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Case Report

Digenic Contribution of Heterozygous ALPK3 and TRIM63 Variants to End-Stage Hypertrophic Cardiomyopathy in a Young Adult

by
Olga S. Chumakova
1,*,
Natalia V. Milovanova
2,
Elena A. Mershina
3,
Sergey I. Kutsev
2 and
Ekaterina Y. Zakharova
2
1
Moscow Healthcare Department, City Clinical Hospital 17, 119620 Moscow, Russia
2
Research Centre for Medical Genetics, 115522 Moscow, Russia
3
Radiology Department, Omonosov Moscow State University, 119192 Moscow, Russia
*
Author to whom correspondence should be addressed.
Cardiogenetics 2026, 16(1), 1; https://doi.org/10.3390/cardiogenetics16010001
Submission received: 27 August 2025 / Revised: 22 December 2025 / Accepted: 29 December 2025 / Published: 1 January 2026
(This article belongs to the Section Molecular Genetics)
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Abstract

Hypertrophic cardiomyopathy (HCM), the most common inherited cardiac disorder, is usually caused by pathogenic variants in sarcomeric genes and is inherited in an autosomal dominant manner. Around 5% of cases are caused by variants in non-sarcomeric genes, which may involve alternative modes of inheritance. This study presents the first reported case of HCM associated with digenic contribution of heterozygous variants in two non-sarcomeric genes: ALPK3 and TRIM63. The patient was incidentally diagnosed with non-obstructive HCM in childhood and developed extreme myocardial hypertrophy with moderate heart failure at the age of 18. Rapid progressive left ventricular dysfunction promptly resulted in death at the age of 26. Genetic testing with an extended HCM panel identified no sarcomeric variants but revealed two truncating variants in the ALPK3 and TRIM63 genes. Whole-genome sequencing excluded any other causes of the disease. Heterozygous ALPK3 variants are typically associated with late-onset HCM, whereas TRIM63 variants are only considered pathogenic in a recessive state. This case, therefore, suggests a synergistic contribution of both variants to the development of a severe phenotype. The potential mechanisms of interaction between the protein products of ALPK3 and TRIM63 within the M-band of the sarcomere are discussed.

1. Introduction

Hypertrophic cardiomyopathy (HCM) is the most common inherited cardiac disorder, typically presenting with asymmetric left ventricular (LV) hypertrophy and hypercontractility, with LV outflow tract obstruction (LVOTO) occurring in approximately two-thirds of patients [1].
Initially, HCM was considered to be a strictly autosomal dominant disorder caused by pathogenic (P) or likely pathogenic (LP) variants in genes encoding sarcomeric contractile proteins, including beta-myosin heavy chain (MYH7, 14q11.2), cardiac myosin-binding protein C (MYBPC3, 11p11.2), cardiac troponins T, I, and C (TNNT2, 1q32.1; TNNI3, 19q13.42; and TNNC1, 3p21.1, respectively), alpha-tropomyosin (TPM1, 15q22.2), myosin regulatory and essential light chains (MYL2, 12q24.11; and MYL3, 3p21.31), and cardiac alpha-actin (ACTC1, 15q14). The MYH7 and MYBPC3 genes encode key sarcomeric thick-filament proteins, and P/LP variants in these genes account for the majority (80%) of reported genotype-positive cases to date [2].
However, accumulating evidence shows that at least half of patients, including those with early-onset or familial disease, lack sarcomeric variants, and disease severity varies widely even among carriers of the same variant. These findings highlight the complexity of HCM heritability and the need for advanced genetic testing in real clinical practice [3].
The clinical variability of HCM is now attributed to non-Mendelian genetic and epigenetic factors. Non-coding RNAs, particularly microRNAs, and epigenetic mechanisms, such as DNA methylation, control gene expression and have been linked to HCM in multiple studies, including ours [4,5,6,7]. Since 2021, growing evidence has highlighted the contribution of common genetic variants (single-nucleotide polymorphisms), prompting the development of polygenic risk scores for HCM, particularly in patients without sarcomeric variants [8,9,10].
Research in sarcomere-negative cohorts shows that approximately 5% of patients (up to 25% of children) have conditions such as cardiac amyloidosis, Fabry disease, storage disorders, and mitochondrial diseases, which can mimic HCM, complicating diagnosis. It is crucial to differentiate these HCM-like phenotypes, as these mostly syndromic genetic diseases have distinct treatments, prognoses, and, sometimes, inheritance patterns [11,12].
The search for causes of non-syndromic HCM continues in genes beyond the sarcomere. Around 5% of sarcomere-negative cases (proportions vary by cohort and gene list) result from variants in genes whose protein products interact with sarcomere components, producing a phenotype largely indistinguishable from classical HCM. Some of these genes, including ALPK3 (15q25.3, autosomal dominant) and TRIM63 (1p36.11, autosomal recessive), are now validated for inclusion in diagnostic panels [13]. Nevertheless, genotype-phenotype correlations in this subgroup remain poorly defined, and reports of co-occurring variants in these genes are exceedingly rare.
Here, we present the first reported case of HCM associated with digenic contribution of heterozygous variants in ALPK3 and TRIM63.
The ALPK3 gene comprises 14 exons, encoding a 1705-amino acid alpha-kinase 3 protein (ALPK3). Over the past decade, ALPK3 has been implicated in HCM susceptibility across a full spectrum of variant types [14]. Biallelic truncating variants, in particular, cause an infantile-onset hypokinetic HCM [15], whereas heterozygous truncating variants have been linked to a late-onset form of the disease (onset at 56 ± 15.9 years) [16].
The TRIM63 gene comprises 9 exons and encodes a 353-amino acid muscle RING-finger protein-1 (MuRF1). The first report linking TRIM63 mutations to HCM in humans was published in 2012 [17]. Subsequent studies have established TRIM63 as a recessive HCM gene: biallelic carriers typically exhibit an adult-onset HCM phenotype [18], whereas heterozygous carriers generally remain unaffected, although subtle hypertrophic traits may be evident through advanced cardiac imaging [19].
Both ALPK3 and TRIM63/MuRF1 have been localized to the M-band of the sarcomere in vitro and in vivo [20,21,22,23], supporting the idea of a synergistic pathogenic mechanism that may underlie the severe clinical phenotype observed in this case, as discussed below.

2. Detailed Case Description

2.1. Clinical Presentation

A 25-year-old male patient (182 cm, 109 kg, body mass index 33 kg/m2) was admitted to the cardiology department with dyspnea at rest and severe peripheral edema.
He had a history of non-obstructive HCM, incidentally diagnosed at age 8 following abnormalities on an electrocardiogram (Figure 1). By age 18, he had developed extreme concentric LV hypertrophy (with a maximal LV wall thickness of 41 mm) and moderate heart failure (HF) symptoms corresponding to New York Heart Association (NYHA) class II, as well as mild arterial hypertension.
Over the next five years, he felt well and self-discontinued all medications. About three months later, his condition deteriorated rapidly, leading to his first hospitalization for decompensated HF at around age 23. Despite new therapy, the symptoms worsened, resulting in repeat hospitalizations six months later (Figure 1). After a third admission, cardioverter–defibrillator implantation and heart transplantation evaluation were recommended, but he declined intervention.
The index admission at age 25 represented the fourth hospitalization within a two-year period and was due to congestive HF. A transthoracic echocardiogram showed LV hypertrophy with a twofold reduction in maximal wall thickness (20 mm), mid-ventricular and apical non-compaction, marked biatrial enlargement, severely impaired LV systolic function (ejection fraction 20%), restrictive LV diastolic dysfunction, and mild hydropericardium (Figure 2a–c).
Cardiac magnetic resonance imaging confirmed LV hypertrophy, with maximal interventricular septal thickness of 15 mm (4–9 mm in the other segments), and pronounced myocardial non-compaction in all segments of the anterior, lateral, and inferior walls and in the middle and apical septal segments (15–20 mm) (Figure 3a–d). Additionally, extensive late gadolinium enhancement was observed in the interventricular septum and right ventricular trabeculae (Figure 3e,f).
The electrocardiogram showed a pseudo-myocardial infarction pattern and QRS voltage abnormalities (Figure 4a). 24 h Holter monitoring recorded four episodes of non-sustained ventricular tachycardia (3–33 beats, 90–158 bpm) (Figure 4b), along with a high frequency of polymorphic premature beats: 1047 supraventricular and 14,642 ventricular.
Routine laboratory tests, including hematology, urinalysis, and biochemistry, were normal, but serum N-terminal pro-brain natriuretic peptide level was markedly elevated at 2757 pg/mL.
Despite receiving optimal guideline-directed medical therapy for HF, including a beta-blocker, sacubitril/valsartan, dapagliflozin, spironolactone, and loop diuretics, the patient’s condition deteriorated progressively over one year. At age 26, he underwent implantation of a mechanical circulatory support device (artificial heart) as a bridge to heart transplantation. Unfortunately, he died before a suitable donor heart became available. His small pedigree is shown in Figure A1. His mother was clinically unaffected, and his father was reportedly asymptomatic but not evaluated.

2.2. Genetic Testing

Genetic testing was performed three years after the patient’s death as part of a scientific grant; earlier analysis had been limited by insurance. The technical aspects are detailed in Appendix A. A custom panel covering 77 genes associated with hypertrophic and restrictive cardiomyopathies was applied as a first-line test (Table A1). Variant pathogenicity was assessed in accordance with the American College of Medical Genetics and Genomics (ACMG) recommendations. Two known variants were identified: ALPK3 splice-site c.4724-1G>A and TRIM63 nonsense c.739C>T (p.Gln247*) (Table 1, Figure A2). No rare sarcomeric variants, including those of uncertain significance, were found. To exclude other causes of the phenotype, including deep intron variants and copy number variations, the whole-genome sequencing was performed, but no additional findings were identified.

2.3. In Silico Protein–Protein Interaction Analysis

A protein–protein interaction analysis using GeneCards (accessed on 8 December 2025; https://www.genecards.org/cgi-bin/carddisp.pl?gene=ALPK3) highlighted MYH7 as a central node connecting ALPK3 and TRIM63 (Figure 5). Based on these data, we hypothesize that in patients carrying P/LP variants in both genes, pathological accumulation of MYH7-encoded myosin may occur, driving severe, early-onset hypertrophy. Potential mechanisms are discussed below.

3. Discussion

Patients diagnosed with HCM in childhood have a significantly higher lifetime risk of developing end-stage HF. Additional risk factors include age at diagnosis under 12 years, male sex, carrying a P/LP sarcomere variant, prior septal reduction therapy, lower initial LV ejection fraction [24], and absence of LVOTO [25]. Our patient had three risk factors: early diagnosis, male sex, and absence of LVOTO. Instead of a sarcomeric variant, he carried two variants in non-sarcomeric genes located in the M-band of the sarcomere.
The ALPK3 was first linked to cardiomyopathy in children presenting in early childhood or in utero with biallelic truncating variants [15]. Most pediatric cases had associated musculoskeletal and facial abnormalities and died shortly after diagnosis; survivors transitioned from a dilated to a hypertrophic phenotype, now recognized as a hallmark of ALPK3-related disease. In 2021, Lopes et al. demonstrated that heterozygous truncating ALPK3 variants can cause late-onset HCM with extensive fibrosis and progressive HF [16].
The ALPK3 splice-site variant c.4724-1G>A (Chr15:84867315A>G) identified in our patient was recently reported in a Korean cohort, where it was detected in seven HCM patients and two controls [26]. Affected individuals ranged from 39 to 97 years, with symptoms reported in only three cases: syncope in two (ages 51 and 55) and HF in one (age 67). In contrast, our patient exhibited a markedly more severe phenotype, suggesting additional modifying genetic factors.
The TRIM63 is a rare HCM gene, first established in 2020 through a large cohort study by Salazar-Mendiguchía et al. involving 4867 HCM patients and 3628 controls. In that study, only biallelic carriers (homozygotes or compound heterozygotes) exhibited disease, supporting autosomal-recessive inheritance [18]. Since then, TRIM63 has been included among validated HCM-associated genes [13].
To date, 24 TRIM63 variants have been reported in HCM patients [27], with the nonsense variant c.739C>T (Chr1:26384973G>A, p.Gln247*) being the most common, present in approximately one-third of cases across five publications [13]. Consistent with previous reports, our recent study found that a heterozygous carrier of this variant showed no signs of cardiomyopathy [28]. Nevertheless, single TRIM63 variants can aggravate HCM: patients with rare heterozygous TRIM63 variants, regardless of whether a sarcomeric mutation is present or not, had earlier onset and exhibited greater LV wall thickness compared to those without such variants [29].

ALPK3 Protein and TRIM63/MuRF1 Protein Interaction

While TRIM63/MuRF1 is a well-established E3 ligase central to sarcomeric protein turnover [30], ALPK3 is a cardiac-enriched pseudokinase with largely unknown functions.
Protein turnover via the ubiquitin proteasome system (UPS) is a critical post-transcriptional mechanism for maintaining basal sarcomere homeostasis in striated muscle. This process involves the targeting of damaged or unnecessary proteins for degradation by the proteasome through a cascade of enzymatic reactions that culminates in the activity of E3 ligases, such as TRIM63/MURF1. TRIM63/MURF1 localizes to the sarcomere M-band, where it transfers ubiquitin molecules to target substrate proteins [30].
Stress-induced effects of TRIM63/MURF1 differ between skeletal and cardiac muscle. In skeletal muscle, it acts as an “atrophy-related” E3 ligase, promoting proteolysis during periods of reduced activity, such as immobilization or aging [31]. In contrast, in cardiomyocytes, TRIM63/MURF1 is predominantly cardioprotective, limiting excessive sarcomeric protein accumulation during pressure overload by ubiquitinating key gene products, including MYH7, MYBPC3, and TNNI3 [17,30,32], downregulating pro-hypertrophic signaling pathways such as calcineurin-NFAT [33], and regulating energy metabolism via creatine kinase and PPARα [34,35]. TRIM63/MURF1 also participates in mechanotransduction through titin interaction [20].
The ALPK3 protein contains an a-kinase domain [36] but exhibits minimal intrinsic catalytic activity in vitro [21,37] and in vivo [37], suggesting primarily non-enzymatic roles. Initial cell-line studies implicated ALPK3 in cardiomyocyte differentiation during early cardiogenesis [38] More recent work has established ALPK3 as an essential component of the sarcomere M-band, where it contributes to sarcomere integrity and proteostasis.
Agarwal et al. demonstrated that ALPK3 localizes to the M-band and colocalizes with the force-buffering proteins myomesins (MYOM1, MYOM2). In vivo, loss of ALPK3 function led to myomesin mislocalization, global sarcomeric disorganization, and abnormal heart morphology, linking ALPK3 deficiency to impaired structural stability [21]. The same study also showed that the regulation of additional M-band proteins involved in sarcomere protein turnover was disrupted, including TRIM63/MURF1, suggesting that ALPK3 is involved in proteostatic regulation as well [21].
A subsequent study by McNamara et al. confirmed the M-band localization of ALPK3 using human pluripotent stem cell-derived cardiomyocytes and demonstrated its interaction with MURF ligases and p62/SQSTM1, which is an adaptor for another protein degradation system—autophagy [22]. Most recently, Feng et al. showed the M-band localization of ALPK3 in both neonatal and adult hearts. They also provided in vivo evidence that ALPK3 deficiency leads to the accumulation of thick-filament proteins and demonstrated the colocalization of ALPK3 and MURF1 in vitro [23]. Based on these findings, the hypothesis has emerged that ALPK3 may serve as an alternative MuRF docking site at the M-band, forming a regulatory ALPK3-MURFs axis in cardiomyocytes [23]. Figure A3 shows a simplified schematic overview of this proposed interaction in normal physiology and in the genetic alteration seen in our patient. Further functional studies are needed to define the underlying mechanisms.
Two in vitro and in vivo functional studies have shown that the TRIM63 p.Gln247* variant impairs E3 ubiquitin ligase activity, leading to protein mislocalization and defective ubiquitylation. This dysfunction promotes cardiac hypertrophy by enhancing pro-hypertrophic signaling pathways and increasing expression of MYH7 mRNA [17,27]. Functional studies of the ALPK3 c.4724-1G>A variant have not yet been performed.
Phenotypes in genetic conditions are influenced by multiple modifiers, including microRNAs, which negatively modulate gene expression by inhibiting translation or promoting target mRNA degradation [39]. MicroRNAs are under intense investigation as potential biomarkers or therapeutic targets in human diseases, including HCM [40,41]. TRIM63/MURF1 regulation has been extensively explored in skeletal muscle atrophy [42]. In cardiomyocytes, in vitro studies show that TRIM63/MURF1 is downregulated by miR-23a [43] and miR-19a/b [44], though in vivo data are inconsistent: miR-23a promotes cardiac hypertrophy in mouse models but is highly expressed in both human HCM and DCM, being more related to end-stage HF [45]; meanwhile, miR-19a/b is unchanged [46] or reduced [47] in secondary cardiac hypertrophy models. Whether these or other microRNAs can be targeted in TRIM63-associated HCM remains to be studied. Data on microRNAs in ALPK3 signaling pathways are limited to a single study showing miR-384-5p exerts a protective effect against cardiac hypertrophy in vitro and in vivo [48].
Although the patient’s severe phenotype is likely driven by rare genetic variants, environmental factors such as arterial hypertension and obesity (both present in our patient) may also have contributed. Observational studies have shown that hypertension, particularly in sarcomere-negative HCM (as in our case), can modify disease severity [8], while obesity worsens prognosis and increases the risk of HF outcomes [49,50], as observed in our patient.
Although WGS was performed, polygenic risk scores were not assessed in our patient. Additionally, analyses of non-coding RNAs and epigenetic modifications were not conducted. Incorporation of these approaches into cardiomyopathy diagnostics is the subject of ongoing and future research.
In summary, early and precise genetic diagnosis can improve risk stratification in cases of digenic inheritance. In the era of gene-based therapies and limited donor hearts, comprehensive molecular testing is increasingly critical, especially when family screening is limited. Our case also illustrates the importance of adherence to guideline-recommended HF therapy, as medication discontinuation rapidly worsened the patient’s condition. P/LP variants in ALPK3 and TRIM63 likely impair MuRF-mediated degradation of thick filaments, accelerating sarcomeric protein accumulation—particularly myosin—and driving severe, early-onset hypertrophy not seen in heterozygotes alone.

4. Conclusions

Despite the lack of experimental evidence, we hypothesize that the severe phenotype observed in this case of non-sarcomeric HCM may arise from the combined effect of two low-penetrance variants in non-sarcomeric genes localized in the M-band of the sarcomere. The growing availability of expanded genetic panels can increase the pool of patients with a precise molecular diagnosis, thereby contributing to a deeper understanding of cardiomyopathy pathogenesis.

5. Limitations

The major limitation of this study is the lack of family screening. Therefore, digenic inheritance remains speculative. The protein–protein interaction analysis was based solely on literature data and, in this particular case, is hypothesis-generating. Further experimental validation in animal models is necessary to confirm these findings.

Author Contributions

Conceptualization, O.S.C. and N.V.M.; methodology, O.S.C. and N.V.M.; validation, N.V.M. and E.A.M.; formal analysis, O.S.C. and N.V.M.; investigation, O.S.C. and N.V.M.; resources, E.Y.Z.; data curation, O.S.C. and E.Y.Z.; writing—original draft preparation, O.S.C. and N.V.M.; writing—review and editing, E.A.M. and E.Y.Z.; visualization, E.A.M.; project administration, E.Y.Z.; funding acquisition, S.I.K. All authors have read and agreed to the published version of the manuscript.

Funding

This work was supported by the Ministry of Science and Higher Education of the Russian Federation (the Federal Scientific Technical Program for Genetic Technologies Development for 2019–2030, agreement No. 075-15-2025-481).

Institutional Review Board Statement

This study was conducted following the Declaration of Helsinki and approved by the Ethics Committee of City Clinical Hospital #17, Moscow (protocol #9, 4 November 2016).

Informed Consent Statement

Informed consent for the study and the use of data from the medical records for publication was obtained from the patient.

Data Availability Statement

The data that support the findings of this study are available from the corresponding author upon reasonable request.

Acknowledgments

The authors express their sincere thanks to Tatiana Baklanova and Natalia Voloshina for their assistance in analyzing the source documents for this publication.

Conflicts of Interest

The authors declare no conflicts of interest.

Appendix A

Technical Aspects of Genetic Testing

Genomic DNA (gDNA) was extracted from whole blood using a Diatom DNA Prep Reagent Kit (Biocom, San Diego, CA, USA), following the manufacturer’s protocol, and stored at −20℃. DNA libraries were constructed with the Ion AmpliSeq™ targeted custom panel and the Ion AmpliSeq™ Library Kit 2.0 (Thermo Fisher Scientific, Inc.). Next-generation sequencing (NGS) was performed using an Ion S5™ (Thermo Fisher Scientific, Inc., Waltham, MA, USA).
The custom panel covered the transcribed sequences of 77 genes (exons and exon–intron regions) associated with hypertrophic and restrictive cardiomyopathies (Table A1). Massive parallel sequencing of the pooled libraries was performed using an Ion 540™ Chip Kit (Thermo Fisher Scientific, Inc., cat. No. A27766) and an Ion 540™ Kit-Chef (Thermo Fisher Scientific, Inc., cat. No. A30011), with an average amplicon length of 175 bp. The panel sequencing quality indicators are presented in Table A2.
Whole-genome sequencing was carried out on genomic DNA extracted from peripheral blood lymphocytes according to standard manufacturer protocols (provided by LLC “Biotech Campus,” Moscow, Russia).
The Genome Reference Consortium Human Build (GRCh38/hg38) was used for data analysis. Bioinformatic analysis of both targeted NGS panel and whole-genome sequencing data was performed using the in-house NGSData software. nalysis of whole-genome sequencing data included several stages. First, point variants were searched in genes relevant to the patient’s clinical phenotype. Second, copy number variations consistent with clinical presentation were assessed. Third, large chromosomal rearrangements (structural variations) were evaluated.
Table A1. List of 77 genes in a custom panel.
Table A1. List of 77 genes in a custom panel.
SymbolFull Gene Name
AARS2Alanine–tRNA ligase, mitochondrial
ACAD9Acyl-CoA dehydrogenase family member 9, mitochondrial
ACADVLVery long-chain specific acyl-CoA dehydrogenase, mitochondrial
ACTA1Actin, alpha 1, skeletal muscle
ACTC1Actin, alpha cardiac muscle 1
ACTN2Alpha-actinin-2
AGKAcylglycerol kinase, mitochondrial
AGLGlycogen debranching enzyme
ALPK3Alpha-protein kinase 3
APOA1Apolipoprotein 1
ATPAF2ATP synthase mitochondrial F1 complex assembly factor 2
BAG3BAG family molecular chaperone regulator 3
BRAFSerine/threonine-protein kinase B-raf
CAV3Caveolin 3
COA5Cytochrome c oxidase assembly factor 5
COA6Cytochrome c oxidase assembly factor 6 homolog
COQ24-hydroxybenzoate polyprenyltransferase, mitochondrial
COX15Cytochrome c oxidase assembly protein COX15 homolog
COX6B1Cytochrome c oxidase subunit 6B1
CSRP3Cysteine and glycine-rich protein 3
DESDesmin
DLDDihydrolipoyl dehydrogenase, mitochondrial
ELAC2Zinc phosphodiesterase ELAC protein 2
FHL1Four and a half LIM domains protein 1
FHL2Four and a half LIM domains 2 (FHL-2)
FHOD3FH1/FH2 domain-containing protein 3
FLNCFilamin-C
FOXRED1FAD-dependent oxidoreductase domain-containing protein 1
FXNFrataxin, mitochondrial
GAALysosomal alpha-glucosidase
GFM1Elongation factor G, mitochondrial
GLAAlpha galactosidase A
GYG1Glycogenin-1
HFEHereditary hemochromatosis protein
HRASGTPase HRas
JPH2Junctophilin 2
KLHL24Kelch-like protein 24
KRASGTPase KRas
LAMP2Laminin subunit alpha-2
LDB3LIM domain-binding protein 3
LIASLipoyl synthase, mitochondrial
LZTR1Leucine-zipper-like transcriptional regulator 1
MAP2K1Dual specificity mitogen-activated protein kinase kinase 1
MAP2K2Dual specificity mitogen-activated protein kinase kinase 2
MLYCDMalonyl-CoA decarboxylase, mitochondrial
MRPL339S ribosomal protein L3, mitochondrial
MRPL4439S ribosomal protein L44, mitochondrial
MRPS2228S ribosomal protein S22, mitochondrial
MTO1Protein MTO1 homolog, mitochondrial
MYBPC3Myosin-binding protein C, cardiac type
MYH7Myosin Heavy Chain 7
MYL2Myosin regulatory light chain 2, ventricular/cardiac muscle isoform
MYL3Myosin light chain 3
MYOZ2Myozenin 2
MYPNMyopalladin
NF1Neurofibromin
NRASGTPase NRas
PLNCardiac phospholamban
PMM2Phosphomannomutase 2
PRKAG25′-AMP-activated protein kinase subunit gamma-2
PTPN11Tyrosine-protein phosphatase non-receptor type 11
RAF1RAF proto-oncogene serine/threonine-protein kinase
RIT1GTP-binding protein Rit1
SCO2Synthesis Of Cytochrome C Oxidase 2
SHOC2SHOC2 Leucine Rich Repeat Scaffold Protein
SLC22A5Solute Carrier Family 22 Member 5
SLC25A3Solute Carrier Family 25 Member 3
SLC25A4Solute Carrier Family 25 Member 4
SOS1SOS Ras/Rac Guanine Nucleotide Exchange Factor 1
SURF1SURF1 Cytochrome C Oxidase Assembly Factor
TMEM70Transmembrane Protein 70
TNNC1Troponin C1, Slow Skeletal And Cardiac Type
TNNI3Troponin I3, Cardiac Type
TNNT2Troponin T2, Cardiac Type
TPM1Tropomyosin 1
TRIM63Tripartite Motif Containing 63
TTRTransthyretin
Table A2. Panel Sequencing Quality Indicators.
Table A2. Panel Sequencing Quality Indicators.
IndicatorMeaning
Total reads2,200,937
Medium Coverage1202x
On target94%
Uniformity of coverage87%
% of target loci covered with high quality99.1%
% uncovered target loci0.9%
total variants567
GenderXy
Cardiogenetics 16 00001 g0a1
Figure A1. Pedigree of a young adult patient (black square indicated by an arrow) with end-stage HCM.
Figure A1. Pedigree of a young adult patient (black square indicated by an arrow) with end-stage HCM.
Cardiogenetics 16 00001 g0a1
Cardiogenetics 16 00001 g0a2
Figure A2. Genetic findings in a young adult patient with end-stage HCM. (a) The heterozygous ALPK3 variant (chr15:84867316G>A), resulting in a nucleotide substitution (NM_020778.5: c.4724-1G>A), was detected in 39% of runs. This point was read a total of 76 times. (b) The heterozygous TRIM63 variant (chr1:26058482G>A), which results in a premature termination codon (NM_032588.3: c.739C>T), was detected in 47% of runs. This point was read 3202 times.
Figure A2. Genetic findings in a young adult patient with end-stage HCM. (a) The heterozygous ALPK3 variant (chr15:84867316G>A), resulting in a nucleotide substitution (NM_020778.5: c.4724-1G>A), was detected in 39% of runs. This point was read a total of 76 times. (b) The heterozygous TRIM63 variant (chr1:26058482G>A), which results in a premature termination codon (NM_032588.3: c.739C>T), was detected in 47% of runs. This point was read 3202 times.
Cardiogenetics 16 00001 g0a2
Cardiogenetics 16 00001 g0a3
Figure A3. Simplifed schematic overview of possible interaction between ALPK3 and TRIM63/MURF1 proteins in cardiomyocytes in (a) normal physiology and (b) in genetic ALPK3/TRIM63 alteration.
Figure A3. Simplifed schematic overview of possible interaction between ALPK3 and TRIM63/MURF1 proteins in cardiomyocytes in (a) normal physiology and (b) in genetic ALPK3/TRIM63 alteration.
Cardiogenetics 16 00001 g0a3

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Figure 1. Timeline of the clinical course and treatment for the patient. Abbreviations: DC, discontinuation (of medications); HF, heart failure; IVS, interventricular septum; LV EF, left ventricular ejection fraction. Hospitalizations are indicated by circled plus symbols.
Figure 1. Timeline of the clinical course and treatment for the patient. Abbreviations: DC, discontinuation (of medications); HF, heart failure; IVS, interventricular septum; LV EF, left ventricular ejection fraction. Hospitalizations are indicated by circled plus symbols.
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Figure 2. Transthoracic echocardiogram. (a,b) Left ventricular hypertrophy, non-compaction myocardium (indicated by the asterisks), biatrial enlargement, and mild pericardial effusion (indicated by the arrows). (c) Reduced mitral annular tissue velocities during systole (s’) and diastole (e’ and a’).
Figure 2. Transthoracic echocardiogram. (a,b) Left ventricular hypertrophy, non-compaction myocardium (indicated by the asterisks), biatrial enlargement, and mild pericardial effusion (indicated by the arrows). (c) Reduced mitral annular tissue velocities during systole (s’) and diastole (e’ and a’).
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Figure 3. Cardiac magnetic resonance imaging. (a–d) SSFP sequence: (a) long axis, 2-chamber projection; (b,c) short axis; (d) long axis, 4-chamber projection. Double-sided arrows indicate hypertrophied septal segments, and asterisks indicate a layer of non-compact myocardium. (e,f) Delayed contrast enhancement, IR sequence with suppression of the signal from the myocardium. Dotted arrows indicate the extended areas of intramyocardial fibrosis (non-coronary pattern) in the interventricular septum and the trabecular part of the right ventricular myocardium.
Figure 3. Cardiac magnetic resonance imaging. (a–d) SSFP sequence: (a) long axis, 2-chamber projection; (b,c) short axis; (d) long axis, 4-chamber projection. Double-sided arrows indicate hypertrophied septal segments, and asterisks indicate a layer of non-compact myocardium. (e,f) Delayed contrast enhancement, IR sequence with suppression of the signal from the myocardium. Dotted arrows indicate the extended areas of intramyocardial fibrosis (non-coronary pattern) in the interventricular septum and the trabecular part of the right ventricular myocardium.
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Figure 4. Electrocardiogram and 24 h Holter monitoring. (a) Pathological Q-waves followed by ST-segment elevation in inferior leads, right ventricular hypertrophy, R-wave regression, and low voltage in left precordial leads, and a premature ventricular beat with left bundle branch block morphology. (b) Longest run of non-sustained ventricular tachycardia of 33 beats (13 s).
Figure 4. Electrocardiogram and 24 h Holter monitoring. (a) Pathological Q-waves followed by ST-segment elevation in inferior leads, right ventricular hypertrophy, R-wave regression, and low voltage in left precordial leads, and a premature ventricular beat with left bundle branch block morphology. (b) Longest run of non-sustained ventricular tachycardia of 33 beats (13 s).
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Figure 5. Protein–protein interaction network analysis highlighting MYH7 protein product as a potential central hub that mediates the functional interplay between the protein products of ALPK3 and TRIM63 (indicated by a red triangle). Interactions between proteins encoded by ALPK3 and TRIM63 genes and the protein encoded by the MYH7 gene have been experimentally proven.
Figure 5. Protein–protein interaction network analysis highlighting MYH7 protein product as a potential central hub that mediates the functional interplay between the protein products of ALPK3 and TRIM63 (indicated by a red triangle). Interactions between proteins encoded by ALPK3 and TRIM63 genes and the protein encoded by the MYH7 gene have been experimentally proven.
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Table 1. Genetic findings in a young adult patient with childhood-onset hypertrophic cardiomyopathy deceased from end-stage heart failure.
Table 1. Genetic findings in a young adult patient with childhood-onset hypertrophic cardiomyopathy deceased from end-stage heart failure.
GeneVariantZygosityPathogenicity (ACMG)gnomAD v3.1.2 FrequencyClinGen for HCM
Inheritance ModeEvidence
ALPK3Chr15:84867315A>G
NM_020778.5:
c.4724-1G>A		HzLikely
Pathogenic		0ARDefinitive
ADStrong
TRIM63Chr1:26384973G>A
NM_032588.3: c.739C>T (p.Gln247*)		HzPathogenic<0.001ARModerate
ADDisputed
ACMG: American College of Medical Genetics; ALPK3: alpha-protein kinase 3; AD: autosomal dominant; AR: autosomal recessive; HCM: hypertrophic cardiomyopathy; gnomAD: Genome Aggregation Database; TRIM63: tripartite motif 63; Hz: heterozygous.
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Chumakova, O.S.; Milovanova, N.V.; Mershina, E.A.; Kutsev, S.I.; Zakharova, E.Y. Digenic Contribution of Heterozygous ALPK3 and TRIM63 Variants to End-Stage Hypertrophic Cardiomyopathy in a Young Adult. Cardiogenetics 2026, 16, 1. https://doi.org/10.3390/cardiogenetics16010001

AMA Style

Chumakova OS, Milovanova NV, Mershina EA, Kutsev SI, Zakharova EY. Digenic Contribution of Heterozygous ALPK3 and TRIM63 Variants to End-Stage Hypertrophic Cardiomyopathy in a Young Adult. Cardiogenetics. 2026; 16(1):1. https://doi.org/10.3390/cardiogenetics16010001

Chicago/Turabian Style

Chumakova, Olga S., Natalia V. Milovanova, Elena A. Mershina, Sergey I. Kutsev, and Ekaterina Y. Zakharova. 2026. "Digenic Contribution of Heterozygous ALPK3 and TRIM63 Variants to End-Stage Hypertrophic Cardiomyopathy in a Young Adult" Cardiogenetics 16, no. 1: 1. https://doi.org/10.3390/cardiogenetics16010001

APA Style

Chumakova, O. S., Milovanova, N. V., Mershina, E. A., Kutsev, S. I., & Zakharova, E. Y. (2026). Digenic Contribution of Heterozygous ALPK3 and TRIM63 Variants to End-Stage Hypertrophic Cardiomyopathy in a Young Adult. Cardiogenetics, 16(1), 1. https://doi.org/10.3390/cardiogenetics16010001

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