Overlapping Phenotype of Adult-Onset ALPK3-Cardiomyopathy in the Setting of Two Novel Variants

Abstract

Inherited cardiomyopathies (CMPs) are fairly common causes of morbidity and mortality, particularly, in young individuals. In substantial number of cases, only morphological diagnostic criteria cannot distinguish one CMP from another because of incomplete penetrance, advanced stage of the disease, or overlapping phenotypes. Genetic testing has become a mandatory tool for definite diagnosis that is required for family screening, individual prognosis, and personalized treatment strategy in routine practice. In parallel, accumulation of genotype-phenotype correlations, especially for rare genes, promotes the deciphering of underling molecular mechanisms and the development of targeting treatment of CMPs. Here we present an adult-onset case comprised morphological features of several CMPs: asymmetric left ventricle (LV) hypertrophy, severe systolic dysfunction, LV hypertrabeculation and restrictive physiology. Using next-generation sequencing, two novel variants (NM_020778.5:c.1958C>G:p.Ser653* and c.3491G>A:p.Arg1164Gln) in alpha-protein kinase 3 (ALPK3) gene were identified and confirmed with Sanger sequencing. The trans-position (location on different alleles) of identified ALPK3 variants was established by plasmid cloning method. The ALPK3 gene, encoding nuclear alpha-protein kinase 3, has only recently been associated with CMPs and there are still few clinical data on ALPK3 variant carriers. To date, only five affected individuals with adultonset CMPs in the setting of biallelic variants of ALPK3 gene have been reported.

Hypertrophic Cardiomyopathy in Underrepresented Populations: Clinical and Genetic Landscape Based on a Russian Single-Center Cohort Study

“…Four probands and one relative from our cohort had disease-causing variants only in non-sarcomeric genes: ALPK3 (2), TRIM63 (1), and FLNC (2). Three of these patients have been described in previous studies [52][53][54]. This paper presents two patients with relatively benign clinical courses who were assigned to the G+ group based on carrying the single variants in FLNC.…”

“…There were no homozygous or compound heterozygous patients with two truncating variants (Figure 1). Compared to patients with a single P/LP/VUS-LP variant (n = 70), patients with two rare variants (n = 10) had a significantly higher SCD risk score (5.9 [3.5-7.3] vs. 2.9 [1.9-4.0], p = 0.011), larger left atrium (52 [43][44][45][46][47][48][49][50][51][52][53][54][55][56][57] vs. 43 [39][40][41][42][43][44][45][46][47][48][49][50] mm, p = 0.017), more frequent high systolic pulmonary artery pressure (63 vs. 14%, p = 0.004), and a trend toward more frequent severe NYHA class III/IV (38 vs. 11%, p = 0.07). The clinical course of HCM was highly variable, ranging from mild symptoms to severe HF progression and SCD in middle age.…”