Abstract
Biallelic damaging variants in ALPK3, encoding alpha-protein kinase 3, cause pediatric-onset cardiomyopathy with manifestations that are incompletely defined. 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). 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.
Highlights
Biallelic damaging variants in ALPK3, encoding alpha-protein kinase 3, cause pediatric-onset cardiomyopathy with manifestations that are incompletely defined
We previously reported seven patients from four unrelated consanguineous families with pediatric cardiomyopathy caused by biallelic predicted proteintruncating variants in ALPK3.5,7 Two additional case reports described severe congenital cardiomyopathy including features of both dilated cardiomyopathy (DCM) and hypertrophic cardiomyopathy (HCM) from homozygous ALPK3 LoF variants.[8,9]
No additional likely pathogenic or pathogenic variants in genes associated with cardiomyopathy, including TTN, nor any pathogenic copy number variants explaining their cardiomyopathy were identified in any of the patients with biallelic ALPK3 variants (Data Supplement and Supplementary Table II)
Summary
Patient recruitmentOur study was carried out in collaboration with clinicians from seven different countries and institutions. We reviewed clinical data of 19 patients with biallelic variants in ALPK3 (NM_020778.4), including nine previously reported patients.[5,7,8,9] HCM was defined as increased ventricular wall thickness (end diastolic wall thickness: zscore ≥2) not solely explained by abnormal loading or structural heart conditions such as valve disease, congenital heart disease, or hypertension. DCM was defined as ventricular dilation (LV end-diastolic dimension N2 SD above mean for body surface area) and systolic dysfunction (fractional shortening or LV ejection fraction N2 SD below mean for age) in the absence of abnormal loading conditions.[10,11] Chromosomal analysis was performed in all index patients with pediatric-onset cardiomyopathy— except patient F10P1. Informed consent was obtained from all participants or their legal guardians
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