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Identification of Genetic Alterations, as Causative Genetic Defects in Long QT Syndrome, Using Next Generation Sequencing Technology.

Campuzano O, Sarquella-Brugada G, Mademont-Soler I, Allegue C, Cesar S, Ferrer-Costa C, Coll M, Mates J, Iglesias A, Brugada J, Brugada R - PLoS ONE (2014)

Bottom Line: Despite that several genes have been associated with the disease, nearly 20% of cases remain without an identified genetic cause.Both variants were confirmed by alternative techniques.Clinical and familiar correlation is crucial to elucidate the role of genetic variants identified to distinguish the pathogenic ones from genetic noise.

View Article: PubMed Central - PubMed

Affiliation: Cardiovascular Genetics Center, University of Girona-IdIBGi, Girona, Spain.

ABSTRACT

Background: Long QT Syndrome is an inherited channelopathy leading to sudden cardiac death due to ventricular arrhythmias. Despite that several genes have been associated with the disease, nearly 20% of cases remain without an identified genetic cause. Other genetic alterations such as copy number variations have been recently related to Long QT Syndrome. Our aim was to take advantage of current genetic technologies in a family affected by Long QT Syndrome in order to identify the cause of the disease.

Methods: Complete clinical evaluation was performed in all family members. In the index case, a Next Generation Sequencing custom-built panel, including 55 sudden cardiac death-related genes, was used both for detection of sequence and copy number variants. Next Generation Sequencing variants were confirmed by Sanger method. Copy number variations variants were confirmed by Multiplex Ligation dependent Probe Amplification method and at the mRNA level. Confirmed variants and copy number variations identified in the index case were also analyzed in relatives.

Results: In the index case, Next Generation Sequencing revealed a novel variant in TTN and a large deletion in KCNQ1, involving exons 7 and 8. Both variants were confirmed by alternative techniques. The mother and the brother of the index case were also affected by Long QT Syndrome, and family cosegregation was observed for the KCNQ1 deletion, but not for the TTN variant.

Conclusions: Next Generation Sequencing technology allows a comprehensive genetic analysis of arrhythmogenic diseases. We report a copy number variation identified using Next Generation Sequencing analysis in Long QT Syndrome. Clinical and familiar correlation is crucial to elucidate the role of genetic variants identified to distinguish the pathogenic ones from genetic noise.

No MeSH data available.


Related in: MedlinePlus

ECG of family members.(A) Twelve-lead ECG of index case. The ECG shows QTc of 500 ms. (B) Twelve-lead ECG of mother’s index case. The ECG shows a normal QTc, and (C) a LQT during tachycardia registered by Holter. (D) Twelve-lead ECG of brother’s index case. The ECG shows QTc of 485 ms.
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pone-0114894-g001: ECG of family members.(A) Twelve-lead ECG of index case. The ECG shows QTc of 500 ms. (B) Twelve-lead ECG of mother’s index case. The ECG shows a normal QTc, and (C) a LQT during tachycardia registered by Holter. (D) Twelve-lead ECG of brother’s index case. The ECG shows QTc of 485 ms.

Mentions: The proband (female, 14 years old) was seen in our Paediatric Arrhythmia Unit for abnormal ECG performed in pre-exercise screening. She was asymptomatic for the cardiac point of view. Baseline ECG showed a corrected QT interval (QTc) using Bazhett formula of 500 ms (Fig. 1A). She was on no medication and had no ionic alteration which could explain the prolonged QT. Echocardiography was normal. 24-hour ECG Holter showed no arrhythmic events, and exercise test showed long QT interval.


Identification of Genetic Alterations, as Causative Genetic Defects in Long QT Syndrome, Using Next Generation Sequencing Technology.

Campuzano O, Sarquella-Brugada G, Mademont-Soler I, Allegue C, Cesar S, Ferrer-Costa C, Coll M, Mates J, Iglesias A, Brugada J, Brugada R - PLoS ONE (2014)

ECG of family members.(A) Twelve-lead ECG of index case. The ECG shows QTc of 500 ms. (B) Twelve-lead ECG of mother’s index case. The ECG shows a normal QTc, and (C) a LQT during tachycardia registered by Holter. (D) Twelve-lead ECG of brother’s index case. The ECG shows QTc of 485 ms.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4262446&req=5

pone-0114894-g001: ECG of family members.(A) Twelve-lead ECG of index case. The ECG shows QTc of 500 ms. (B) Twelve-lead ECG of mother’s index case. The ECG shows a normal QTc, and (C) a LQT during tachycardia registered by Holter. (D) Twelve-lead ECG of brother’s index case. The ECG shows QTc of 485 ms.
Mentions: The proband (female, 14 years old) was seen in our Paediatric Arrhythmia Unit for abnormal ECG performed in pre-exercise screening. She was asymptomatic for the cardiac point of view. Baseline ECG showed a corrected QT interval (QTc) using Bazhett formula of 500 ms (Fig. 1A). She was on no medication and had no ionic alteration which could explain the prolonged QT. Echocardiography was normal. 24-hour ECG Holter showed no arrhythmic events, and exercise test showed long QT interval.

Bottom Line: Despite that several genes have been associated with the disease, nearly 20% of cases remain without an identified genetic cause.Both variants were confirmed by alternative techniques.Clinical and familiar correlation is crucial to elucidate the role of genetic variants identified to distinguish the pathogenic ones from genetic noise.

View Article: PubMed Central - PubMed

Affiliation: Cardiovascular Genetics Center, University of Girona-IdIBGi, Girona, Spain.

ABSTRACT

Background: Long QT Syndrome is an inherited channelopathy leading to sudden cardiac death due to ventricular arrhythmias. Despite that several genes have been associated with the disease, nearly 20% of cases remain without an identified genetic cause. Other genetic alterations such as copy number variations have been recently related to Long QT Syndrome. Our aim was to take advantage of current genetic technologies in a family affected by Long QT Syndrome in order to identify the cause of the disease.

Methods: Complete clinical evaluation was performed in all family members. In the index case, a Next Generation Sequencing custom-built panel, including 55 sudden cardiac death-related genes, was used both for detection of sequence and copy number variants. Next Generation Sequencing variants were confirmed by Sanger method. Copy number variations variants were confirmed by Multiplex Ligation dependent Probe Amplification method and at the mRNA level. Confirmed variants and copy number variations identified in the index case were also analyzed in relatives.

Results: In the index case, Next Generation Sequencing revealed a novel variant in TTN and a large deletion in KCNQ1, involving exons 7 and 8. Both variants were confirmed by alternative techniques. The mother and the brother of the index case were also affected by Long QT Syndrome, and family cosegregation was observed for the KCNQ1 deletion, but not for the TTN variant.

Conclusions: Next Generation Sequencing technology allows a comprehensive genetic analysis of arrhythmogenic diseases. We report a copy number variation identified using Next Generation Sequencing analysis in Long QT Syndrome. Clinical and familiar correlation is crucial to elucidate the role of genetic variants identified to distinguish the pathogenic ones from genetic noise.

No MeSH data available.


Related in: MedlinePlus