title: Deletions involving genes WHSC1 and LETM1 may be necessary, but are not sufficient to cause Wolf-Hirschhorn Syndrome.
abstract: Wolf-Hirschhorn syndrome (WHS) is a complex genetic disorder caused by the loss of genomic material from the short arm of chromosome 4. Genotype-phenotype correlation studies indicated that the loss of genes within 4p16.3 is necessary for expression of the core features of the phenotype. Within this region, haploinsufficiency of the genes WHSC1 and LETM1 is thought to be a major contributor to the pathogenesis of WHS. We present clinical findings for three patients with relatively small (<400 kb) de novo interstitial deletions that overlap WHSC1 and LETM1. 3D facial analysis was performed for two of these patients. Based on our findings, we propose that hemizygosity of WHSC1 and LETM1 is associated with a clinical phenotype characterized by growth deficiency, feeding difficulties, and motor and speech delays. The deletion of additional genes nearby WHSC1 and LETM1 does not result in a marked increase in the severity of clinical features, arguing against their haploinsufficiency. The absence of seizures and typical WHS craniofacial findings in our cohort suggest that deletion of distinct or additional 4p16.3 genes is necessary for expression of these features. Altogether, these results show that although loss-of-function for WHSC1 and/or LETM1 contributes to some of the features of WHS, deletion of additional genes is required for the full expression of the phenotype, providing further support that WHS is a contiguous gene deletion disorder.
authors: 1] Cytogenetics Department, ARUP Laboratories, Salt Lake City, UT, USA [2] Department of Pathology, University of Utah, Salt Lake City, UT, USA.
authors: Erica F
authors: EF
authors: Andersen
authors: Department of Pediatrics, University of Utah, Salt Lake City, UT, USA.
authors: John C
authors: JC
authors: Carey
authors: Department of Genetic Medicine, Division of Medical Genetics, Seattle Children's Hospital, Seattle, WA, USA.
authors: Dawn L
authors: DL
authors: Earl
authors: Division of Clinical Genetics, Boston Children's Hospital, Boston, MA, USA.
authors: Deyanira
authors: D
authors: Corzo
authors: Molecular Medicine Unit, UCL Institute of Child Health, London, UK.
authors: Michael
authors: M
authors: Suttie
authors: Molecular Medicine Unit, UCL Institute of Child Health, London, UK.
authors: Peter
authors: P
authors: Hammond
authors: 1] Cytogenetics Department, ARUP Laboratories, Salt Lake City, UT, USA [2] Department of Pathology, University of Utah, Salt Lake City, UT, USA [3] Department of Pediatrics, University of Utah, Salt Lake City, UT, USA.
authors: Sarah T
authors: ST
authors: South
mesh_terms: D002135:Calcium-Binding Proteins / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D002894:Chromosomes, Human, Pair 4 / Q000235:genetics*; D005260:Female; D055106:Genome-Wide Association Study; D011495:Histone-Lysine N-Methyltransferase / Q000235:genetics*; D006801:Humans; D007091:Image Processing, Computer-Assisted; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D010641:Phenotype; D012097:Repressor Proteins / Q000235:genetics*; D017384:Sequence Deletion; D054877:Wolf-Hirschhorn Syndrome / Q000175:diagnosis / Q000235:genetics*
chemical_list: D002135:Calcium-Binding Proteins; C488528:LETM1 protein, human; D008565:Membrane Proteins; D012097:Repressor Proteins; D011495:Histone-Lysine N-Methyltransferase; C419586:NSD2 protein, human
references: Hum Mol Genet. 1997 Feb;6(2):317-24
references: 9063753
references: Eur J Hum Genet. 2000 Jul;8(7):519-26
references: 10909852
references: Genomics. 1999 Jul 15;59(2):203-12
references: 10409432
references: Am J Med Genet C Semin Med Genet. 2008 Nov 15;148C(4):246-51
references: 18932224
references: Hum Mol Genet. 1998 Jul;7(7):1071-82
references: 9618163
references: Dis Model Mech. 2009 May-Jun;2(5-6):283-94
references: 19383940
references: Clin Cancer Res. 2011 May 1;17(9):2919-33
references: 21385930
references: J Med Genet. 2006 Jun;43(6):478-89
references: 16199540
references: Am J Hum Genet. 2003 Mar;72(3):590-7
references: 12563561
references: J Cell Sci. 2012 Feb 1;125(Pt 3):625-33
references: 22331352
references: Am J Med Genet A. 2012 May;158A(5):996-1004
references: 22438245
references: Mol Cell. 2007 May 11;26(3):349-65
references: 17499042
references: J Biol Chem. 2004 Jul 16;279(29):30307-15
references: 15138253
references: J Med Genet. 2004 Sep;41(9):691-8
references: 15342700
references: Eur J Hum Genet. 2008 Jan;16(1):45-52
references: 17726485
references: J Med Genet. 2008 Feb;45(2):71-80
references: 17873117
references: Nature. 2009 Jul 9;460(7252):287-91
references: 19483677
references: Genomics. 2004 Feb;83(2):254-61
references: 14706454
references: Nat Rev Genet. 2012 Apr 03;13(5):343-57
references: 22473383
references: Am J Med Genet. 2001 Apr 1;99(4):338-42
references: 11252005
references: Am J Med Genet A. 2013 Oct;161A(10):2453-63
references: 23918156
references: Mol Cell Biol. 2008 Mar;28(6):2023-34
references: 18172012
references: J Biol Chem. 2010 Feb 26;285(9):6443-52
references: 20028984
references: Eur J Hum Genet. 2012 Jan;20(1):33-40
references: 21792232
references: J Immunol. 2013 Jan 15;190(2):756-63
references: 23241889
references: Brain Dev. 2005 Aug;27(5):362-4
references: 16023553
references: Am J Med Genet A. 2010 Apr;152A(4):1028-32
references: 20358621
references: Eur J Hum Genet. 2009 Jan;17(1):129-32
references: 18830230
references: Adv Pediatr. 2001;48:75-113
references: 11480768
references: Nature. 2011 Feb 3;470(7332):124-8
references: 21293379
references: Am J Med Genet C Semin Med Genet. 2008 Nov 15;148C(4):257-69
references: 18932124
references: Genomics. 1999 Sep 1;60(2):218-25
references: 10486213
references: Hum Mol Genet. 2010 Mar 15;19(6):987-1000
references: 20026556
references: Am J Respir Cell Mol Biol. 2001 Jan;24(1):90-98
references: 11152655
references: Science. 2009 Oct 2;326(5949):144-7
references: 19797662
references: Am J Med Genet C Semin Med Genet. 2008 Nov 15;148C(4):270-4
references: 18932125
references: Blood. 1998 Nov 1;92(9):3025-34
references: 9787135
references: Hum Mol Genet. 2008 Jan 15;17(2):201-14
references: 17925330
references: Hum Mol Genet. 2007 Sep 1;16(17):2061-71
references: 17606466
references: Proc Natl Acad Sci U S A. 2011 Aug 9;108(32):13130-4
references: 21788515
references: Gene. 2012 Oct 1;507(1):85-91
references: 22842548
references: Am J Med Genet A. 2005 Jul 15;136(2):175-8
references: 15948183
references: Hum Mol Genet. 2011 Oct 1;20(19):3769-78
references: 21729882
references: Am J Med Genet. 2000 Sep 18;94(3):254-61
references: 10995514
references: Blood. 2008 Mar 15;111(6):3145-54
references: 18156491
references: Hum Mol Genet. 2012 May 15;21(10):2181-93
references: 22328085
references: Am J Med Genet A. 2007 Jun 1;143A(11):1169-73
references: 17480006