enzo R Porrello  32   33 , Mohammed M Akhtar  1   2 , Joanna Jager  1 , Michael Ashworth  34 , Petros Syrris  1 , David A Elliott  32   33 , Lorenzo Monserrat  26 , Perry M Elliott  1   2
Affiliations

Alpha-protein kinase 3 (ALPK3) truncating variants are a cause of autosomal dominant hypertrophic cardiomyopathy

Luis R Lopes et al. Eur Heart J. .

Abstract

Aims: The aim of this study was to determine the frequency of heterozygous truncating ALPK3 variants (ALPK3tv) in patients with hypertrophic cardiomyopathy (HCM) and confirm their pathogenicity using burden testing in independent cohorts and family co-segregation studies.

Methods and results: In a discovery cohort of 770 index patients with HCM, 12 (1.56%) were heterozygous for ALPK3tv [odds ratio(OR) 16.11, 95% confidence interval (CI) 7.94-30.02, P = 8.05e-11] compared to the Genome Aggregation Database (gnomAD) population. In a validation cohort of 2047 HCM probands, 32 (1.56%) carried heterozygous ALPK3tv (OR 16.17, 95% CI 10.31-24.87, P < 2.2e-16, compared to gnomAD). Combined logarithm of odds score in seven families with ALPK3tv was 2.99. In comparison with a cohort of genotyped patients with HCM (n = 1679) with and without pathogenic sarcomere gene variants (SP+ and SP-), ALPK3tv carriers had a higher prevalence of apical/concentric patterns of hypertrophy (60%, P < 0.001) and of a short PR interval (10%, P = 0.009). Age at diagnosis and maximum left ventricular wall thickness were similar to SP- and left ventricular systolic impairment (6%) and non-sustained ventricular tachycardia (31%) at baseline similar to SP+. After 5.3 ± 5.7 years, 4 (9%) patients with ALPK3tv died of heart failure or had cardiac transplantation (log-rank P = 0.012 vs. SP- and P = 0.425 vs. SP+). Imaging and histopathology showed extensive myocardial fibrosis and myocyte vacuolation.

Conclusions: Heterozygous ALPK3tv are pathogenic and segregate with a characteristic HCM phenotype.

Keywords: ALPK3; Genetics; Hypertrophic cardiomyopathy.

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Figures

None
Truncating variants in ALPK3 are a cause of 1–2% of autosomal dominant hypertrophic cardiomyopathy and are associated with a phenotype characterized by extensive fibrosis and a predominantly concentric or apical pattern of left ventricular hypertrophy without left ventricular outflow tract obstruction. (A) Main phenotype characteristics and outcomes. ALPK3tv, alpha-protein kinase 3-truncating variants; CK, creatine kinase; HCM, hypertrophic cardiomyopathy; ICD, implantable cardioverter–defibrillator; LVH, left ventricular hypertrophy; LVSD, left ventricular systolic dysfunction; SCD, sudden cardiac death. (B) Cardiac magnetic resonance imaging showing the prevalent phenotype of severe mid to apical hypertrophy and extensive late gadolinium enhancement in three patients. Left to right: 4-chamber view end-diastole cine image, 4-chamber view late gadolinium enhancement image, short axis late gadolinium enhancement image. (C) Kaplan–Meier analysis comparing incidence of an outcome of heart failure death and transplant between ALP3tv patients, sarcomere positive and sarcomere negative. SARC+: sarcomere positive; SARC−: sarcomere negative.
Figure 1
Figure 1
Pedigrees for the families in which co-segregation analyses were performed. (A) Proband #36 (p.Glu1146Glyfs*12); (B) proband #23 (p.Trp1563*); (C) proband #37 (p.Glu1179Argfs*93); (D) proband #18 (p.Pro45Alafs*37); (E) proband #32 (p.Pro45Alafs*37); (F) proband #43 (p.Glu1098*); and (G) proband #38 (p.Lys184*). Arrows indicate the probands. Filled symbols, affected. N: not affected. Squares: males. Circles: females. Vertical bar inside symbol: ALPK3tv carrier. WT,: wall thickness; LVNC,: left ventricular non-compaction.
Figure 2
Figure 2
Kaplan–Meier estimates for age at diagnosis of HCM in probands and relatives with alpha-protein kinase 3-truncating variants (ALPK3tv). The analysis included non-affected relatives. “Time” represents age in years.
Figure 3
Figure 3
Scatter plot of age vs. maximum left ventricular wall thickness in ALPK3tv carriers. This graph was based on information available on all heterozygous carriers from both cohorts (validation and discovery, probands and relatives). The maximum left ventricular wall thickness was taken from magnetic resonance (or echocardiography results when magnetic resonance study was not performed). A positive correlation between maximum left ventricular wall thickness and age is seen for females. MLVWT, maximum left ventricular wall thickness.
Figure 4
Figure 4
Distribution of rare ALPK3-truncating variants along the gene.
Figure 5
Figure 5
ECG (A), cine CMR image (B), and late gadolinium enhancement (C) images (four-chamber view on the left and mid short axis view on the right) of proband # 6 from the discovery cohort (ALPK3 p.Gln1258*) illustrating some of the common phenotype traits of this cohort, including very high voltages on the ECG and extensive fibrosis. CMR, cardiovascular magnetic resonance; ANOVA, analysis of variance.
Figure 6
Figure 6
Kaplan–Meier analysis comparing incidence of an outcome of heart failure death and cardiac transplant between ALP3tv patients, sarcomere positive and sarcomere negative. Patients with ALPK3tv (probands and affected relatives from discovery and validation cohorts) with available follow-up data (45 out of 51) were compared to adult patients with HCM with available genotype and follow-up data.
Figure 7
Figure 7
Histopathology images for index patient # 23. (A) A section of myocardium stained with Masson trichrome. There are four dysplastic vessels in the field. The muscle of the tunica media is irregularly distributed around the circumference of the vessels and in places is almost absent. There is accompanying mural fibrosis. The surrounding myocardium shows patchy interstitial fibrosis and focal myocyte vacuolation. (B) Low power view of myocardium showing a collagenous scar. The scar tissue contains thin-walled ectatic vessels and interdigitates with the surrounding myocardium that is vacuolated and shows foci of fine interstitial fibrosis (Masson-trichrome stain). (C) Low-power view of myocardium stained with Masson trichrome. The field shows an area of central pallor caused by a localized focus of vacuolated myocytes. There is fine interstitial fibrosis. There is no myocyte disarray. A dysplastic vessel is visible at the left edge of the field. (D) High-power view of a section of myocardium stained with Masson trichrome. It contains myocytes with irregular central areas of clearing of the cytoplasm to give vacuoles. Some of the vacuoles are traversed by fine strands of cytoplasm and other contain abundant normal mitochondria (seen as small red dots). Many of the vacuoles, however, are empty. Periodic acid-Schiff staining was negative. Desmin and plakoglobin staining was normal (Supplementary material online).
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