Long QT and Brugada syndrome gene mutations in New Zealand.
BACKGROUND
Genetic testing in long QT syndrome (LQTS) is moving from research into clinical practice. We have recently piloted a molecular genetics program in a New Zealand research laboratory with a view to establishing a clinical diagnostic service.


OBJECTIVE
This study sought to report the spectrum of LQTS and Brugada mutations identified by a pilot LQTS gene testing program in New Zealand.


METHODS
Eighty-four consecutive index cases referred for LQT gene testing, from New Zealand and Australia, were evaluated. The coding sequence and splice sites of 5 LQTS genes (KCNQ1, HERG, SCN5A, KCNE1, and KCNE2) were screened for genomic variants by transgenomics denaturing high-performance liquid chromatography (dHPLC) system and automated DNA sequencing.


RESULTS
Forty-five LQTS mutations were identified in 43 patients (52% of the cohort): 25 KCNQ1 mutations (9 novel), 13 HERG mutations (7 novel), and 7 SCN5A mutations (2 novel). Forty patients had LQTS, and 3 had Brugada syndrome. Mutations were identified in 14 patients with resuscitated sudden cardiac death: 4 KCNQ1, 5 HERG, 5 SCN5A. In 17 cases there was a family history of sudden cardiac death in a first-degree relative: 8 KCNQ1, 6 HERG, 2 SCN5A, and 1 case with mutations in both KCNQ1 and HERG.


CONCLUSIONS
The spectrum of New Zealand LQTS and Brugada mutations is similar to previous studies. The high proportion of novel mutations (40%) dictates a need to confirm pathogenicity for locally prevalent mutations. Careful screening selection criteria, cellular functional analysis of novel mutations, and development of locally relevant control sample cohorts will all be essential to establishing regional diagnostic services.
Chung
Seo-Kyung
SK
Department of Molecular Medicine and Pathology, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand.
MacCormick
Judith M
JM
McCulley
Caroline H
CH
Crawford
Jackie
J
Eddy
Carey-Anne
CA
Mitchell
Edwin A
EA
Shelling
Andrew N
AN
French
John K
JK
Skinner
Jonathan R
JR
Rees
Mark I
MI
D000293:Adolescent; D000328:Adult; D053840:Brugada Syndrome / Q000175:diagnosis / Q000235:genetics*; D016887:Cardiopulmonary Resuscitation; D002648:Child; D002675:Child, Preschool; D002872:Chromosome Deletion; D004252:DNA Mutational Analysis; D016757:Death, Sudden, Cardiac / Q000209:etiology / Q000517:prevention & control; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels / Q000235:genetics; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics; D014644:Genetic Variation / Q000235:genetics; D006801:Humans; D054643:INDEL Mutation / Q000235:genetics; D007223:Infant; D051657:KCNQ1 Potassium Channel / Q000235:genetics; D008133:Long QT Syndrome / Q000175:diagnosis / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009124:Muscle Proteins / Q000235:genetics; D020125:Mutation, Missense / Q000235:genetics; D062554:NAV1.5 Voltage-Gated Sodium Channel; D009520:New Zealand; D016366:Open Reading Frames / Q000235:genetics; D010865:Pilot Projects; D016133:Polymerase Chain Reaction; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D024642:Potassium Channels, Voltage-Gated / Q000235:genetics; D022821:RNA Splice Sites / Q000235:genetics; D012307:Risk Factors; D017422:Sequence Analysis, DNA; D020539:Sequence Analysis, Protein; D015222:Sodium Channels / Q000235:genetics
D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; C489622:KCNE1 protein, human; C489619:KCNE2 protein, human; C000606913:KCNH2 protein, human; D051657:KCNQ1 Potassium Channel; C496909:KCNQ1 protein, human; D009124:Muscle Proteins; D062554:NAV1.5 Voltage-Gated Sodium Channel; D024642:Potassium Channels, Voltage-Gated; D022821:RNA Splice Sites; C568320:SCN5A protein, human; D015222:Sodium Channels