Sudden Infant Death Syndrome: Case-Control Frequency Differences at Genes Pertinent to Early Autonomic Nervous System Embryologic Development

We have previously identified polymorphisms in the serotonin transporter gene promoter region and in intron 2 that were more common among sudden infant death syndrome (SIDS) cases compared with control subjects. To elucidate further the genetic profile that might increase an infant's vulnerability to SIDS, we focused on the recognized relationship between autonomic nervous system (ANS) dysregulation and SIDS. We therefore studied genes pertinent to early embryologic development of the ANS, including MASH1, BMP2, PHOX2a, PHOX2b, RET, ECE1, EDN1, TLX3, and EN1 in 92 probands with SIDS and 92 gender- and ethnicity-matched control subjects. Eleven protein-changing rare mutations were identified in 14 of 92 SIDS cases among the PHOX2a, RET, ECE1, TLX3, and EN1 genes. Only 1 of these mutations (TLX3) was identified in 2 of 92 control subjects. Black infants accounted for 10 of these mutations in SIDS cases and 2 control subjects. Four protein-changing common polymorphisms were identified in BMP2, RET, ECE1, and EDN1, but the allele frequency did not differ between SIDS cases and control subjects. However, among SIDS cases, the allele frequency for the BMP2 common polymorphism demonstrated ethnic differences; among control subjects, the allele frequency for the BMP2 and the ECE1 common polymorphisms also demonstrated ethnic differences. These data represent further refinement of the genetic profile that might place an infant at risk for SIDS.

[1]  B. Maher,et al.  Sudden infant death syndrome: Association with a promoter polymorphism of the serotonin transporter gene , 2003, American journal of medical genetics. Part A.

[2]  S. Takashima,et al.  Serotonin Transporter Gene Variation Is a Risk Factor for Sudden Infant Death Syndrome in the Japanese Population , 2001, Pediatrics.

[3]  M. Hirsch,et al.  Control of noradrenergic differentiation and Phox2a expression by MASH1 in the central and peripheral nervous system. , 1998, Development.

[4]  D. Shannon,et al.  RET proto-oncogene is important for the development of respiratory CO2 sensitivity. , 1997, Journal of the autonomic nervous system.

[5]  H. Hoffman,et al.  Cardiac and respiratory patterns in normal infants and victims of the sudden infant death syndrome. , 1988, Sleep.

[6]  J. A. Martin,et al.  ADVANCE REPORT OF FINAL NATALITY STATISTIC, 1992 , 1994 .

[7]  K. Kochanek,et al.  Advance report of final mortality statistics, 1991 , 1995 .

[8]  S. Korsmeyer,et al.  Rnx deficiency results in congenital central hypoventilation , 2000, Nature Genetics.

[9]  A. Munnich,et al.  Mutations of the RET-GDNF signaling pathway in Ondine's curse. , 1998, American journal of human genetics.

[10]  R. Gilbert,et al.  Interaction between bedding and sleeping position in the sudden infant death syndrome: a population based case-control study. , 1990, BMJ.

[11]  H. Kinney,et al.  Decreased Serotonergic Receptor Binding in Rhombic Lip‐Derived Regions of the Medulla Oblongata in the Sudden Infant Death Syndrome , 2000, Journal of neuropathology and experimental neurology.

[12]  A. Wakizaka,et al.  Point mutation in exon 12 of the receptor tyrosine kinase proto-oncogene RET in Ondine-Hirschsprung syndrome. , 1998, Pediatrics.

[13]  S. Schwartz,et al.  Congenital central hypoventilation syndrome: mutation analysis of the receptor tyrosine kinase RET. , 1996, American journal of medical genetics.

[14]  David J. Anderson,et al.  Specification of Neurotransmitter Identity by Phox2 Proteins in Neural Crest Stem Cells , 1999, Neuron.

[15]  A. Munnich,et al.  Exclusion of RNX as a major gene in congenital central hypoventilation syndrome (CCHS, Ondine's curse) , 2003, American journal of medical genetics. Part A.

[16]  T. Dwyer,et al.  Thermal environment and sudden infant death syndrome: case-control study. , 1992, BMJ.

[17]  B. Maher,et al.  Genetic segregation analysis of autonomic nervous system dysfunction in families of probands with idiopathic congenital central hypoventilation syndrome. , 2001, American journal of medical genetics.

[18]  David J. Anderson,et al.  MASH1 maintains competence for BMP2-induced neuronal differentiation in post-migratory neural crest cells , 1997, Current Biology.

[19]  B. Maher,et al.  Association of the serotonin transporter gene with sudden infant death syndrome: A haplotype analysis , 2003, American journal of medical genetics. Part A.

[20]  H. Schackert,et al.  Association of germline mutations and polymorphisms of the RET proto-oncogene with idiopathic congenital central hypoventilation syndrome in 33 patients , 2003, Journal of medical genetics.

[21]  M. Marazita,et al.  Congenital central hypoventilation syndrome: inheritance and relation to sudden infant death syndrome. , 1993, American journal of medical genetics.

[22]  B. Jacobs,et al.  Structure and function of the brain serotonin system. , 1992, Physiological reviews.

[23]  X. Morin,et al.  The homeobox gene Phox2b is essential for the development of autonomic neural crest derivatives , 1999, Nature.

[24]  G. Vardon,et al.  Ventilatory Responses to Hypercapnia and Hypoxia in Mash-1 Heterozygous Newborn and Adult Mice , 1999, Pediatric Research.

[25]  Wolfgang Wurst,et al.  Fate of Midbrain Dopaminergic Neurons Controlled by the Engrailed Genes , 2001, The Journal of Neuroscience.

[26]  小沢 愉理,et al.  Alteration of serotonergic receptors in the brain stems of human patients with respiratory disorders , 2003 .

[27]  D. Anderson,et al.  MASH1 activates expression of the paired homeodomain transcription factor Phox2a, and couples pan-neuronal and subtype-specific components of autonomic neuronal identity. , 1998, Development.

[28]  H. Kinney,et al.  Expression of the Homeobox‐containing Genes EN1 and EN2 in Human Fetal Midgestational Medulla and Cerebellum , 1997, Journal of neuropathology and experimental neurology.

[29]  P. Franco,et al.  Decreased Autonomic Responses to Obstructive Sleep Events in Future Victims of Sudden Infant Death Syndrome , 1999, Pediatric Research.

[30]  David J. Anderson,et al.  Two rat homologues of Drosophila achaete-scute specifically expressed in neuronal precursors , 1990, Nature.

[31]  M. Willinger.  Defining the sudden infant death syndrome (SIDS) , 1991 .

[32]  B. Maher,et al.  Case/control family study of autonomic nervous system dysfunction in idiopathic congenital central hypoventilation syndrome. , 2001, American journal of medical genetics.

[33]  M. Yanagisawa,et al.  Impaired Ventilatory Responses to Hypoxia in Mice Deficient in Endothelin-Converting-Enzyme-1 , 2001, Pediatric Research.

[34]  D. Shannon,et al.  Idiopathic congenital central hypoventilation syndrome: diagnosis and management. American Thoracic Society. , 1999, American journal of respiratory and critical care medicine.

[35]  David J. Anderson,et al.  Mammalian achaete-scute homolog 1 is required for the early development of olfactory and autonomic neurons , 1993, Cell.

[36]  S. Shirasawa,et al.  Congenital central hypoventilation syndrome: a novel mutation of the RET gene in an isolated case. , 2002, The Tohoku journal of experimental medicine.

[37]  A. Joyner,et al.  MASH-1: a marker and a mutation for mammalian neural crest development. , 1994, Perspectives on developmental neurobiology.

[38]  R. Ravazzolo,et al.  Mutational analysis of the RNX gene in congenital central hypoventilation syndrome. , 2002, American journal of medical genetics.

[39]  P. Franco,et al.  Polysomnographic study of the autonomic nervous system in potential victims of sudden infant death syndrome , 1998, Clinical Autonomic Research.

[40]  Mary T. Carbone,et al.  Cardiorespiratory recordings from infants dying suddenly and unexpectedly at home. , 1994, Pediatrics.

[41]  Tomohiko Nakamura,et al.  Molecular analysis of congenital central hypoventilation syndrome , 2003, Human Genetics.

[42]  E. Arias,et al.  Annual summary of vital statistics--2002. , 2003, Pediatrics.

[43]  Y. Yazaki,et al.  Impaired ventilatory responses to hypoxia and hypercapnia in mutant mice deficient in endothelin-1. , 1996, The American journal of physiology.

[44]  M. Ledwidge,et al.  Neurocardiogenic syncope: a model for SIDS , 1998, Archives of disease in childhood.

[45]  A. Munnich,et al.  Polyalanine expansion and frameshift mutations of the paired-like homeobox gene PHOX2B in congenital central hypoventilation syndrome , 2003, Nature Genetics.

[46]  L. S. James,et al.  Defining the sudden infant death syndrome (SIDS): deliberations of an expert panel convened by the National Institute of Child Health and Human Development. , 1991, Pediatric pathology.

[47]  E. Mitchell,et al.  Symptoms, sweating and reactivity of infants who die of SIDS compared with community controls , 1996, Journal of paediatrics and child health.

[48]  B. Maher,et al.  Idiopathic congenital central hypoventilation syndrome: Analysis of genes pertinent to early autonomic nervous system embryologic development and identification of mutations in PHOX2b , 2003, American journal of medical genetics. Part A.

[49]  J. Groswasser,et al.  Sleep and cardiorespiratory characteristics of infant victims of sudden death: a prospective case-control study. , 1992, Sleep.

[50]  X. Morin,et al.  Expression and interactions of the two closely related homeobox genes Phox2a and Phox2b during neurogenesis. , 1997, Development.