Elsevier

American Heart Journal

Volume 225, July 2020, Pages 108-119
American Heart Journal

Clinical Investigation
Expanding the clinical and genetic spectrum of ALPK3 variants: Phenotypes identified in pediatric cardiomyopathy patients and adults with heterozygous variants

https://doi.org/10.1016/j.ahj.2020.03.023Get rights and content
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open access

Introduction

Biallelic damaging variants in ALPK3, encoding alpha-protein kinase 3, cause pediatric-onset cardiomyopathy with manifestations that are incompletely defined.

Methods and Results

We analyzed clinical manifestations of damaging biallelic ALPK3 variants in 19 pediatric patients, including nine previously published cases. Among these, 11 loss-of-function (LoF) variants, seven compound LoF and deleterious missense variants, and one homozygous deleterious missense variant were identified. Among 18 live-born patients, 8 exhibited neonatal dilated cardiomyopathy (44.4%; 95% CI: 21.5%-69.2%) that subsequently transitioned into ventricular hypertrophy. The majority of patients had extracardiac phenotypes, including contractures, scoliosis, cleft palate, and facial dysmorphisms. We observed no association between variant type or location, disease severity, and/or extracardiac manifestations. Myocardial histopathology showed focal cardiomyocyte hypertrophy, subendocardial fibroelastosis in patients under 4 years of age, and myofibrillar disarray in adults.

Rare heterozygous ALPK3 variants were also assessed in adult-onset cardiomyopathy patients. Among 1548 Dutch patients referred for initial genetic analyses, we identified 39 individuals with rare heterozygous ALPK3 variants (2.5%; 95% CI: 1.8%-3.4%), including 26 missense and 10 LoF variants. Among 149 U.S. patients without pathogenic variants in 83 cardiomyopathy-related genes, we identified six missense and nine LoF ALPK3 variants (10.1%; 95% CI: 5.7%-16.1%). LoF ALPK3 variants were increased in comparison to matched controls (Dutch cohort, P = 1.6×10−5; U.S. cohort, P = 2.2×10−13).

Conclusion

Biallelic damaging ALPK3 variants cause pediatric cardiomyopathy manifested by DCM transitioning to hypertrophy, often with poor contractile function. Additional extracardiac features occur in most patients, including musculoskeletal abnormalities and cleft palate. Heterozygous LoF ALPK3 variants are enriched in adults with cardiomyopathy and may contribute to their cardiomyopathy. Adults with ALPK3 LoF variants therefore warrant evaluations for cardiomyopathy.

Abbreviations

ACM
arrythmogenic cardiomyopathy
CADD
combined annotation dependent depletion
DCM
dilated cardiomyopathy
HCM
hypertrophic cardiomyopathy
LoF
loss-of-function
LVNC
left ventricular noncompaction
LVH
left ventricular hypertrophy
MAF
minor allele frequency
NGS
next-generation sequencing

Cited by (0)

Declarations of interest

None.

Authorship contributions

Dr. J.C. Herkert coordinated the study overall, analyzed and interpreted data, co-drafted the initial manuscript, and revised and submitted the manuscript; Dr. J.M.A. Verhagen collected and interpreted data, co-drafted the initial manuscript, and revised the manuscript; Dr. R. Yotti, Dr. A. Haghighi, Dr. D.G. Phelan, Dr. P.A. James, Dr. N.J. Brown, Dr. C. Stutterd, Dr. I. Macciocca, Dr. K. Leong, Dr. Y. van Bever, Dr. A.E. Roberts, Ms. R. Agarwal, Dr. J. Seidman, Dr. N.K. Lakdawala, Dr. F. Fernández-Avilés, Dr. M.A. Burke, Dr. M. Pierpont, Dr. E. Braunlin, Dr. A.O. Ḉağlayan, Dr. D.Q.C.M. Barge-Schaapveld, Dr. L. van Osch-Gevers and Prof. I.M. van Langen acquired clinical data, interpreted data, and critically reviewed the manuscript; Dr. J.D.H. Jongbloed, Dr. P.J. Lockhart, Dr. D.J. Amor, Dr. C.E. Seidman, and Dr. I.M.B.H. van de Laar initiated, conceptualized and designed the study, interpreted data, and critically reviewed the manuscript; Dr. M.A. van Slegtenhorst developed laboratory and administrative logistics, interpreted data, and critically reviewed the manuscript; Mr. L.G. Boven developed laboratory, administrative and analytical logistics, performed laboratory work and analyzed and interpreted data; Ms. M.L.C. Bulthuis performed laboratory work and critically reviewed the manuscript; Dr. E. Birnie performed statistical analyses. All authors approved the final manuscript as submitted.

1

The authors wish it to be known that, in their opinion, the first 2 authors should be regarded as joint First Authors.

2

The authors wish it to be known that, in their opinion, the last 5 authors should be regarded as joint Last Authors.