Contribution of Long-QT Syndrome Genetic Variants in Sudden Infant Death Syndrome
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A cohort of 52 French unrelated infant cases who died unexpectedly before they reached 12 months of age was blindly investigated to better quantify the contribution of long-QT syndrome (LQTS) genetic variants in French cases of sudden infant death syndrome (SIDS). After a standardized autopsy protocol, a blinded molecular screening of the KCNQ1, KCNH2, SCN5A, KCNE1, and KCNE2 genes was performed on each case. These postmortem investigations enabled us to reclassify 18 as non-SIDS cases, 32 as SIDS cases, and 2 as suspected SIDS cases. Among the 18 non-SIDS cases, no LQTS mutation was identified. In contrast, our results led to a possible explanation for the death of at least three infants in the SIDS cohort. Half of the LQTS gene variants identified were located on the SCN5A gene. This study confirms that LQTS mutations may represent one of the leading genetic causes of SIDS. If autopsy fails to provide an explanation for an unexplained infant death, medicolegal investigation should be extended with a molecular screening of major LQTS genes. Identification of more LQTS mutations in SIDS cases could provide new insights into the pathophysiology of SIDS and, consequently, reduce the number of unexplained sudden infant deaths.
KeywordsMutations Long-QT syndrome Sudden infant death syndrome Polymorphisms Arrythmia
This work was supported by PHRC 97061 and by the French Ministery of Research (Diagnosis Network on Neuromuscular Diseases). The authors thank Ms. C. Bulle, V. Chanavat, E. Froidefond, R. Perraudin, and O. Vial for expert technical assistance.
- 2.Ackerman MJ, Splawski I, Makielski JC, Tester DJ, Will ML, Timothy KW, Keating MT, Jones G, Chadha M, Burrow CR, Stephens JC, Xu C, Judson R, Curran ME (2004) Spectrum and prevalence of cardiac sodium channel variants among black, white, Asian, and Hispanic individuals: implications for arrhythmogenic susceptibility and Brugada/long QT syndrome genetic testing. Heart Rhythm 1:600–607PubMedCrossRefGoogle Scholar
- 10.Friedlander Y, Vatta M, Sotoodehnia N, Sinnreich R, Li H, Manor O, Towbin JA, Siscovick DS, Kark JD (2005) Possible association of the human KCNE1 (minK) gene and QT interval in healthy subjects: evidence from association and linkage analyses in Israeli families. Ann Hum Genet 69:645–656PubMedCrossRefGoogle Scholar
- 14.Lupoglazoff JM, Denjoy I, Villain E, Fressart V, Simon F, Bozio A, Berthet M, Benammar N, Hainque B, Guicheney P (2004) Long QT syndrome in neonates: conduction disorders associated with HERG mutations and sinus bradycardia with KCNQ1 mutations. J Am Coll Cardiol 43:826–830PubMedCrossRefGoogle Scholar
- 16.Millat G, Chevalier P, Restier-Miron L, Da Costa A, Bouvagnet P, Kugener B, Fayol L, Gonzalez Armengod C, Oddou B, Chanavat V, Froidefond E, Perraudin R, Rousson R, Rodriguez-Lafrasse C (2006) Spectrum of pathogenic mutations and associated polymorphisms in a cohort of 44 unrelated patients with long QT syndrome. Clin Genet 70:214–227PubMedCrossRefGoogle Scholar
- 18.Pfeufer A, Jalilzadeh S, Perz S, Mueller JC, Hinterseer M, Illig T, Akyol M, Huth C, Schopfer-Wendels A, Kuch B, Steinbeck G, Holle R, Nabauer M, Wichmann HE, Meitinger T, Kaab S (2005) Common variants in myocardial ion channel genes modify the QT interval in the general population: results from the KORA study. Circ Res 96:693–701PubMedCrossRefGoogle Scholar
- 19.Piippo K, Swan H, Pasternack M, Chapman H, Paavonen K, Viitasalo M, Toivonen L, Kontula K (2001) A founder mutation of the potassium channel KCNQ1 in long QT syndrome: implications for estimation of disease prevalence and molecular diagnostics. J Am Coll Cardiol 37:562–568PubMedCrossRefGoogle Scholar
- 32.Viswanathan PC, Benson DW, Balser JR (2003) A common SCN5A polymorphism modulates the biophysical effects of an SCN5A mutation. J Clin Invest 111:315–316Google Scholar
- 34.Wedekind H, Smits JP, Schulze-Bahr E, Arnold R, Veldkamp MW, Bajanowski T, Borggrefe M, Brinkmann B, Warnecke I, Funke H, Bhuiyan ZA, Wilde AA, Breithardt G, Haverkamp W (2001) De novo mutation in the SCN5A gene associated with early onset of sudden infant death. Circulation 104:1158–1164PubMedCrossRefGoogle Scholar
- 36.Weese-Mayer DE, Ackerman MJ, Marazita ML, Berry-Kravis EM (2007) Sudden Infant Death Syndrome: review of implicated genetic factors. Am J Med Genet A 143:771–788Google Scholar