The role of the sodium current complex in a nonreferred nationwide cohort of sudden infant death syndrome

Bo Gregers Winkel; Lei Yuan; Morten S. Olesen; Golnaz Sadjadieh; Yinman Wang; Bjarke Risgaard; Reza Jabbari; Stig Haunsø; Anders Gaarsdal Holst; Mads Vilhelm Hollegaard; Jacob Tfelt-Hansen; Thomas Jespersen

doi:10.1016/j.hrthm.2015.03.013

The role of the sodium current complex in a nonreferred nationwide cohort of sudden infant death syndrome

Bo Gregers Winkel, Lei Yuan, Morten S. Olesen, Golnaz Sadjadieh, Yinman Wang, Bjarke Risgaard, Reza Jabbari, Stig Haunsø, Anders Gaarsdal Holst, Mads Vilhelm Hollegaard, Jacob Tfelt-Hansen, Thomas Jespersen

14 Citationer (Scopus)

Abstract

BACKGROUND: Sudden infant death syndrome (SIDS) is the most common cause of death in infants between the age of 1 month and 1 year. Rare variants in Nav1.5 encoded by SCN5A are known to play a role in SIDS; however, the combined role of the sodium current complex is unknown.

OBJECTIVE: The purpose of this study was to investigate the role of the sodium current complex in a nonreferred nationwide cohort of SIDS cases.

METHODS: DNA was extracted from dried blood spot samples from the Danish Neonatal Screening Biobank. In total, 66 non-referred SIDS cases born in Denmark in the period of 2000-2006 were screened for genetic variants in the 8 major genes involved in the regulation of the Nav1.5 channel complex: SCN5A, SCN1B, SCN2B, SCN3B, SCN4B, GPD1L, SNTA1, and CAV3. Patch-clamp analyses were performed on variants not previously characterized.

RESULTS: In total, 8 patients (12%) had nonsynonymous rare variants in the sodium current genes. SCN5A harbored 6 rare variants (R458C, R535*, S1103Y, R1193Q, S1609L, and Q1909R); CAV3, 1 rare variant (T78M); GPD1L, 1 rare variant (R220H); and SCN3B, 1 rare variant (L10P). Four variants were considered likely pathogenic and 5 variants of unknown significance. SCN5A R1193Q and GPD1L R220H (both considered variants of unknown significance) were present in the same infant. Functional analysis of variants not previously characterized (R458C, S1609L, and Q1909R in SCN5A) predominantly revealed increased transient and sustained sodium current.

CONCLUSION: In a nonreferred nationwide Danish cohort of SIDS cases, up to 5/66 (7.5%) of SIDS cases can be explained by genetic variants in the sodium channel complex genes.

Originalsprog	Engelsk
Tidsskrift	Heart rhythm : the official journal of the Heart Rhythm Society
Vol/bind	12
Udgave nummer	6
Sider (fra-til)	1241-1249
Antal sider	9
ISSN	1547-5271
DOI	https://doi.org/10.1016/j.hrthm.2015.03.013
Status	Udgivet - 1 jun. 2015

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10.1016/j.hrthm.2015.03.013

Citationsformater

Winkel, B. G., Yuan, L., Olesen, M. S., Sadjadieh, G., Wang, Y., Risgaard, B., Jabbari, R., Haunsø, S., Holst, A. G., Hollegaard, M. V., Tfelt-Hansen, J., & Jespersen, T. (2015). The role of the sodium current complex in a nonreferred nationwide cohort of sudden infant death syndrome. Heart rhythm : the official journal of the Heart Rhythm Society, 12(6), 1241-1249. https://doi.org/10.1016/j.hrthm.2015.03.013

Winkel, BG, Yuan, L, Olesen, MS, Sadjadieh, G, Wang, Y, Risgaard, B, Jabbari, R, Haunsø, S, Holst, AG, Hollegaard, MV, Tfelt-Hansen, J & Jespersen, T 2015, 'The role of the sodium current complex in a nonreferred nationwide cohort of sudden infant death syndrome', Heart rhythm : the official journal of the Heart Rhythm Society, bind 12, nr. 6, s. 1241-1249. https://doi.org/10.1016/j.hrthm.2015.03.013

@article{a7e3f7b7cd6341bcb1983d6bbcef7ebb,

title = "The role of the sodium current complex in a nonreferred nationwide cohort of sudden infant death syndrome",

abstract = "BACKGROUND: Sudden infant death syndrome (SIDS) is the most common cause of death in infants between the age of 1 month and 1 year. Rare variants in Nav1.5 encoded by SCN5A are known to play a role in SIDS; however, the combined role of the sodium current complex is unknown.OBJECTIVE: The purpose of this study was to investigate the role of the sodium current complex in a nonreferred nationwide cohort of SIDS cases.METHODS: DNA was extracted from dried blood spot samples from the Danish Neonatal Screening Biobank. In total, 66 non-referred SIDS cases born in Denmark in the period of 2000-2006 were screened for genetic variants in the 8 major genes involved in the regulation of the Nav1.5 channel complex: SCN5A, SCN1B, SCN2B, SCN3B, SCN4B, GPD1L, SNTA1, and CAV3. Patch-clamp analyses were performed on variants not previously characterized.RESULTS: In total, 8 patients (12%) had nonsynonymous rare variants in the sodium current genes. SCN5A harbored 6 rare variants (R458C, R535*, S1103Y, R1193Q, S1609L, and Q1909R); CAV3, 1 rare variant (T78M); GPD1L, 1 rare variant (R220H); and SCN3B, 1 rare variant (L10P). Four variants were considered likely pathogenic and 5 variants of unknown significance. SCN5A R1193Q and GPD1L R220H (both considered variants of unknown significance) were present in the same infant. Functional analysis of variants not previously characterized (R458C, S1609L, and Q1909R in SCN5A) predominantly revealed increased transient and sustained sodium current.CONCLUSION: In a nonreferred nationwide Danish cohort of SIDS cases, up to 5/66 (7.5%) of SIDS cases can be explained by genetic variants in the sodium channel complex genes.",

keywords = "Denmark, Female, Genetic Variation, Humans, Infant, Infant, Newborn, Male, Sodium Channels, Sudden Infant Death",

author = "Winkel, {Bo Gregers} and Lei Yuan and Olesen, {Morten S.} and Golnaz Sadjadieh and Yinman Wang and Bjarke Risgaard and Reza Jabbari and Stig Hauns{\o} and Holst, {Anders Gaarsdal} and Hollegaard, {Mads Vilhelm} and Jacob Tfelt-Hansen and Thomas Jespersen",

year = "2015",

month = jun,

day = "1",

doi = "10.1016/j.hrthm.2015.03.013",

language = "English",

volume = "12",

pages = "1241--1249",

journal = "Heart rhythm : the official journal of the Heart Rhythm Society",

issn = "1547-5271",

publisher = "Elsevier",

number = "6",

}

TY - JOUR

T1 - The role of the sodium current complex in a nonreferred nationwide cohort of sudden infant death syndrome

AU - Winkel, Bo Gregers

AU - Yuan, Lei

AU - Olesen, Morten S.

AU - Sadjadieh, Golnaz

AU - Wang, Yinman

AU - Risgaard, Bjarke

AU - Jabbari, Reza

AU - Haunsø, Stig

AU - Holst, Anders Gaarsdal

AU - Hollegaard, Mads Vilhelm

AU - Tfelt-Hansen, Jacob

AU - Jespersen, Thomas

PY - 2015/6/1

Y1 - 2015/6/1

N2 - BACKGROUND: Sudden infant death syndrome (SIDS) is the most common cause of death in infants between the age of 1 month and 1 year. Rare variants in Nav1.5 encoded by SCN5A are known to play a role in SIDS; however, the combined role of the sodium current complex is unknown.OBJECTIVE: The purpose of this study was to investigate the role of the sodium current complex in a nonreferred nationwide cohort of SIDS cases.METHODS: DNA was extracted from dried blood spot samples from the Danish Neonatal Screening Biobank. In total, 66 non-referred SIDS cases born in Denmark in the period of 2000-2006 were screened for genetic variants in the 8 major genes involved in the regulation of the Nav1.5 channel complex: SCN5A, SCN1B, SCN2B, SCN3B, SCN4B, GPD1L, SNTA1, and CAV3. Patch-clamp analyses were performed on variants not previously characterized.RESULTS: In total, 8 patients (12%) had nonsynonymous rare variants in the sodium current genes. SCN5A harbored 6 rare variants (R458C, R535*, S1103Y, R1193Q, S1609L, and Q1909R); CAV3, 1 rare variant (T78M); GPD1L, 1 rare variant (R220H); and SCN3B, 1 rare variant (L10P). Four variants were considered likely pathogenic and 5 variants of unknown significance. SCN5A R1193Q and GPD1L R220H (both considered variants of unknown significance) were present in the same infant. Functional analysis of variants not previously characterized (R458C, S1609L, and Q1909R in SCN5A) predominantly revealed increased transient and sustained sodium current.CONCLUSION: In a nonreferred nationwide Danish cohort of SIDS cases, up to 5/66 (7.5%) of SIDS cases can be explained by genetic variants in the sodium channel complex genes.

AB - BACKGROUND: Sudden infant death syndrome (SIDS) is the most common cause of death in infants between the age of 1 month and 1 year. Rare variants in Nav1.5 encoded by SCN5A are known to play a role in SIDS; however, the combined role of the sodium current complex is unknown.OBJECTIVE: The purpose of this study was to investigate the role of the sodium current complex in a nonreferred nationwide cohort of SIDS cases.METHODS: DNA was extracted from dried blood spot samples from the Danish Neonatal Screening Biobank. In total, 66 non-referred SIDS cases born in Denmark in the period of 2000-2006 were screened for genetic variants in the 8 major genes involved in the regulation of the Nav1.5 channel complex: SCN5A, SCN1B, SCN2B, SCN3B, SCN4B, GPD1L, SNTA1, and CAV3. Patch-clamp analyses were performed on variants not previously characterized.RESULTS: In total, 8 patients (12%) had nonsynonymous rare variants in the sodium current genes. SCN5A harbored 6 rare variants (R458C, R535*, S1103Y, R1193Q, S1609L, and Q1909R); CAV3, 1 rare variant (T78M); GPD1L, 1 rare variant (R220H); and SCN3B, 1 rare variant (L10P). Four variants were considered likely pathogenic and 5 variants of unknown significance. SCN5A R1193Q and GPD1L R220H (both considered variants of unknown significance) were present in the same infant. Functional analysis of variants not previously characterized (R458C, S1609L, and Q1909R in SCN5A) predominantly revealed increased transient and sustained sodium current.CONCLUSION: In a nonreferred nationwide Danish cohort of SIDS cases, up to 5/66 (7.5%) of SIDS cases can be explained by genetic variants in the sodium channel complex genes.

KW - Denmark

KW - Female

KW - Genetic Variation

KW - Humans

KW - Infant

KW - Infant, Newborn

KW - Male

KW - Sodium Channels

KW - Sudden Infant Death

U2 - 10.1016/j.hrthm.2015.03.013

DO - 10.1016/j.hrthm.2015.03.013

M3 - Journal article

C2 - 25757662

SN - 1547-5271

VL - 12

SP - 1241

EP - 1249

JO - Heart rhythm : the official journal of the Heart Rhythm Society

JF - Heart rhythm : the official journal of the Heart Rhythm Society

IS - 6

ER -

The role of the sodium current complex in a nonreferred nationwide cohort of sudden infant death syndrome

Abstract

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