Hypertrophic cardiomyopathy is the first inherited cardiac condition for which a genetic causality was established in the 80’s. The last 40 years brought a tremendous amount of scientific work, to such extent that we are now able to explain around 60% of its inheritability. However, many challenges still remain to closing the gap of its “missed heritability”, and to achieve appropriate variant interpretation in regards to broad genetic datasets.1,2
ALPK3 is a nuclear kinase containing two immunoglobulins (Ig)-like domains that is expressed at the earliest steps of cardiac development, modulating cardiomyocyte differentiation.3 Although its downstream effectors are still largely unknown, ALPK3 may act as a transcriptional regulator of early transcription factors including HEY2, a central effector of the Notch signaling pathway.3 Starting from consanguineous families, ALPK3 was first associated with a recessive form of newborn or early-onset dilated cardiomyopathy (DCM), later converting to HCM.3,4 Potentially related to ALPK3’s action on early cardiac transcription factors, this type of cardiomyopathy is associated with extracardiac features including musculoskeletal and craniofacial abnormalities such as scoliosis, cleft palate, and facial dysmorphism.4
In this work, Lopes et al. provide a deep analysis of the pathogenicity of ALPK3 heterozygous variants through the study of a broad cohort of 770 HCM probands in the UK, and validate their results in a cohort of 2047 HCM cases from several countries.5,6 ALPK3 truncating variants (tv) are causative for 1,56% of HCM in both cohorts, with an Odds ratio of 16. The HCM cases in these cohorts are characterized by a late onset (56 +/- 15 year), with an age-related and apparently high penetrance (95 % in males and 80 % in females by 75 years), although this should be interpreted with caution and reassessed in the general population. Interestingly, ALPK3 defines a new subset of HCM patients with a poor prognosis despite an apical/concentric pattern of hypertrophy, with heart failure, death or transplantation outcomes similar to sarcomeric-positive HCM patients. Electrical left ventricular hypertrophy is frequent (70%) and a short PR is observed on the ECG in up to 10% of cases. Wall thickness exceeding 20 mm can be found in 35% of cases, but LVOT obstruction is present at rest in only 16% of cases. Cardiac tissue displaying extensive myocardial fibrosis is detected by MRI in about half of the patients. Histologically, cardiomyocyte vacuolization is observed, but disarray is absent even in the most severe cases. Raised CK levels can also be present is some cases, with hypertrophic myopathic features on skeletal muscle biopsy.
Interestingly, ALPK3 variants were also associated with DCM, ACM, restrictive cardiomyopathy and Brugada syndrome in the validation cohort, although in only one case for each phenotype.5 This observation may reinforce the initial observation that ALPK3 drives various cardiomyopathy patterns, and highlights the existence of a growing molecular intersection between cardiomyopathy subgroups. This observed phenotypic variability raises questions regarding the molecular mechanisms underlying this pleiotropy. In particular, the interplay between ALPK3 and early cardiac transcription factors like HEY2, acting on ventricular patterning, opens up a broad field of research on the role of embryological pathways in mediating the observed cardiac phenotypes in cardiomyopathies.
Overall, this study provides an in-depth analysis of ALPK3 variants in HCM using large cohorts, broadening the spectrum of the molecular architecture of HCM. ALPK3-related disease presents with a wide spectrum of clinical phenotypes s ranging from “cardio-cranio-skeletal” syndromes in bi-allelic variant carriers, to late onset apical/concentric LVH associated with HF and poor outcomes in heterozygous ALPK3-tv carriers, with additional neuromuscular features in some cases. In the era of personalized medicine, this study opens new avenues to improve risk stratification in HCM, allowing a tailored management of this HCM subgroup. One could also foresee the development of targeted therapies for those patients in the future.
Now, the question is: should we offer genetic testing to all apical HCM patients? This study provides an invaluable insight by identifying a subgroup of apical HCM patients for which a worse prognosis is now established. So, these data support the importance of genetic counselling and testing in apical HCM.