Editing Brugada syndrome (section)

=== Genetics ===
Brugada syndrome is inherited in an [[Dominance (genetics)|autosomal dominant]] manner, meaning that only one copy of the defective gene is needed to produce the syndrome. However, a person diagnosed with the condition may be the first in their family to have Brugada syndrome if it has arisen as a new mutation.<ref name=Sar2016 />  The gene in which mutations are most commonly found in Brugada syndrome, known as ''[[SCN5A]]'', is responsible for the cardiac sodium channel. Mutations in SCN5A associated with Brugada syndrome generally cause the flow of sodium ions to decrease.  However, only 20% of cases of Brugada syndrome are associated with mutations in ''SCN5A'', as in the majority of patients with Brugada syndrome genetic testing is unable to identify the genetic mutation responsible.<ref name=Sar2016 /> Over 290 mutations in the ''SCN5A'' gene have been discovered to date, each altering sodium channel function in subtly different ways.<ref name="Kapplinger_2010" />  This variation partially explains the differences in severity of the condition between different persons, ranging from a highly dangerous condition causing death at a young age to a benign condition that may not cause any problems at all.  However, the genetics of Brugada syndrome are complex, and it is likely that the condition results from the interactions of many genes.  Because of these complex interactions, some members of a family who carry a particular mutation may show evidence of Brugada syndrome while other carrying the same mutation may not, referred to as variable [[penetrance]].<ref name="Hedley">{{cite journal | vauthors = Hedley PL, Jørgensen P, Schlamowitz S, Moolman-Smook J, Kanters JK, Corfield VA, Christiansen M | title = The genetic basis of Brugada syndrome: a mutation update | journal = Human Mutation | volume = 30 | issue = 9 | pages = 1256–66 | date = September 2009 | pmid = 19606473 | doi = 10.1002/humu.21066 | doi-access = free }}</ref> Mutations in the SCN5A gene seem to have a prognostic value.<ref>{{cite journal |last1=Ciconte G, Monasky MM, Santinelli V, Micaglio E, Vicedomini G, Anastasia L, Negro G, Borrelli V, Giannelli L, Santini F, de Innocentiis C, Rondine R, Locati ET, Bernardini A, Mazza BC, Mecarocci V, Ćalović Ž, Ghiroldi A, D'Imperio S, Benedetti S, Di Resta C, Rivolta I, Casari G, Petretto E, Pappone C |title=Brugada syndrome genetics is associated with phenotype severity |journal=Eur Heart J |date=2021 |volume=42 |issue=11 |pages=1082–1090 |doi=10.1093/eurheartj/ehaa942|pmc=7955973 |pmid=33221895 |doi-access=free }}</ref><ref>{{cite journal |last1=Pappone C, Ciconte G, Micaglio E, Monasky MM |title=Common modulators of Brugada syndrome phenotype do not affect SCN5A prognostic value |journal=Eur Heart J |date=2021 |volume=42 |issue=13 |pages=1273–1274 |doi=10.1093/eurheartj/ehab071 |pmc=8014514 |pmid=33595071 |doi-access=free }}</ref><ref>{{cite journal |last1=Postema PG, Walsh R, Bezzina CR |title=Illuminating the path from genetics to clinical outcome in Brugada syndrome |journal=Eur Heart J |date=2021 |volume=42 |issue=11 |pages=1091–1093 |doi=10.1093/eurheartj/ehaa994|pmc=7955964 |pmid=33444429 |doi-access=free }}</ref>

Several other genes have been identified in association with Brugada syndrome. Some are responsible for other proteins that form part of the [[sodium channel]], known as sodium channel β subunits ([[SCN1B]], [[SCN2B]], [[SCN3B]]) while others form different types of sodium channel ([[SCN10A]]). Some genes encode ion channels that carry calcium or potassium ions ([[CACNA1c|CACNA1C]], [[CACNB2]], [[KCND3]], [[KCNE3]], [[KCNJ8]], KCNT1),<ref name="pmid17556198">{{cite journal|vauthors=Antzelevitch C|date=June 2007|title=Genetic basis of Brugada syndrome|journal=Heart Rhythm|volume=4|issue=6|pages=756–7|doi=10.1016/j.hrthm.2007.03.015|pmc=1989771|pmid=17556198}}</ref> while others generate proteins that interact with ion channels. ([[GPD1L]], [[Plakophilin-2|PKP2]], MOG1, [[FGF12]]). Another gene associated with this condition is [[RRAD (gene)|RRAD]].<ref name=Belbachir2019>{{cite journal |last1=Belbachir |first1=N |last2=Portero |first2=V |last3=Al Sayed |first3=ZR |last4=Gourraud |first4=JB |last5=Dilasser |first5=F |last6=Jesel |first6=L |last7=Guo |first7=H |last8=Wu |first8=H |last9=Gaborit |first9=N |last10=Guilluy |first10=C |last11=Girardeau |first11=A |last12=Bonnaud |first12=S |last13=Simonet |first13=F |last14=Karakachoff |first14=M |last15=Pattier |first15=S |last16=Scott |first16=C |last17=Burel |first17=S |last18=Marionneau |first18=C |last19=Chariau |first19=C |last20=Gaignerie |first20=A |last21=David |first21=L |last22=Genin |first22=E |last23=Deleuze |first23=JF |last24=Dina |first24=C |last25=Sauzeau |first25=V |last26=Loirand |first26=G |last27=Baró |first27=I |last28=Schott |first28=JJ |last29=Probst |first29=V |last30=Wu |first30=JC |last31=Redon |first31=R |last32=Charpentier |first32=F |last33=Le Scouarnec |first33=S |title=RRAD mutation causes electrical and cytoskeletal defects in cardiomyocytes derived from a familial case of Brugada syndrome. |journal=European Heart Journal |volume=40 |issue=37 |pages=3081–3094 |date=21 May 2019 |doi=10.1093/eurheartj/ehz308 |pmid=31114854|pmc=6769825 }}</ref> The genes associated with Brugada syndrome and their description include:

{| class="wikitable"
! Type || OMIM || Gene || Notes
 |-
 | BrS1 ||  {{OMIM|601144||none}} || [[SCN5A]] || [[Nav1.5|Na<sub>V</sub>1.5]] – α subunit of the cardiac [[sodium channel]] carrying the sodium current ''I''<sub>Na</sub>.<ref name=Ant2016/>
 |-
 | BrS2 || {{OMIM|611778||none}} || [[GPD1L]] || Glycerol-3-phosphate dehydrogenase like peptide – reduced GPD1-L activity leads to phosphorylation of Na<sub>V</sub>1.5 and decreased ''I''<sub>Na</sub>.<ref name=Ant2016 />
 |-
 | BrS3 || {{OMIM|114205||none}} || [[CACNA1C]] || [[Cav1.2|Ca<sub>V</sub>1.2]] – α subunit of voltage-dependent calcium channel carrying the L-type calcium current ''I''<sub>Ca(L)</sub>.<ref name=":2">{{cite journal | vauthors = Garcia-Elias A, Benito B | title = Ion Channel Disorders and Sudden Cardiac Death | journal = International Journal of Molecular Sciences | volume = 19 | issue = 3 | pages = 692 | date = February 2018 | pmid = 29495624 | pmc = 5877553 | doi = 10.3390/ijms19030692 | doi-access = free }}</ref>
 |-
 | BrS4 || {{OMIM|600003||none}} || [[CACNB2]] || Ca<sub>V</sub>β2B – β-2 subunit of the voltage-gated calcium channel carrying the L-type calcium current ''I''<sub>Ca(L)</sub>.<ref name=":2" />
|-
 | BrS5 || {{OMIM|600235||none}} || [[SCN1B]] || Na<sub>V</sub>β1 – β-1 subunit of the sodium channel carrying the sodium current ''I''<sub>Na</sub>.<ref name=":2" />
|-
| BrS6 || {{OMIM|604433||none}} || [[KCNE3]] || MiRP2 – β subunit to voltage-gated potassium channels. Modulates the transient outward potassium current ''I''<sub>to</sub>.<ref name=":2" />
|-
| BrS7 || {{OMIM|608214||none}} || [[SCN3B]] || Na<sub>V</sub>β3 – β-3 subunit of the cardiac sodium channel carrying the sodium current ''I''<sub>Na</sub>.<ref name=Ant2016 />
|-
|BrS8|| {{OMIM|600935||none}} || [[KCNJ8]] || Kir6.1, carries the inward rectifier potassium current ''I''<sub>Kir</sub>.<ref name=Ant2016 />
|-
|BrS9|| {{OMIM|114204||none}} || [[CACNA2D1]] || α2δ subunit of the voltage-gated calcium channel carrying the L-type calcium current ''I''<sub>Ca(L)</sub>.<ref name=Ant2016 />
|-
|BrS10|| {{OMIM|605411||none}} || [[KCND3]] ||  K<sub>V</sub>4.3, α-subunit of the transient outward potassium channel ''I''<sub>to</sub>.<ref name=Ant2016 />
|-
|BrS11|| {{OMIM|607954||none}} || RANGRF ||  Encodes MOG1 – influences trafficking of Na<sub>V</sub>1.5.<ref name=Ant2016 />
|-
|BrS12|| {{OMIM|602701||none}}|| [[SLMAP]] || Sarcolemmal membrane–associated protein, a component of [[T-tubules]] and the [[sarcoplasmic reticulum]] – influences trafficking of Na<sub>V</sub>1.5.<ref name=Ant2016 />
|-
|BrS13|| {{OMIM|601439||none}} || [[ABCC9]] ||  SUR2A, the adenosine triphosphate (ATP)-binding cassette transporter of the ''I''<sub>K(ATP)</sub> channel.<ref name=Ant2016 />

|-
|BrS14|| {{OMIM|601327||none}} || [[SCN2B]] || Na<sub>V</sub>β2 – Beta-2 subunit of the cardiac sodium channel carrying the sodium current ''I''<sub>Na</sub>.<ref name=Ant2016 />
|-
|BrS15|| {{OMIM|602861||none}} || [[PKP2]] ||  Plakophillin-2 – interacts with ''I''<sub>Na</sub>.<ref name=Ant2016 />
|-
|BrS16|| {{OMIM|601513||none}}|| [[FGF12]] || Fibroblast growth factor homologous factor-1 – mutation decreases ''I''<sub>Na</sub>.<ref name=Ant2016 />
|-
| BrS17 || {{OMIM|604427||none}} || [[SCN10A]] || [[Nav1.8|Na<sub>V</sub>1.8]] – α subunit of the neuronal sodium channel.<ref name=":2" /><ref>{{cite journal | vauthors = Hu D, Barajas-Martínez H, Pfeiffer R, Dezi F, Pfeiffer J, Buch T, Betzenhauser MJ, Belardinelli L, Kahlig KM, Rajamani S, DeAntonio HJ, Myerburg RJ, Ito H, Deshmukh P, Marieb M, Nam GB, Bhatia A, Hasdemir C, Haïssaguerre M, Veltmann C, Schimpf R, Borggrefe M, Viskin S, Antzelevitch C | title = Mutations in SCN10A are responsible for a large fraction of cases of Brugada syndrome | journal = Journal of the American College of Cardiology | volume = 64 | issue = 1 | pages = 66–79 | date = July 2014 | pmid = 24998131 | pmc = 4116276 | doi = 10.1016/j.jacc.2014.04.032 }}</ref><ref>{{cite journal |last1=Monasky MM, Micaglio E, Vicedomini G, Locati ET, Ciconte G, Giannelli L, Giordano F, Crisà S, Vecchi M, Borrelli V, Ghiroldi A, D'Imperio S, Di Resta C, Benedetti S, Ferrari M, Santinelli V, Anastasia L, Pappone C |title=Comparable clinical characteristics in Brugada syndrome patients harboring SCN5A or novel SCN10A variants |journal=Europace |date=2019 |volume=21 |issue=10 |pages=1550–1558 |doi=10.1093/europace/euz186 |pmid=31292628 |url=https://pubmed.ncbi.nlm.nih.gov/31292628/ |access-date=27 April 2021}}</ref><ref>{{cite journal |last1=Monasky MM, Micaglio E, Ciconte G, Pappone C |title=Brugada Syndrome: Oligogenic or Mendelian Disease? |journal=Int J Mol Sci |date=2020 |volume=21 |issue=5 |page=1687 |doi=10.3390/ijms21051687 | pmc=7084676  |pmid=32121523 |doi-access=free }}</ref>
|-
|BrS18||{{OMIM|604674||none}} || [[HEY2]] ||  Transcription factor identified in [[genome-wide association study]].<ref name=Ant2016 />
|-
|BrS19|| {{OMIM|603961||none}}|| [[SEMA3A]] || Semaphorin.<ref name=Ant2016 />
|-
|BrS20|| {{OMIM|601142||none}}|| [[KCNAB2]] || K<sub>V</sub>β2, voltage-gated potassium channel β2 subunit - mutation increases ''I''<sub>to</sub>.<ref name=":2" /> 
|-

 |}
Some mutations associated with Brugada syndrome can also cause other heart conditions.  Those who show more than one cardiac conditions at the same time caused by a single mutation are described as having an '[[overlap syndrome]]'.  An example of an overlap syndrome is Brugada and [[long QT syndrome]] (LQT3) caused by a mutation in SCN5A that reduces the peak sodium current but simultaneously leaves a persistent current leak.<ref name="Ant2013" /> Brugada syndrome has been described as overlapping with [[Arrhythmogenic right ventricular dysplasia|arrhythmogenic right ventricular cardiomyopathy]] (ARVC) caused by a mutation in the PKP2 gene, causing a Brugada ECG pattern but structural changes in the heart characteristic of ARVC.<ref>{{cite journal | vauthors = Hoogendijk MG | title = Diagnostic dilemmas: overlapping features of brugada syndrome and arrhythmogenic right ventricular cardiomyopathy | journal = Frontiers in Physiology | volume = 3 | pages = 144 | date = 2012 | pmid = 22654761 | pmc = 3358709 | doi = 10.3389/fphys.2012.00144 | doi-access = free }}</ref> Another example of an overlap syndrome would be Brugada syndrome and [[Major aortopulmonary collateral artery|major aortopulmonary collateral arteries]] (MAPCAs) caused by a mutation in [[KCNT1]] that leads to an abnormal [[Mutation|gain-of-function]] in potassium channels of [[neuron]]s and [[Cardiac muscle|cardiomyocytes]].<ref>{{Cite web |title=KCNT1 protein expression summary - The Human Protein Atlas |url=https://www.proteinatlas.org/ENSG00000107147-KCNT1 |access-date=2022-11-18 |website=www.proteinatlas.org}}</ref><ref>{{Cite journal |last1=Kohli |first1=Utkarsh |last2=Ravishankar |first2=Chitra |last3=Nordli |first3=Douglas |date=December 2020 |title=Cardiac phenotypic spectrum of KCNT1 mutations |url=https://www.cambridge.org/core/journals/cardiology-in-the-young/article/abs/cardiac-phenotypic-spectrum-of-kcnt1-mutations/DF2D85CF208D8666366856D0A7022CF0 |journal=Cardiology in the Young |language=en |volume=30 |issue=12 |pages=1935–1939 |doi=10.1017/S1047951120002735 |pmid=32883383 |s2cid=221497594 |issn=1047-9511}}</ref>