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. 2020 Jul:225:108-119.
doi: 10.1016/j.ahj.2020.03.023. Epub 2020 Apr 21.

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

Johanna C Herkert  1 , Judith M A Verhagen  2 , Raquel Yotti  3 , Alireza Haghighi  4 , Dean G Phelan  5 , Paul A James  6 , Natasha J Brown  7 , Chloe Stutterd  6 , Ivan Macciocca  8 , Kai'En Leong  9 , Marian L C Bulthuis  10 , Yolande van Bever  11 , Marjon A van Slegtenhorst  11 , Ludolf G Boven  12 , Amy E Roberts  13 , Radhika Agarwal  14 , Jonathan Seidman  14 , Neal K Lakdawala  15 , Francisco Fernández-Avilés  3 , Michael A Burke  16 , Mary Ella Pierpont  17 , Elizabeth Braunlin  17 , Ahmet Okay Ḉağlayan  18 , Daniela Q C M Barge-Schaapveld  19 , Erwin Birnie  12 , Lennie van Osch-Gevers  20 , Irene M van Langen  12 , Jan D H Jongbloed  12 , Paul J Lockhart  5 , David J Amor  21 , Christine E Seidman  22 , Ingrid M B H van de Laar  11
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Free article

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

Johanna C Herkert et al. Am Heart J. 2020 Jul.
Free article

Abstract

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.

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