title: Presence of autism, hyperserotonemia, and severe expressive language impairment in Williams-Beuren syndrome.
abstract: BACKGROUND
  Deletion of the Williams-Beuren syndrome (WBS) critical region (WBSCR), at 7q11.23, causes a developmental disorder commonly characterized by hypersociability and excessive talkativeness and often considered the opposite behavioral phenotype to autism. Duplication of the WBSCR leads to severe delay in expressive language. Gene-dosage effects on language development at 7q11.23 have been hypothesized.
  
  
  METHODS
  Molecular characterization of the WBSCR was performed by fluorescence in situ hybridization and high-resolution single-nucleotide polymorphism array in two individuals with severe autism enrolled in a genetic study of autism who showed typical WBS facial dysmorphism on systematic clinical genetic examination. The serotonin transporter promoter polymorphism (5-HTTLPR, locus SLC6A4) was genotyped. Platelet serotonin levels and urinary 6-sulfatoxymelatonin excretion were measured. Behavioral and cognitive phenotypes were examined.
  
  
  RESULTS
  The two patients had common WBSCR deletions between proximal and medial low copy repeat clusters, met diagnostic criteria for autism and displayed severe impairment in communication, including a total absence of expressive speech. Both patients carried the 5-HTTLPR ss genotype and exhibited platelet hyperserotonemia and low melatonin production.
  
  
  CONCLUSIONS
  Our observations indicate that behaviors and neurochemical phenotypes typically associated with autism can occur in patients with common WBSCR deletions. The results raise intriguing questions about phenotypic heterogeneity in WBS and regarding genetic and/or environmental factors interacting with specific genes at 7q11.23 sensitive to dosage alterations that can influence the development of social communication skills. Thus, the influence of WBSCR genes on social communication expression might be dramatically modified by other genes, such as 5-HTTLPR, known to influence the severity of social communication impairments in autism, or by environmental factors, such as hyperserotonemia, given that hyperserotonemia is found in WBS associated with autism but not in WBS without autism. In this regard, WBS provides a potentially fruitful model with which to develop integrated genetic, cognitive, behavioral and neurochemical approaches to study genotype-phenotype correlations, possible gene-environment interactions and genetic background effects. The results underscore the importance of considering careful clinical and molecular genetic examination of individuals diagnosed with autism.
authors: Department of Child and Adolescent Psychiatry, Centre Hospitalier Guillaume Regnier and Medical School of the University of Rennes 1, Rennes 35000, France. s.tordjman@yahoo.fr.
authors: Sylvie
authors: S
authors: Tordjman
authors: George M
authors: GM
authors: Anderson
authors: David
authors: D
authors: Cohen
authors: Solenn
authors: S
authors: Kermarrec
authors: Michèle
authors: M
authors: Carlier
authors: Yvan
authors: Y
authors: Touitou
authors: Pascale
authors: P
authors: Saugier-Veber
authors: Céline
authors: C
authors: Lagneaux
authors: Claire
authors: C
authors: Chevreuil
authors: Alain
authors: A
authors: Verloes
references: J Am Acad Child Adolesc Psychiatry. 2007 Mar;46(3):323-331
references: 17314718
references: Science. 1999 Dec 17;286(5448):2355-8
references: 10600749
references: CNS Spectr. 2007 Dec;12(12):903-7
references: 18163035
references: J Med Genet. 2003 Jul;40(7):526-30
references: 12843326
references: Am J Med Genet A. 2012 May;158A(5):969-79
references: 22488915
references: Mol Psychiatry. 1998 May;3(3):238-46
references: 9672899
references: Biol Psychiatry. 2005 Jan 15;57(2):134-8
references: 15652871
references: Mol Psychiatry. 2002;7(8):831-6
references: 12232775
references: Life Sci. 1987 Mar 16;40(11):1063-70
references: 3821372
references: J Autism Dev Disord. 1989 Mar;19(1):137-41
references: 2468644
references: Curr Psychiatry Rep. 2006 Dec;8(6):452-7
references: 17094925
references: Science. 1996 Nov 29;274(5292):1527-31
references: 8929413
references: J Am Acad Child Adolesc Psychiatry. 2010 Aug;49(8):752-71
references: 20643310
references: Neuron. 2011 Jun 9;70(5):863-85
references: 21658581
references: Genet Med. 2003 Jul-Aug;5(4):311-21
references: 12865760
references: Acta Paedopsychiatr. 1968;35(4):100-36
references: 4880460
references: PLoS One. 2012;7(10):e47457
references: 23118870
references: Psychoneuroendocrinology. 2012 Dec;37(12):1990-7
references: 22613035
references: Cell Mol Life Sci. 2009 Apr;66(7):1178-97
references: 19039520
references: Hum Genet. 1997 Dec;101(2):243-6
references: 9402979
references: PLoS One. 2012;7(3):e30778
references: 22412832
references: Eur J Hum Genet. 2000 Dec;8(12):955-63
references: 11175284
references: Am J Hum Genet. 2006 Aug;79(2):332-41
references: 16826523
references: J Cogn Neurosci. 2000;12 Suppl 1:7-29
references: 10953231
references: Child Neuropsychol. 2007 Sep;13(5):444-67
references: 17805996
references: Mol Psychiatry. 2001 Jul;6(4):434-9
references: 11443529
references: N Engl J Med. 2005 Oct 20;353(16):1694-701
references: 16236740
references: J Med Genet. 2007 Feb;44(2):136-43
references: 16971481
references: Expert Rev Mol Med. 2007 Jun 13;9(15):1-16
references: 17565757
references: Am J Med Genet A. 2004 Dec 15;131(3):255-64
references: 15534874
references: J Am Acad Child Adolesc Psychiatry. 1998 Jul;37(7):767-76
references: 9666633
references: J Am Acad Child Adolesc Psychiatry. 2010 Sep;49(9):921-33
references: 20732628
references: World J Biol Psychiatry. 2006;7(3):186-8
references: 16861145
references: J Am Acad Child Adolesc Psychiatry. 2006 Sep;45(9):1094-1103
references: 16926617
references: J Pediatr. 1988 Aug;113(2):318-26
references: 2456379
references: Neurology. 2006 Feb 14;66(3):390-5
references: 16476938
references: Hum Mol Genet. 2003 Oct 15;12 Spec No 2:R229-37
references: 12952863
references: Dev Med Child Neurol. 1997 Aug;39(8):527-33
references: 9295848
references: J Pediatr. 1985 Feb;106(2):247-9
references: 3968612
references: J Autism Dev Disord. 1994 Jun;24(3):381-93
references: 8050990
references: Genet Med. 2007 Jul;9(7):427-41
references: 17666889
references: Biol Psychiatry. 2006 Jul 15;60(2):186-91
references: 16616719
references: J Autism Dev Disord. 2007 Nov;37(10):1934-40
references: 17165147
references: J Neuropsychiatry Clin Neurosci. 1993 Winter;5(1):94-101
references: 8428142
references: Ann N Y Acad Sci. 1990;600:331-40; discussion 341-2
references: 2252319
references: Int J Lang Commun Disord. 2004 Jan-Mar;39(1):45-64
references: 14660186
references: Science. 2005 Nov 18;310(5751):1184-7
references: 16293761
references: Proc Natl Acad Sci U S A. 2004 Dec 7;101(49):17316-21
references: 15563601
references: J Pediatr. 1961 Mar;58:315-20
references: 13747230
references: J Neurodev Disord. 2010 Jun;2(2):99-108
references: 20585377
references: J Child Psychol Psychiatry. 2008 Jun;49(6):576-608
references: 18489677
references: Am J Psychiatry. 2006 Dec;163(12):2148-56
references: 17151167
references: Nat Rev Neurosci. 2008 Feb;9(2):85-96
references: 18209729
references: J Med Genet. 2007 Jul;44(7):452-8
references: 17400790
references: Am J Hum Genet. 2003 Jul;73(1):131-51
references: 12796854
references: Ment Retard Dev Disabil Res Rev. 2000;6(2):148-58
references: 10899809
references: Clin Endocrinol (Oxf). 1991 Jul;35(1):21-7
references: 1889136