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

Johanna C Herkert*, Judith M A Verhagen, Raquel Yotti, Alireza Haghighi, Dean G Phelan, Paul A James, Natasha J Brown, Chloe Stutterd, Ivan Macciocca, Kai'En Leong, Marian L C Bulthuis, Yolande van Bever, Marjon A van Slegtenhorst, Ludolf G Boven, Amy E Roberts, Radhika Agarwal, Jonathan Seidman, Neal K Lakdawala, Francisco Fernández-Avilés, Michael A BurkeMary Ella Pierpont, Elizabeth Braunlin, Ahmet Okay Ḉağlayan, Daniela Q C M Barge-Schaapveld, Erwin Birnie, Lennie van Osch-Gevers, Irene M van Langen, Jan D H Jongbloed, Paul J Lockhart, David J Amor, Christine E Seidman, Ingrid M B H van de Laar

*Bijbehorende auteur voor dit werk

OnderzoeksoutputAcademicpeer review

5 Citaten (Scopus)
53 Downloads (Pure)


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.

Originele taal-2English
Pagina's (van-tot)108-119
Aantal pagina's12
TijdschriftAmerican Heart Journal
Vroegere onlinedatum21-apr-2020
StatusPublished - jul-2020

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