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PHOX2B polyalanine repeat length is associated with sudden infant death syndrome and unclassified sudden infant death in the Dutch population

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Abstract

Unclassified sudden infant death (USID) is the sudden and unexpected death of an infant that remains unexplained after thorough case investigation including performance of a complete autopsy and review of the circumstances of death and the clinical history. When the infant is below 1 year of age and with onset of the fatal episode apparently occurring during sleep, this is referred to as sudden infant death syndrome (SIDS). USID and SIDS remain poorly understood despite the identification of several environmental and some genetic risk factors. In this study, we investigated genetic risk factors involved in the autonomous nervous system in 195 Dutch USID/SIDS cases and 846 Dutch, age-matched healthy controls. Twenty-five DNA variants from 11 genes previously implicated in the serotonin household or in the congenital central hypoventilation syndrome, of which some have been associated with SIDS before, were tested. Of all DNA variants considered, only the length variation of the polyalanine repeat in exon 3 of the PHOX2B gene was found to be statistically significantly associated with USID/SIDS in the Dutch population after multiple test correction. Interestingly, our data suggest that contraction of the PHOX2B exon 3 polyalanine repeat that we found in six of 160 SIDS and USID cases and in six of 814 controls serves as a probable genetic risk factor for USID/SIDS at least in the Dutch population. Future studies are needed to confirm this finding and to understand the functional effect of the polyalanine repeat length variation, in particular contraction, in exon 3 of the PHOX2B gene.

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Acknowledgments

We are grateful to all participants of the study as well as to the LWW for having collected and provided relevant information. We thank the following colleagues for having provided tissue material and record information to this study: R.R. de Krijger, Erasmus Medisch Centrum, Rotterdam; J.V.M.G. Bovee, Leids Universitair Medisch Centrum, Leiden; L.C.D. Wijnaendts, Vrije Universiteit, Amsterdam; P.G.J. Nikkels, Academisch Ziekenhuis Utrecht, Utrecht; A.H. Mulder, Ziekenhuis Rijnstate, Arnhem; R. Boorsma, Laboratorium voor de Volksgezondheid Friesland, Leeuwarden; J.C. van der Linde, Jeroen Bosch Ziekenhuis, Den Bosch; P. Blok, Ziekenhuis Leyenburg, the Hague; C. van der Hulsbergen, Academisch Ziekenhuis Nijmegen St Radboud, Nijmegen; A. Timmer, Universitair Medisch Centrum Groningen, Groningen; S.J.F. Schoots, St. Samenwerkende Ziekenhuizen Oost Groningen, Wintschoten; F.J. ten Kate, Academisch Medisch Centrum, Amsterdam; A. Maes, Nederlands Forensisch Instituut, the Hague; P. Westenend, Pathologisch Laboratorium voor Dordrecht en Omstreken, Dordrecht; W.S. Kwee, St. Jansgasthuis and Laurentius Ziekenhuis, Roermond and Weert; D. Willebrand, Streeklaboratorium voor de Volksgezondheid, Haarlem; R.N. Breeuwsma, Medisch Centrum Alkmaar, Alkmaar; M. Brinkhuis, Laboratorium voor Pathologie Oost Nederland, Enschede; N. Vandevijver, Atrium, Heerlen; Nijhuis, Onze Lieve Vrouwe Gasthuis, Amsterdam; M. Baldewijns, Academisch Ziekenhuis Maastricht, Maastricht; C.M. van Dijk, Groene Hart Ziekenhuis, Gouda; E. de Ruijter, Amphia Ziekenhuis, Breda; J.A. Ruizeveld de Winter, Pathan, Rotterdam; I. van Lijnschoten, Stichting PAMM, Eindhoven; R.F.M. Schapers, St. Pathologisch Laboratorium Noord-Limburg, Venlo; C. Wauters, Canisius-Wilhelmina Ziekenhuis, Nijmegen; C.A. Seldenrijk, St. Antonius Ziekenhuis, Nieuwegein; E.C.M. Ooms, Haaglanden, the Hague; H. Beerman, Medisch Centrum Rotterdam Zuid, Rotterdam; J.G. Smits, Streeklaboratorium Zeeland, Middelburg; R. Dutrieux, Zaans Medisch Centrum, Zaandam; A.M. Croonen, Lab Klinische Pathologie Centraal Brabant, Tilburg; E.M. van der Loo, Reinier de Graafziekenhuis, Delft; J.W. Arends, Deventer Ziekenhuizen, Deventer; and W.A. van Houten, Laboratorium voor Pathologie St. Sazinon, Hoogeveen. We also like to thank Arwin Ralf, Kaye Ballantyne and Ying Choi for their support in DNA analyses. This study was supported by the Erasmus University Medical Center Rotterdam and in part by funding provided by the Netherlands Forensic Institute. The Generation R Study gratefully acknowledges the contribution of children and parents, general practitioners, hospitals, midwives and pharmacies in Rotterdam. The Generation R Study is made possible by financial support from the Erasmus Medical Center, Rotterdam, the Erasmus University Rotterdam, the Netherlands Organization for Health Research and Development (ZonMw), the Netherlands Organisation for Scientific Research (NWO), the Ministry of Health, Welfare and Sport of the Netherlands.

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Author notes

  1. Germaine Liebrechts-Akkerman & Ariadne H. A. G. Ooms

    Present address: Department of Pathology, Erasmus MC University Medical Center Rotterdam, Rotterdam, The Netherlands

  2. Kate van Duijn

    Present address: Department of Statistics and Bioinformatics, Leiden University Medical Center, Leiden, The Netherlands

  3. Mark Vermeulen

    Present address: Department of Vaccine Generation, Crucell, Leiden, The Netherlands

Authors and Affiliations

  1. Department of Forensic Molecular Biology, Erasmus MC University Medical Center Rotterdam, P.O. Box 2040, 3000 CA, Rotterdam, The Netherlands

    Germaine Liebrechts-Akkerman, Fan Liu, Oscar Lao, Ariadne H. A. G. Ooms, Kate van Duijn, Mark Vermeulen & Manfred Kayser

  2. The Generation R Study Group, Erasmus MC University Medical Center Rotterdam, Rotterdam, The Netherlands

    Vincent W. Jaddoe & Albert Hofman

  3. Department of Epidemiology, Erasmus MC University Medical Center Rotterdam, Rotterdam, The Netherlands

    Vincent W. Jaddoe & Albert Hofman

  4. Department of Paediatrics, Erasmus MC University Medical Center Rotterdam, Rotterdam, The Netherlands

    Vincent W. Jaddoe

  5. Department of Pediatrics, Orbis Medical Centre, Sittard, The Netherlands

    Adèle C. Engelberts

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  1. Germaine Liebrechts-Akkerman
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  2. Fan Liu
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  9. Adèle C. Engelberts
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  10. Manfred Kayser
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Correspondence to Manfred Kayser.

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Liebrechts-Akkerman, G., Liu, F., Lao, O. et al. PHOX2B polyalanine repeat length is associated with sudden infant death syndrome and unclassified sudden infant death in the Dutch population. Int J Legal Med 128, 621–629 (2014). https://doi.org/10.1007/s00414-013-0962-0

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  • DOI: https://doi.org/10.1007/s00414-013-0962-0

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