Non dominant-negative KCNJ2 gene mutations leading to Andersen-Tawil syndrome with an isolated cardiac phenotype

Limberg, Maren M.; Zumhagen, Sven; Netter, Michael F.; Coffey, Alison J.; Grace, Andrew A.; Rogers, Jane; Boeckelmann, Doris; Rinné, Susanne; Stallmeyer, Birgit; Decher, Niels; Schulze‐Bahr, Eric

doi:10.1007/s00395-013-0353-1

Cited by 23 publications

(15 citation statements)

References 38 publications

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“…In terms of the latter, Kcnj16 −/− mice exhibit no observable behavioral or physical abnormalities. 26 Critically, the findings of this present report support those of Limberg et al, 27 who recently showed that KCNJ2 gene mutations without a dominant negative effect on Kir2.x channels result in an isolated cardiac phenotype, without any of the typical dysmorphic, skeletal muscular, or neurocognitive features typical of ATS. Usually, individuals with ATS are considered to be at lower risk of sudden cardiac death than for other LQT syndromes.…”

supporting

confidence: 86%

Array Comparative Genomic Hybridization Identifies a Heterozygous Deletion of the Entire KCNJ2 Gene as a Cause of Sudden Cardiac Death

Marquis-Nicholson

Prosser

Love

et al. 2014

Circ Cardiovasc Genet

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Background-Large gene rearrangements, not detectable by standard molecular genetic sequencing techniques, are present in a minority of patients with long QT syndrome. We aimed to screen for large rearrangements in genes responsible for long QT syndrome as part of the molecular autopsy of a 36-year-old woman who died suddenly and had a negative autopsy. A retrospective analysis of an ECG identified a long QT interval, but sequencing of known LQT genes was uninformative. Methods and Results-Array comparative genomic hybridization was used to screen for deletions and duplications in 101 genes implicated in cardiac disorders and sudden death using a postmortem blood sample. A 542 kb deletion encompassing the entire KCNJ2 gene was identified in the decedent. The mother had electrocardiographic U-wave changes consistent with Andersen-Tawil syndrome and exaggerated by exercise but none of the characteristic noncardiac features. Fluorescence in situ hybridization confirmed the deletion in the decedent and established its presence in the mother. Conclusions-A novel application of array comparative genomic hybridization and fluorescence in situ hybridization has identified that long QT syndrome and sudden cardiac death may occur as a result of a deletion of an entire gene. The case also supports recent research suggesting that noncardiac features of Andersen-Tawil syndrome occur only with missense or minor gene rearrangements in the KCNJ2 gene, resulting in a dominant negative effect on Kir2.x channels. Methods Deletion/Duplication Analysis-aCGHGenomic DNA was extracted from peripheral blood EDTA samples using the Gentra Puregene DNA Extraction kit (Qiagen), according to the manufacturer's instructions. The analysis of the proband and parents was undertaken as part of a coronial investigation and clinical follow-up, respectively, and proceeded according to informed consent and Health and Disability Ethics Committee approval (reference AKX 02/00/107). A Roche NimbleGen 12x135K Custom CGH Array was used for deletion/duplication analysis. This bespoke CGH array was designed to interrogate the coding regions of 101 genes associated with a range of cardiac and neuromuscular disorders, including those responsible for LQT1(KCNQ1), LQT2 (KCNH2), LQT3 and Brugada syndrome (SCN5A, SCN1B, SCN3B, GPD1L), LQT4 (ANK2), LQT5 (KCNE1), LQT6 (KCNE2), ATS/LQT7 (KCNJ2), Timothy syndrome/LQT8 (CACNA1c), LQT9 (CAV3), LQT10 (SCN4B), LQT11 (AKAP9), and LQT12 (SNTA1). See the Data Supplement for the full gene list. The probe densities in exons and introns, as well as extragenic regions of the human genome, have been described elsewhere. [8][9][10] Two hundred and fifty nanograms of genomic DNA were processed according to the manufacturer's instructions (NimbleGen Array User's Guide: CGH and CNV Arrays v6.0; http://www.nimblegen. com). In brief, extracted genomic DNA from samples and Promega controls were denatured in the presence of Cy3-(test) or Cy5-(control) labeled random primers and incubated with the Klenow fragment of DNA polymerase, toge...

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supporting

confidence: 86%

Array Comparative Genomic Hybridization Identifies a Heterozygous Deletion of the Entire KCNJ2 Gene as a Cause of Sudden Cardiac Death

Marquis-Nicholson

Prosser

Love

et al. 2014

Circ Cardiovasc Genet

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“…In a large study by Kimura et al that involved 57 ATS probands, C‐peptide region mutations were more common in typical ATS while N‐terminal mutations were more common in those with atypical and cardiac‐only phenotypes . Limberg et al described two mutations involving the C‐terminus that resulted in defective Kir2.1 channel trafficking (W322C mutation) or gating (N318S mutation), and which manifested with a cardiac‐only phenotype . The G144A mutation in our patients involves the selectivity filter region of the gene and results in a gating abnormality of the K + channel .…”

Section: Discussionmentioning

confidence: 64%

Short‐term response to phenytoin sodium in Andersen‐Tawil syndrome‐1 with a cardiac‐dominant phenotype

Maneesh

Pai

Prabhu

et al. 2018

Pacing Clinical Electrophis

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Background Andersen‐Tawil syndrome (ATS) is a rare familial periodic paralysis that typically also affects the heart and skeletal system. Ventricular arrhythmias (VAs) are profound and difficult to control, but minimally symptomatic. In this report, we describe an atypical phenotype of ATS in two related families. We also report our experience with phenytoin sodium for the control of resistant VAs in these patients. Methods and Results Between 2014 and 2018, seven siblings were diagnosed with ATS on the basis of cardiac arrhythmias and genetic evaluation. Heterozygous mutation with c.431G > C (p.G144A) in exon 2 of KCNJ2 gene was observed in all patients. Characteristic cardiac manifestations were noted in all patients but periodic paralysis or objective neurological involvement was distinctly absent. Phenytoin was considered for control of symptomatic VA in three patients. Intake of oral phenytoin (5 mg/kg/day) for 1 month completely suppressed VA (<1% in 24‐h Holter monitoring) in two patients, and significantly in the third (8% per 24 h) patient. Phenytoin was well‐tolerated in all three patients. Conclusions We describe a cardiac‐predominant phenotype in ATS. ATS should be suspected in patients with typical cardiac manifestations even in the absence of periodic paralysis. Our initial experience with short‐term use of phenytoin for control of resistant VAs is encouraging.

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“…In a large family with p.Arg67Tyr mutation, periodic paralysis was observed only in men and cardiac abnormalities only in women, with congenital anomalies noted in both sexes. 28 Limberg et al 29 reported that carriers of 2 mutations-p.Asp318Ser and Try322Cys-present only with isolated cardiac manifestations. In a young woman with ATS and p.Arg218Try mutation, Junker et al 9 observed a marked and long-lasting improvement in cardiac and muscular symptoms after taking acetazolamide and amiodarone.…”

Section: Discussionmentioning

confidence: 99%

Imipramine for incessant ventricular arrhythmias in 2 unrelated patients with Andersen-Tawil syndrome

Bigelow¹,

Khalifa

Clark³

2015

Heart Rhythm

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Non dominant-negative KCNJ2 gene mutations leading to Andersen-Tawil syndrome with an isolated cardiac phenotype

Cited by 23 publications

References 38 publications

Array Comparative Genomic Hybridization Identifies a Heterozygous Deletion of the Entire KCNJ2 Gene as a Cause of Sudden Cardiac Death

Array Comparative Genomic Hybridization Identifies a Heterozygous Deletion of the Entire KCNJ2 Gene as a Cause of Sudden Cardiac Death

Short‐term response to phenytoin sodium in Andersen‐Tawil syndrome‐1 with a cardiac‐dominant phenotype

Imipramine for incessant ventricular arrhythmias in 2 unrelated patients with Andersen-Tawil syndrome

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