Oxford Molecular Genetics Laboratory
Genetics Laboratories, Churchill Hospital, Old Road, Headington, Oxford, OX3 7LE
www.ouh.nhs.uk/geneticslab
BRUGADA SYNDROME 17 GENE PANEL (OMIM 601144)
INTRODUCTION
Brugada Syndrome (BS) is an autosomal dominant inherited arrhythmogenic disease, characterised by ST-segment elevation on ECG, incomplete
right bundle-branch block, and increased risk of sudden cardiac death as the result of ventricular fibrillation (VF). It is a heterogeneous disorder, with
pathogenic variants reported in >10 genes of which those in SCN5A account for >20%.
The Oxford Medical Genetics Laboratory provides molecular genetic testing for seventeen Brugada syndrome-related genes (see table below).
BRUGADA TYPE
GENE SYMBOL
CLINICAL SENSITIVITY (%)
1
SCN5A
~15-30[a]
2
3
4
GPD1L
CACNA1C
CACNB2
rare[g-t]
~6[b-c]
rare
5
6
7
SCN1B
KCNE3
SCN3B
rare
rare
rare
8
HCN4
9
10
12
13
other
other
other
other
other
CACNA2D1
KCND3
SLMAP
SCN2B
DLG1 (sap97)
KCNJ8
KCNE1L
TRPM4
SCN10A
rare
rare
rare
rare
rare
rare
rare
rare
~6[e]
~17[f]
REFERRAL PROCEDURE
•
Diagnostic referrals are accepted for probands with a suspected or confirmed diagnosis of Brugada syndrome.
o
Referrals are accepted from Cardiology, Clinical Genetics and other relevant medical specialities.
o
Clinical information and details of relevant family history should be provided with all referrals either on the original request form or on
a separate pre-referral form (Cardiac arrhythmia pre-referral form).
•
Family test referrals are only accepted from Clinical Genetics specialists.
o
Referrals for affected family members (i.e. segregation analysis) must be accompanied by appropriate clinical information.
o
Referrals for unaffected family members will only be considered for variants with clear evidence for pathogenicity.
•
Clinical advice is available from Dr Edward Blair, Consultant Clinical Geneticist, at the Churchill Hospital (Ed.Blair@ouh.nhs.uk).
•
Further information about the test can be obtained from the laboratory (OxfordCardiac@nhs.net).
SAMPLE REQUIREMENTS
•
This analysis requires 5 µg of DNA (at a minimum concentration of 30ng/µl).
•
Blood samples, including post-mortem blood (provided it is not clotted) is suitable (1-5ml EDTA).
N.B. Cord blood samples should be accompanied by a maternal sample.
•
Fresh or frozen tissue - generally spleen although other tissues are acceptable (1cm cubed)
•
Formalin-fixed paraffin-embedded (FFPE) will be accepted for panel testing but poor quality of extracted DNA from these samples may mean
analysis is not possible or coverage is lower than quoted. In general, Sanger gap filling is not usually possible from this material.
STRATEGY AND TECHNICAL INFORMATION
•
Diagnostic Screens:
o
Gene target enrichment is undertaken using Agilent’s HaloPlex Target Enrichment System.
o
Libraries are sequenced on an Illumina MiSeq Desktop Sequencer.
o
Sequence data are analysed on a custom-designed bioinformatic pipeline.
o
Where possible, regions of interest (ROIs) in the following genes are 100% covered either by >30 reads or by Sanger sequencing:
SCN5A, HCN4
o
Coverage of ROIs in the remaining genes varies, but is typically 88–100% at >30 reads.
o
Genomic rearrangements (large deletion/duplications) involving SCN5A are thought to be a rare cause of Brugada syndrome; a single
case report of a partial deletion of the SCN5A gene causing BS has been reported in the literature.[g] If a diagnosis of Brugada
syndrome is strongly suspected, MLPA dosage analysis may be undertaken as a separate test.
•
Family tests
o
Familial variants are targeted for analysis by Sanger sequencing of the relevant exon.
TARGET REPORTING TIMES
Diagnostic screen:
Family test:
MLPA Dosage Analysis
60-80 working days
10 days
10 days
Please see the current price list on the Oxford Genetics laboratory Molecular genetics page
References: [a] Kapplinger et al (2010) Heart Rhythm 7:33- 46 [b] Burashnikov et al (2010) Heart Rhythm 7:1872-1882 [c] Cordeiro et al (2009) J. Mol. Cell. Cardiol. 46:695-70 [d] Antzelevitch et al
(2007) Circulation 115:442-449 [e] Liu et al (2013) PLoS One 8(1):e54131 [f] Hu et al (2014) J Am Coll Cardiol. 64(1):66-79; [g] Eastaugh et al (2011) J. Cardiovasc Electrophysiol 22:1073-1076
N.B. Details are correct for the date of printing only. Last updated August, 2015