Molecular diagnosis in a child with sudden infant death syndrome

Schwartz, Peter J.; Priori, Silvia G.; Bloise, Raffaella; Napolitano, Carlo; Ronchetti, E; Piccinini, A.; Goj, Carlo; Breithardt, Günter; Schulze‐Bahr, Eric; Wedekind, Horst; Nastoli, Janni

doi:10.1016/s0140-6736(01)06450-9

Cited by 155 publications

(94 citation statements)

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“…The consequences of KCNQ1 and KCNH2 mutations associated with SIDS were not previously known [5,[13][14][15]], but we hypothesized that significant functional impairments were likely in some cases. However, it was difficult to predict a priori which variants would cause potassium channel dysfunction and promote arrhythmia susceptibility.…”

Section: Cardiac Potassium Channel Dysfunction In Sidsmentioning

confidence: 99%

“…In 2001, Schwartz and colleagues reported discovery of a de novo KCNQ1 mutation (P117L) in a SIDS victim [13]. The same mutation was also observed to segregate with autosomal dominant LQTS at reduced penetrance in an unrelated Italian family [13]. Another missense KCNQ1 variant (H105L) without functional consequences was discovered among 41 German SIDS cases [14].…”

Section: Introductionmentioning

confidence: 99%

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Cardiac potassium channel dysfunction in sudden infant death syndrome

Wang

Desai

Crotti

et al. 2008

Journal of Molecular and Cellular Cardiology

100

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Life-threatening arrhythmias have been suspected as one cause of the sudden infant death syndrome (SIDS), and this hypothesis is supported by the observation that mutations in arrhythmia susceptibility genes occur in 5-10% of cases. However, the functional consequences of cardiac potassium channel gene mutations associated with SIDS and how these alleles might mechanistically predispose to sudden death are unknown. To address these questions, we studied four missense KCNH2 (encoding HERG) variants, one compound KCNH2 genotype, and a missense KCNQ1 mutation all previously identified in Norwegian SIDS cases. Three of the six variants exhibited functional impairments while three were biophysically similar to wild-type channels (KCNH2 variants V279M, R885C, S1040G). When coexpressed with WT-HERG, R273Q and K897T/R954C generated currents resembling the rapid component of the cardiac delayed rectifier current (I Kr ) but with significantly diminished amplitude. Action potential modeling demonstrated that this level of functional impairment was sufficient to evoke increased action potential duration and pausedependent early afterdepolarizations. By contrast, KCNQ1-I274V causes a gain-of-function in I Ks characterized by increased current density, faster activation, and slower deactivation leading to accumulation of instantaneous current upon repeated stimulation. Action potential simulations using a Markov model of heterozygous I274V-I Ks incorporated into the Luo-Rudy (LRd) ventricular cell model demonstrated marked rate-dependent shortening of action potential duration predicting a short QT phenotype. Our results indicate that certain potassium channel mutations associated with SIDS confer overt functional defects consistent with either LQTS or SQTS, and further emphasize the role of congenital arrhythmia susceptibility in this syndrome.

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Section: Cardiac Potassium Channel Dysfunction In Sidsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Cardiac potassium channel dysfunction in sudden infant death syndrome

Wang

Desai

Crotti

et al. 2008

Journal of Molecular and Cellular Cardiology

100

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“…6 While the pathophysiological mechanisms underlying most of these tragic deaths remain elusive, heritable cardiac arrhythmia syndromes such as long QT syndrome (LQTS), Brugada syndrome (BrS), and catecholoaminergic polymorphic ventricular tachycardia (CPVT) appear to account for 10-15% of SIDS, with the majority of SIDS related mutations being identified in the SCN5A-encoded cardiac sodium channel alpha subunit (Nav1.5) or its interacting proteins. [7][8][9][10][11][12][13][14][15] In 2002, Splawski and colleagues reported on the common African American-specific polymorphism S1103Y-SCN5A (denoted previously as S1102Y) with a prevalence of 13% among African Americans and associated with an increased risk for arrhythmia susceptibility, particularly in the context of other acquired risk factors such as medications, hypokalemia or structural heart disease. 16 Subsequently, Burke and colleagues observed an overrepresentation of S1103Y among African American adolescents and adults whose deaths were classified as autopsy negative sudden unexplained death (SUD).…”

Section: Introductionmentioning

confidence: 99%

Overrepresentation of the proarrhythmic, sudden death predisposing sodium channel polymorphism S1103Y in a population-based cohort of African-American sudden infant death syndrome

Norstrand¹,

Tester²,

Ackerman³

2008

Heart Rhythm

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“…SIDS infants may have a congenital defect of arousal or cardiorespiratory control. Polymorphisms in the serotonin transporter gene (Narita et al 2001) and mutations of the sodiumchannel (Ackerman et al 2001) or potassiumchannel (Schwartz et al 2001) gene have been reported in association with SIDS. Congenital central hypoventilation syndrome (CCHS or Ondine's curse) is a disorder characterized by an idiopathic failure of the autonomic control of breathing and has been regarded as one of the compromised conditions of SIDS.…”

mentioning

confidence: 99%