Novel PRKAG2 variant presenting as liver cirrhosis: report of a family with 2 cases and review of literature

Beyzaei, Zahra; Ezgu, Fatih Süheyl; Geramizadeh, Bita; Alborzi, Alireza; Shojazadeh, Alireza

doi:10.1186/s12920-021-00879-1

Cited by 4 publications

(2 citation statements)

References 17 publications

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“…It is expressed in both skeletal muscle and cardiac muscle and has been shown to be involved in cardiac conduction disorders [ 73 ]. Furthermore, dysfunctional mutations in PRKAG2 have been proposed in liver cirrhosis [ 74 ]. Both liver disease and cardiac arrhythmias are prevalent in 45,X [ 3 , 60 ].…”

Section: Discussionmentioning

confidence: 99%

X chromosome dosage and the genetic impact across human tissues

et al. 2023

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Background Sex chromosome aneuploidies (SCAs) give rise to a broad range of phenotypic traits and diseases. Previous studies based on peripheral blood samples have suggested the presence of ripple effects, caused by altered X chromosome number, affecting the methylome and transcriptome. Whether these alterations can be connected to disease-specific tissues, and thereby having clinical implication for the phenotype, remains to be elucidated. Methods We performed a comprehensive analysis of X chromosome number on the transcriptome and methylome in blood, fat, and muscle tissue from individuals with 45,X, 46,XX, 46,XY, and 47,XXY. Results X chromosome number affected the transcriptome and methylome globally across all chromosomes in a tissue-specific manner. Furthermore, 45,X and 47,XXY demonstrated a divergent pattern of gene expression and methylation, with overall gene downregulation and hypomethylation in 45,X and gene upregulation and hypermethylation in 47,XXY. In fat and muscle, a pronounced effect of sex was observed. We identified X chromosomal genes with an expression pattern different from what would be expected based on the number of X and Y chromosomes. Our data also indicate a regulatory function of Y chromosomal genes on X chromosomal genes. Fourteen X chromosomal genes were downregulated in 45,X and upregulated in 47,XXY, respectively, in all three tissues (AKAP17A, CD99, DHRSX, EIF2S3, GTPBP6, JPX, KDM6A, PP2R3B, PUDP, SLC25A6, TSIX, XIST, ZBED1, ZFX). These genes may be central in the epigenetic and genomic regulation of sex chromosome aneuploidies. Conclusion We highlight a tissue-specific and complex effect of X chromosome number on the transcriptome and methylome, elucidating both shared and non-shared gene-regulatory mechanism between SCAs.

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Section: Discussionmentioning

confidence: 99%

X chromosome dosage and the genetic impact across human tissues

et al. 2023

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“…The incidence of PCS is low, and since the clinical manifestations are diverse, the misdiagnosis rate is relatively high (Banankhah et al, 2018 ). PRKAG2 syndrome is a progressive cardiomyopathy characterized by high rates of atrial fibrillation, conduction disease, advanced heart failure, and life‐threatening arrhythmias (Beyzaei et al, 2021 ; Coban‐Akdemir et al, 2020 ; Jääskeläinen et al, 2019 ; Maron & Maron, 2020 ; Pena et al, 2021 ; Spentzou et al, 2020 ; van der Steld et al, 2017 ). Dominant variants of PRKAG2 seldom occur in sporadic cases but appear to run in families.…”

Section: Introductionmentioning

confidence: 99%

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

Gong

et al. 2022

Molec Gen & Gen Med

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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.

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When Paying Attention Pays Back: Missense Mutation c.1006G>A p. (Val336Ile) in PRKAG2 Gene Causing Left Ventricular Hypertrophy and Conduction Abnormalities in a Caucasian Patient: Case Report and Literature Review

Micaglio,

Tondi,

Benedetti

et al. 2024

IJMS

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PRKAG2 cardiomyopathy is a rare genetic disorder that manifests early in life with an autosomal dominant inheritance pattern. It harbors left ventricular hypertrophy (LVH), ventricular pre-excitation and progressively worsening conduction system defects. Its estimated prevalence among patients with LVH ranges from 0.23 to about 1%, but it is likely an underdiagnosed condition. We report the association of the PRKAG2 missense variant c.1006G>A p. (Val336Ile) with LVH, conduction abnormalities (short PR interval and incomplete right bundle branch bock) and early-onset arterial hypertension (AH) in a 44-year-old Caucasian patient. While cardiac magnetic resonance (CMR) showed a mild hypertrophic phenotype with maximal wall thickness of 17 mm in absence of tissue alterations, the electric phenotype was relevant including brady–tachy syndrome and recurrent syncope. The same variant has been detected in the patient’s sister and daughter, with LVH + early-onset AH and electrocardiographic (ECG) alterations + lipothymic episodes, respectively. Paying close attention to the coexistence of LVH and ECG alterations in the proband has been helpful in directing genetic tests to exclude primary cardiomyopathy. Hence, identifying the genetic basis in the patient allowed for familial screening as well as a proper follow-up and therapeutic management of the affected members. A review of the PRKAG2 cardiomyopathy literature is provided alongside the case report.

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Novel PRKAG2 variant presenting as liver cirrhosis: report of a family with 2 cases and review of literature

Cited by 4 publications

References 17 publications

X chromosome dosage and the genetic impact across human tissues

X chromosome dosage and the genetic impact across human tissues

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

When Paying Attention Pays Back: Missense Mutation c.1006G>A p. (Val336Ile) in PRKAG2 Gene Causing Left Ventricular Hypertrophy and Conduction Abnormalities in a Caucasian Patient: Case Report and Literature Review

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