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 Burke; Mary 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

doi:10.1016/j.ahj.2020.03.023

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

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

Authors

Johanna C Herkert¹, Judith M A Verhagen², Raquel Yotti³, Alireza Haghighi⁴, Dean G Phelan⁵, Paul A James⁶, Natasha J Brown⁷, Chloe Stutterd⁶, Ivan Macciocca⁸, Kai'En Leong⁹, Marian L C Bulthuis¹⁰, Yolande van Bever¹¹, Marjon A van Slegtenhorst¹¹, Ludolf G Boven¹², Amy E Roberts¹³, Radhika Agarwal¹⁴, Jonathan Seidman¹⁴, Neal K Lakdawala¹⁵, Francisco Fernández-Avilés³, Michael A Burke¹⁶, Mary Ella Pierpont¹⁷, Elizabeth Braunlin¹⁷, Ahmet Okay Ḉağlayan¹⁸, Daniela Q C M Barge-Schaapveld¹⁹, Erwin Birnie¹², Lennie van Osch-Gevers²⁰, Irene M van Langen¹², Jan D H Jongbloed¹², Paul J Lockhart⁵, David J Amor²¹, Christine E Seidman²², Ingrid M B H van de Laar¹¹

Affiliations

¹ University of Groningen, University Medical Center Groningen, Department of Genetics, Groningen, The Netherlands. Electronic address: j.c.herkert@umcg.nl.
² Department of Clinical Genetics, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands. Electronic address: j.m.a.verhagen@erasmusmc.nl.
³ Instituto de Investigación Sanitaria Gregorio Maranón, and CIBERCV, Instituto de Salud Carlos III (ISCIII), Madrid, Spain.
⁴ Department of Genetics, Harvard Medical School Boston, MA, USA; Department of Medicine (Genetics), Brigham and Women's Hospital, Boston, MA, USA.
⁵ Bruce Lefroy Centre for Genetic Health Research, Murdoch Children's Research Institute, Victoria, Australia; Department of Pediatrics, Faculty of Medicine, Dentistry and Health Sciences, The University of Melbourne, Victoria, Australia.
⁶ Genetic Medicine, Royal Melbourne Hospital, Victoria, Australia.
⁷ Department of Pediatrics, Faculty of Medicine, Dentistry and Health Sciences, The University of Melbourne, Victoria, Australia; Victorian Clinical Genetics Services, Murdoch Children's Research Institute, Victoria, Australia.
⁸ Victorian Clinical Genetics Services, Murdoch Children's Research Institute, Victoria, Australia.
⁹ Department of Cardiology, The Royal Children's Hospital, Victoria, Australia.
¹⁰ University of Groningen, University Medical Center Groningen, Department of Pathology and Medical Biology, Groningen, The Netherlands.
¹¹ Department of Clinical Genetics, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands.
¹² University of Groningen, University Medical Center Groningen, Department of Genetics, Groningen, The Netherlands.
¹³ Department of Cardiology, Boston Children Hospital, Boston, MA, USA.
¹⁴ Department of Genetics, Harvard Medical School Boston, MA, USA.
¹⁵ Department of Medicine (Genetics), Brigham and Women's Hospital, Boston, MA, USA.
¹⁶ Department of Medicine, Division of Cardiology, Emory University, Atlanta, GA, USA.
¹⁷ Department of Pediatrics, University of Minnesota, Minneapolis, MN, USA.
¹⁸ Department of Medical Genetics, School of Medicine, Department of Molecular Medicine, Institute of Health Sciences, Dokuz Eylül University, Izmir, Turkey; Departments of Neurosurgery, Neurobiology and Genetics, Yale School of Medicine, New Haven, CT, USA.
¹⁹ Department of Clinical Genetics, Leiden University Medical Centre, Leiden, The Netherlands.
²⁰ Department of Pediatric Cardiology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands.
²¹ Bruce Lefroy Centre for Genetic Health Research, Murdoch Children's Research Institute, Victoria, Australia; Department of Pediatrics, Faculty of Medicine, Dentistry and Health Sciences, The University of Melbourne, Victoria, Australia; Victorian Clinical Genetics Services, Murdoch Children's Research Institute, Victoria, Australia.
²² Department of Genetics, Harvard Medical School Boston, MA, USA; Department of Medicine (Genetics), Brigham and Women's Hospital, Boston, MA, USA; Howard Hughes Medical Institute, Chevy Chase, MD, USA.

PMID: 32480058
DOI: 10.1016/j.ahj.2020.03.023

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.

MeSH terms

Abnormalities, Multiple / genetics
Adult
Age of Onset
Cardiomyopathies / diagnostic imaging
Cardiomyopathies / genetics*
Cardiomyopathies / physiopathology
Cardiomyopathy, Dilated / genetics
Cardiomyopathy, Hypertrophic / genetics
Child
Child, Preschool
Chromosomes, Human, Pair 15 / genetics
Echocardiography
Electrocardiography
Heterozygote*
Humans
Infant
Loss of Function Mutation*
Muscle Proteins / genetics*
Mutation, Missense*
Phenotype
Protein Kinases / genetics*

Substances

Alpk3 protein human
Muscle Proteins
Protein Kinases