Controversial molecular functions of CBS versus non‐CBS domain variants of PRKAG2 in arrhythmia and cardiomyopathy: A case report and literature review

• Published in: Molecular genetics & genomic medicine Vol. 10; no. 7; pp. e1962 - n/a
• Main Authors: Gong, Xue, Yu, Peiyu, Wu, Ting, He, Yunru, Zhou, Kaiyu, Hua, Yimin, Lin, Sha, Wang, Tao, Huang, He, Li, Yifei
• Format: Journal Article
• Language: English
• Published: United States John Wiley & Sons, Inc 01.07.2022; John Wiley and Sons Inc; Wiley
• Subjects: AMPK signaling; Arrhythmia; Autosomal dominant inheritance; Cardiomyocytes; Cardiomyopathy; case report; Clinical Report; Clinical Reports; Congestive heart failure; Domains; Females; Gene expression; Genetic disorders; Genomes; genomic sequence; Heart failure; Hereditary diseases; Infants; Kinases; Literature reviews; Phenotypes; PRKAG2 cardiac syndrome; Proteins; scRNA‐seq; Ventricle; case report; scRNA-seq; genomic sequence; AMPK signaling; PRKAG2 cardiac syndrome
• ISSN: 2324-9269; 2324-9269
• DOI: 10.1002/mgg3.1962

Background PRKAG2 cardiac syndrome is a rare autosomal dominant genetic disorder caused by a PRKAG2 gene variant. There are several major adverse cardiac presentations, including hypertrophic cardiomyopathy (HCM) and life‐threatening arrhythmia. Two cases with pathogenic variants in the PRKAG2 gene are reported here who presents different cardiac phenotypes. Methods Exome sequencing and variant analysis of PRKAG2 were performed to obtain genetic data, and clinical characteristics were determined. Results The first proband was a 9‐month‐old female infant (Case 1), and was identified with severe DCM and resistant heart failure. The second proband was a 10‐year‐old female infant (Case 2), and presented with HCM and ventricular preexcitation. Exome sequencing identified a de novo c.425C > T (p.T142I) heterozygous variant in the PRKAG2 gene for Case 1, and a c.869A > T (p.K290I) for Case 2. The mutated sites in the protein were labeled and identified as p.K290 in the CBS domain and p.T142 in the non‐CBS domain. Differences in the molecular functions of CBS and non‐CBS domains have not been resolved, and variants might lead to the different cardiomyopathy phenotypes. Single‐cell RNA analysis demonstrated similar expression levels of PRKAG2 in cardiomyocytes and conductive tissues. These results suggest that the arrhythmia induced by the PRKAG2 variant was the primary change, and not secondary to cardiomyopathy. Conclusion In summary, this is the first case report to describe a DCM phenotype with early onset in patients possessing a PRKAG2 c.425C > T (p.T142I) pathogenic variant. Our results aid in understanding the molecular function of non‐CBS variants in terms of the disordered sequence of transcripts. Moreover, we used scRNA‐seq to show that electrically conductive cells express a higher level of PRKAG2 than do cardiomyocytes. Therefore, variants in PRKAG2 are expected to also alter the biological function of the conduction system. Differences in the molecular functions of CBS and non‐CBS domains have not been resolved, and mutations might lead to the different cardiomyopathy phenotypes. Single cell RNA analysis demonstrated similar expression levels of PRKAG2 in cardiomyocytes and conductive tissues. These results suggest that the arrhythmia induced by the PRKAG2 mutation was the primary change, and not secondary to cardiomyopathy.