Identification of a
            <i>POLG</i>
            Variant in a Family With Arrhythmogenic Cardiomyopathy and Left Ventricular Fibrosis

Spracklen, Timothy; Kasher, Paul R.; Kraus, Sarah; Botha, Tarryn L.; Page, Donna J.; Kamuli, Stephen; Booi, Zandile; Chin, Ashley; Laing, Nakita; Keavney, Bernard; Ntusi, Ntobeko; Shaboodien, Gasnat

doi:10.1161/circgen.120.003138

Cited by 5 publications

(3 citation statements)

References 5 publications

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“…Furthermore, in our study, we identified (L)P variants in the POLG gene in two patients with BrS and ACM, respectively. Our data are in accordance with recently published data in which the POLG gene was associated with the ACM phenotype [ 74 ].…”

Section: Discussionsupporting

confidence: 93%

Next-Generation Sequencing Gene Panels in Inheritable Cardiomyopathies and Channelopathies: Prevalence of Pathogenic Variants and Variants of Unknown Significance in Uncommon Genes

et al. 2022

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The diffusion of next-generation sequencing (NGS)-based approaches allows for the identification of pathogenic mutations of cardiomyopathies and channelopathies in more than 200 different genes. Since genes considered uncommon for a clinical phenotype are also now included in molecular testing, the detection rate of disease-causing variants has increased. Here, we report the prevalence of genetic variants detected by using a NGS custom panel in a cohort of 133 patients with inherited cardiomyopathies (n = 77) or channelopathies (n = 56). We identified 82 variants, of which 50 (61%) were identified in genes without a strong or definitive evidence of disease association according to the NIH-funded Clinical Genome Resource (ClinGen; “uncommon genes”). Among these, 35 (70%) were variants of unknown significance (VUSs), 13 (26%) were pathogenic (P) or likely pathogenic (LP) mutations, and 2 (4%) benign (B) or likely benign (LB) variants according to American College of Medical Genetics (ACMG) classifications. These data reinforce the need for the screening of uncommon genes in order to increase the diagnostic sensitivity of the genetic testing of inherited cardiomyopathies and channelopathies by allowing for the identification of mutations in genes that are not usually explored due to a currently poor association with the clinical phenotype.

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Section: Discussionsupporting

confidence: 93%

Next-Generation Sequencing Gene Panels in Inheritable Cardiomyopathies and Channelopathies: Prevalence of Pathogenic Variants and Variants of Unknown Significance in Uncommon Genes

et al. 2022

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“…A case with headache, myopathy, and ischemic stroke was described by Min et al [ 31 ], and two patients (one with myopathy and one with PEO) were reported by Da Pozzo et al [ 32 ]. The heterozygous Y831C mutation was also found in all affected members of a South African family with arrhythmogenic cardiomyopathy (ACM) and left ventricular fibrosis [ 33 ]. Due to the ambiguous role of Y831C, the authors investigated zebra fish embryos and observed that larvae expressing the mutated POLG gene (c.2492A>G) developed abnormal hearts.…”

Section: Discussionmentioning

confidence: 99%

The Y831C Mutation of the POLG Gene in Dementia

et al. 2023

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Background: The POLG gene encodes the catalytic subunit of DNA polymerase γ, which is crucial for mitochondrial DNA (mtDNA) repair and replication. Gene mutation alters the stability of mtDNA and is associated with several clinical presentations, such as dysarthria and ophthalmoplegia (SANDO), progressive external ophthalmoplegia (PEO), spinocerebellar ataxia and epilepsy (SCAE), Alpers syndrome, and sensory ataxic neuropathy. Recent evidence has also indicated that POLG mutations may be involved in some neurodegenerative disorders, although systematic screening is currently lacking. Methods: To investigate the frequency of POLG gene mutations in neurodegenerative disorders, we screened a group of 33 patients affected by neurodegenerative diseases, including Parkinson’s disease, some atypical parkinsonisms, and dementia of different types. Results: Mutational analysis revealed the presence of the heterozygous Y831C mutation in two patients, one with frontotemporal dementia and one with Lewy body dementia. The allele frequency of this mutation reported by the 1000 Genomes Project in the healthy population is 0.22%, while in our group of patients, it was 3.03%, thus showing a statistically significant difference between the two groups. Conclusions: Our results may expand the genotype-phenotype spectrum associated with mutations in the POLG gene and strengthen the hypothesis of a pathogenic role of the Y831C mutation in neurodegeneration.

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“…Because POLG1 carriers can manifest with cardiomyopathy, 2,3 we should be told if the included patients were systematically screened for cardiac involvement.…”

Section: Letter To the Editormentioning

confidence: 99%

Heterogeneous Manifestation of POLG1 Variants: Heterogeneity of POLG1 Phenotypes

Finsterer¹

2022

J Child Neurol

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We read with interest the article by Jha et al 1 about a retrospective study of 22 patients carrying a pathogenic POLG1 mutation collected over a period of 5.5 years (January 2015-August 2020). Phenotypically, these patients were classified as Alpers-Huttenlocher disease (n = 8), progressive external ophthalmoplegia (n = 8), Leigh syndrome (n = 2), and ataxianeuropathy spectrum disorders (n = 2). 1 Two patients remained unclassified. 1 The most common clinical abnormalities included developmental delay (n = 14), neuroregression (n = 14), encephalopathy (n = 11), epilepsy (n = 11), ophthalmoplegia (n = 8), and liver dysfunction (n = 8). The study is appealing but raises concerns that need to be discussed.According to the Method section, only patients <15 years of age were included. 1 However, according to Table 1, age at onset ranged from 7.8 to 53 years. 1 This discrepancy should be clarified. Furthermore, the lowest age at diagnosis was, according to Table 1, 19 years. 1 This figure does not comply with the inclusion criteria either. Additionally, the earliest age at onset was 7.8 years, 1 but the earliest age at onset of developmental delay was 4 years. 1 This discrepancy too requires clarification.According to Table 1, more than two-thirds of the parents were consanguineous, but in the Result section only 8 patients with consanguineous parents were described. 1 This discrepancy requires an explanation.A limitation of the study is its retrospective design. Therefore, it cannot be expected that all included patients underwent the same protocol of diagnostic workup and received the same treatment.Because POLG1 carriers can manifest with cardiomyopathy, 2,3 we should be told if the included patients were systematically screened for cardiac involvement.Because some patients carrying a pathogenic POLG1 variant may manifest with Parkinson disease, 3 we should be told if any of the 22 included patients developed typical stigmata of Parkinson disease, such as rigidity, tremor, or bradykinesia.Because 2 patients developed neuropathy of peripheral nerves, 1 we should be informed which type of neuropathy was diagnosed. Specifically, was there demyelinating or axonal neuropathy, or a mixture of both? There are also POLG1-mutation carriers who manifested with small fiber neuropathy.Because POLG1 mutation carriers frequently develop cognitive impairment, 3 we should be informed if developmental

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Identification of a POLG Variant in a Family With Arrhythmogenic Cardiomyopathy and Left Ventricular Fibrosis

Cited by 5 publications

References 5 publications

Next-Generation Sequencing Gene Panels in Inheritable Cardiomyopathies and Channelopathies: Prevalence of Pathogenic Variants and Variants of Unknown Significance in Uncommon Genes

Next-Generation Sequencing Gene Panels in Inheritable Cardiomyopathies and Channelopathies: Prevalence of Pathogenic Variants and Variants of Unknown Significance in Uncommon Genes

The Y831C Mutation of the POLG Gene in Dementia

Heterogeneous Manifestation of POLG1 Variants: Heterogeneity of POLG1 Phenotypes

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