ALPK3: a full spectrum cardiomyopathy gene?
Roddy Walsh, Connie R. Bezzina
Abstract
ALPK3 is associated with cardiomyopathy phenotypes through genetic variants that span the spectrum of effect size, population frequency, and dosage of the protein product.Biallelic truncating variants cause a severe early-onset cardiomyopathy phenotype, with several studies describing cases in countries with high rates of consanguinity (blue) which are advantageous for identifying rare recessive forms of disease.The study by Lopes et al. has demonstrated that heterozygous ALPK3tv are causative in 1.5% of adult-onset HCM in a cohort from the UK and genetic testing referrals from several other countries (red).These cases are characterized by relatively late-onset, apical/concentric patterns of hypertrophy and potentially poor prognosis.The ALPK3 gene also occurs at a locus significantly associated with HCM, DCM, and relevant left ventricular traits by recent GWAS.If confirmed as the causal gene at this locus, ALPK3 would be associated with cardiomyopathy risk across the full spectrum of variant classes-from full gene knockout to common regulatory variants.