<i>De novo</i> mutation in the <i><scp>KCNQ1</scp></i> gene causal to Jervell and Lange‐Nielsen syndrome

Al‐Aama, Jumana Y.; Al-Ghamdi, Saleh; Bdier, Amnah Y.; Wilde, Arthur A.M.; Bhuiyan, Zahurul A.

doi:10.1111/cge.12300

Cited by 7 publications

(3 citation statements)

References 26 publications

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“…Genetic investigation showed compound heterozygote KCNQ1 mutations, c.820_830del/c.1251+1G>T (Table ). Subsequent investigation revealed that the c.820_830del mutation was de novo . RNA analysis of lymphocytes showed that exon‐9 was skipped in one allele and the second allele lacked the c.820 to c.830 (data not shown).…”

Section: Resultsmentioning

confidence: 98%

Genotype–phenotype analysis of Jervell and Lange‐Nielsen syndrome in six families from Saudi Arabia

et al. 2013

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We sought to explore the genotype-phenotype of Jervell and Lange-Nielsen syndrome (JLNS) patients in Saudi Arabia. We have also assessed the plausible effect of consanguinity into the pathology of JLNS. Six families with at least one JLNS-affected member attended our clinic between 2011 and 2013. Retrospective and prospective clinical data were collected and genetic investigation was performed. Pathogenic mutations in the KCNQ1 gene were detected in all JLNS patients. The homozygous mutations detected were Leu273Phe, Asp202Asn, Ile567Thr, and c.1486_1487delCT and compound heterozygous mutations were c.820_ 830del and c.1251+1G>T. All living JLNS patients except one had a QTc of >500 ms and a history of recurrent syncope. β-Blockers abolished the cardiac-related events in all patients except two siblings with homozygous Ile567Thr mutation. Four of the six mutations were originally reported in autosomal dominant long QT syndrome (LQTS) patients. Eighty percent of the heterozygote mutation carriers showed prolongation of QTc, but majority of these reported no symptoms attributable to arrhythmias. Mutations detected in this study will be advantageous in tribe and region-specific cascade screening of LQTS in Saudi Arabia.

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Section: Resultsmentioning

confidence: 98%

Genotype–phenotype analysis of Jervell and Lange‐Nielsen syndrome in six families from Saudi Arabia

et al. 2013

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“…Specialized cardiogenetic centers should take the initiative to search for the genetic defects, mutations, and perform genotype-phenotype studies in all forms of hereditary arrhythmias. It also should be kept in consideration that not all genetic arrhythmias would have a family history, as in many cases arrhythmia causal mutation are de novo in origin, i.e., the proband is the first patient in that family with the mutation and he/she is the source to transmit the mutation in downstream generations (110, 111). Due to the very high rate of consanguineous marriages in Saudi Arabia, we expect a lot more founder mutations exert a crucial role in congenital arrhythmias in this country.…”

Section: Lqts: Saudi Perspectivementioning

confidence: 99%

Congenital Long QT Syndrome: An Update and Present Perspective in Saudi Arabia

Bhuiyan

Al-Shahrani²,

Al‐Aama

et al. 2013

Front. Pediatr.

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Primary cardiac arrhythmias are often caused by defects, predominantly in the genes responsible for generation of cardiac electrical potential, i.e., cardiac rhythm generation. Due to the variability in underlying genetic defects, type, and location of the mutations and putative modifiers, clinical phenotypes could be moderate to severe, even absent in many individuals. Clinical presentation and severity could be quite variable, syncope, or sudden cardiac death could also be the first and the only manifestation in a patient who had previously no symptoms at all. Despite usual familial occurrence of such cardiac arrhythmias, disease causal genetic defects could also be de novo in significant number of patients. Long QT syndrome (LQTS) is the most eloquently investigated primary cardiac rhythm disorder. A genetic defect can be identified in ∼70% of definitive LQTS patients, followed by Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT) and Brugada syndrome (BrS), where a genetic defect is found in <40% cases. In addition to these widely investigated hereditary arrhythmia syndromes, there remain many other relatively less common arrhythmia syndromes, where researchers also have unraveled the genetic etiology, e.g., short QT syndrome (SQTS), sick sinus syndrome (SSS), cardiac conduction defect (CCD), idiopathic ventricular fibrillation (IVF), early repolarization syndrome (ERS). There exist also various other ill-defined primary cardiac rhythm disorders with strong genetic and familial predisposition. In the present review we will focus on the genetic basis of LQTS and its clinical management. We will also discuss the presently available genetic insight in this context from Saudi Arabia.

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“…Therefore, a precise genotype-phenotype correlation in LQT1 and JLNS1 is not established, which complicates both genetic counseling and clinical risk evaluation in carriers [9, 12–16]. A frameshift variant (NM_000218.2[KCNQ1]:c.567dupG [17]) is reported to cause not only JLNS1 when homozygous, but also causes severe LQT1 when heterozygous.…”

Section: Introductionmentioning

confidence: 99%

A novel KCNQ1 nonsense variant in the isoform-specific first exon causes both jervell and Lange-Nielsen syndrome 1 and long QT syndrome 1: a case report

et al. 2017

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BackgroundAccording to previous KCNQ1 (potassium channel, voltage gated, KQT-like subfamily, member 1) gene screening studies, missense variants, but not nonsense or frame-shift variants, cause the majority of long QT syndrome (LQTS; Romano-Ward syndrome [RWS]) 1 cases. Several missense variants are reported to cause RWS by a dominant-negative mechanism, and some KCNQ1 variants can cause both Jervell and Lange-Nielsen Syndrome (JLNS; in an autosomal recessive manner) and LQTS1 (in an autosomal dominant manner), while other KCNQ1 variants cause only JLNS. The human KCNQ1 gene is known to have two transcript isoforms (kidney isoform and pancreas isoform), and both isoforms can form a functional cardiac potassium channel.Case presentationHere, we report a novel nonsense KCNQ1 variant causing not only JLNS, but also significant QTc prolongation identical to RWS in an autosomal dominant manner. Our case study supports that haploinsufficiency in the KCNQ1 gene is causative of significant QTc prolongation identical to RWS. Interestingly, the nonsense variant (NM_000218.2:c.115G > T [p.Glu39X]) locates in exon 1a of KCNQ1, which is a kidney-isoform specific exon. The variant is located closer to the N-terminus than previously identified nonsense or frame-shift variants.ConclusionTo the best of our knowledge, this is the first report showing that a nonsense variant in exon 1a of KCNQ1, which is the kidney-isoform specific exon, causes JLNS. Our findings may be informative to the genetic pathogenesis of RWS and JLNS caused by KCNQ1 variants.Electronic supplementary materialThe online version of this article (doi:10.1186/s12881-017-0430-7) contains supplementary material, which is available to authorized users.

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De novo mutation in the KCNQ1 gene causal to Jervell and Lange‐Nielsen syndrome

Cited by 7 publications

References 26 publications

Genotype–phenotype analysis of Jervell and Lange‐Nielsen syndrome in six families from Saudi Arabia

Genotype–phenotype analysis of Jervell and Lange‐Nielsen syndrome in six families from Saudi Arabia

Congenital Long QT Syndrome: An Update and Present Perspective in Saudi Arabia

A novel KCNQ1 nonsense variant in the isoform-specific first exon causes both jervell and Lange-Nielsen syndrome 1 and long QT syndrome 1: a case report

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