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Clinical characterization of individuals with deletions of genes in holoprosencephaly pathways by aCGH refines the phenotypic spectrum of HPE

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Abstract

Holoprosencephaly (HPE) is the most common developmental forebrain anomaly in humans. Both environmental and genetic factors have been identified to play a role in the HPE phenotype. Previous studies of the genetic bases of HPE have taken a phenotype-first approach by examining groups of patients with HPE for specific mutations or deletions in known or candidate HPE genes. In this study, we characterized the presence or absence of HPE or a microform in 136 individuals in which microarray-based comparative genomic hybridization (aCGH) identified a deletion of one of 35 HPE loci. Frank holoprosencephaly was present in 11 individuals with deletions of one of the common HPE genes SHH, ZIC2, SIX3, and TGIF1, in one individual with a deletion of the HPE8 locus at 14q13, and in one individual with a deletion of FGF8, whereas deletions of other HPE loci and candidate genes (FOXA2 and LRP2) expressed microforms of HPE. Although individuals with deletions of other HPE candidates (DISP1, LSS, HHIP, SMO, BMP4, CDON, CDC42, ACVR2A, OTX2, and WIF1) had clinically significant features, none had frank HPE or a microform. A search for significant aCGH findings in individuals referred for testing for HPE revealed a novel association of a duplication involving GSK3B at 3q13.33 with HPE or a microform, seen in two unrelated individuals.

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References

  • Aguilella C, Dubourg C, Attia-Sobol J, Vigneron J, Blayau M, Pasquier L, Lazaro L, Odent S, David V (2003) Molecular screening of the TGIF gene in holoprosencephaly: identification of two novel mutations. Hum Genet 112:131–134

    CAS  PubMed  Google Scholar 

  • Alanay Y, Aktas D, Utine E, Talim B, Onderoglu L, Caglar M, Tuncbilek E (2005) Is Dandy–Walker malformation associated with “distal 13q deletion syndrome”? Findings in a fetus supporting previous observations. Am J Med Genet A 136:265–268

    PubMed  Google Scholar 

  • Ariani F, Hayek G, Rondinella D, Artuso R, Mencarelli MA, Spanhol-Rosseto A, Pollazzon M, Buoni S, Spiga O, Ricciardi S, Meloni I, Longo I, Mari F, Broccoli V, Zappella M, Renieri A (2008) FOXG1 is responsible for the congenital variant of Rett syndrome. Am J Hum Genet 83:89–93

    CAS  PubMed  Google Scholar 

  • Bachiller D, Klingensmith J, Kemp C, Belo JA, Anderson RM, May SR, McMahon JA, McMahon AP, Harland RM, Rossant J, De Robertis EM (2000) The organizer factors Chordin and Noggin are required for mouse forebrain development. Nature 403:658–661

    CAS  PubMed  Google Scholar 

  • Bakrania P, Efthymiou M, Klein JC, Salt A, Bunyan DJ, Wyatt A, Ponting CP, Martin A, Williams S, Lindley V, Gilmore J, Restori M, Robson AG, Neveu MM, Holder GE, Collin JR, Robinson DO, Farndon P, Johansen-Berg H, Gerrelli D, Ragge NK (2008) Mutations in BMP4 cause eye, brain, and digit developmental anomalies: overlap between the BMP4 and hedgehog signaling pathways. Am J Hum Genet 82:304–319

    CAS  PubMed  Google Scholar 

  • Balci S, Teksen F, Dokmeci F, Cengiz B, Comert RB, Can B, Ozdamar S (2004) Prenatal diagnosis of Meckel-Gruber syndrome and Dandy–Walker malformation in four consecutive affected siblings, with the fourth one being diagnosed prenatally at 22 weeks of gestation. Turk J Pediatr 46:283–288

    PubMed  Google Scholar 

  • Ballif BC, Theisen A, Coppinger J, Gowans GC, Hersh JH, Madan-Khetarpal S, Schmidt KR, Tervo R, Escobar LF, Friedrich CA, McDonald M, Campbell L, Ming JE, Zackai EH, Bejjani BA, Shaffer LG (2008a) Expanding the clinical phenotype of the 3q29 microdeletion syndrome and characterization of the reciprocal microduplication. Mol Cytogenet 1:8

    PubMed  Google Scholar 

  • Ballif BC, Theisen A, McDonald-McGinn DM, Zackai EH, Hersh JH, Bejjani BA, Shaffer LG (2008b) Identification of a previously unrecognized microdeletion syndrome of 16q11.2q12.2. Clin Genet 74:469–475

    CAS  PubMed  Google Scholar 

  • Baris HN, Tan WH, Kimonis VE, Irons MB (2007) Diagnostic utility of array-based comparative genomic hybridization in a clinical setting. Am J Med Genet A 143A:2523–2533

    PubMed  Google Scholar 

  • Barr M Jr, Cohen MM Jr (2002) Autosomal recessive alobar holoprosencephaly with essentially normal faces. Am J Med Genet 112:28–30

    PubMed  Google Scholar 

  • Barr M Jr, Hanson JW, Currey K, Sharp S, Toriello H, Schmickel RD, Wilson GN (1983) Holoprosencephaly in infants of diabetic mothers. J Pediatr 102:565–568

    PubMed  Google Scholar 

  • Bejjani BA, Saleki R, Ballif BC, Rorem EA, Sundin K, Theisen A, Kashork CD, Shaffer LG (2005) Use of targeted array-based CGH for the clinical diagnosis of chromosomal imbalance: is less more? Am J Med Genet A 134:259–267

    PubMed  Google Scholar 

  • Belloni E, Muenke M, Roessler E, Traverso G, Siegel-Bartelt J, Frumkin A, Mitchell HF, Donis-Keller H, Helms C, Hing AV, Heng HH, Koop B, Martindale D, Rommens JM, Tsui LC, Scherer SW (1996) Identification of Sonic hedgehog as a candidate gene responsible for holoprosencephaly. Nat Genet 14:353–356

    CAS  PubMed  Google Scholar 

  • Bendavid C, Dubourg C, Gicquel I, Pasquier L, Saugier-Veber P, Durou MR, Jaillard S, Frebourg T, Haddad BR, Henry C, Odent S, David V (2006a) Molecular evaluation of foetuses with holoprosencephaly shows high incidence of microdeletions in the HPE genes. Hum Genet 119:1–8

    CAS  PubMed  Google Scholar 

  • Bendavid C, Haddad BR, Griffin A, Huizing M, Dubourg C, Gicquel I, Cavalli LR, Pasquier L, Shanske AL, Long R, Ouspenskaia M, Odent S, Lacbawan F, David V, Muenke M (2006b) Multicolour FISH and quantitative PCR can detect submicroscopic deletions in holoprosencephaly patients with a normal karyotype. J Med Genet 43:496–500

    CAS  PubMed  Google Scholar 

  • Bendavid C, Dubourg C, Pasquier L, Gicquel I, Le Gallou S, Mottier S, Durou MR, Henry C, Odent S, David V (2007) MLPA screening reveals novel subtelomeric rearrangements in holoprosencephaly. Hum Mutat 28:1189–1197

    CAS  PubMed  Google Scholar 

  • Bhatia N, Thiyagarajan S, Elcheva I, Saleem M, Dlugosz A, Mukhtar H, Spiegelman VS (2006) Gli2 is targeted for ubiquitination and degradation by beta-TrCP ubiquitin ligase. J Biol Chem 281:19320–19326

    CAS  PubMed  Google Scholar 

  • Breedveld GJ, van Dongen JW, Danesino C, Guala A, Percy AK, Dure LS, Harper P, Lazarou LP, van der Linde H, Joosse M, Gruters A, MacDonald ME, de Vries BB, Arts WF, Oostra BA, Krude H, Heutink P (2002) Mutations in TITF-1 are associated with benign hereditary chorea. Hum Mol Genet 11:971–979

    CAS  PubMed  Google Scholar 

  • Brown SA, Warburton D, Brown LY, Yu CY, Roeder ER, Stengel-Rutkowski S, Hennekam RC, Muenke M (1998) Holoprosencephaly due to mutations in ZIC2, a homologue of Drosophila odd-paired. Nat Genet 20:180–183

    CAS  PubMed  Google Scholar 

  • Brown KA, Pietenpol JA, Moses HL (2007) A tale of two proteins: differential roles and regulation of Smad2 and Smad3 in TGF-beta signaling. J Cell Biochem 101:9–33

    CAS  PubMed  Google Scholar 

  • Brownlees J, Irving NG, Brion JP, Gibb BJ, Wagner U, Woodgett J, Miller CC (1997) Tau phosphorylation in transgenic mice expressing glycogen synthase kinase-3beta transgenes. Neuroreport 8:3251–3255

    CAS  PubMed  Google Scholar 

  • Burke R, Nellen D, Bellotto M, Hafen E, Senti KA, Dickson BJ, Basler K (1999) Dispatched, a novel sterol-sensing domain protein dedicated to the release of cholesterol-modified hedgehog from signaling cells. Cell 99:803–815

    CAS  PubMed  Google Scholar 

  • Caruso PA, Poussaint TY, Tzika AA, Zurakowski D, Astrakas LG, Elias ER, Bay C, Irons MB (2004) MRI and 1H MRS findings in Smith-Lemli-Opitz syndrome. Neuroradiology 46:3–14

    CAS  PubMed  Google Scholar 

  • Casas KA, Mononen TK, Mikail CN, Hassed SJ, Li S, Mulvihill JJ, Lin HJ, Falk RE (2004) Chromosome 2q terminal deletion: report of 6 new patients and review of phenotype-breakpoint correlations in 66 individuals. Am J Med Genet A 130A:331–339

    PubMed  Google Scholar 

  • Chen L, Liao G, Yang L, Campbell K, Nakafuku M, Kuan CY, Zheng Y (2006) Cdc42 deficiency causes Sonic hedgehog-independent holoprosencephaly. Proc Natl Acad Sci USA 103:16520–16525

    CAS  PubMed  Google Scholar 

  • Chieri P, Iolster N (1983) Monosomy 10qter due to a balanced maternal translocation: t(10;8)(q23;p23). Clin Genet 24:147–150

    CAS  PubMed  Google Scholar 

  • Chuang PT, McMahon AP (1999) Vertebrate Hedgehog signalling modulated by induction of a Hedgehog-binding protein. Nature 397:617–621

    CAS  PubMed  Google Scholar 

  • Cohen MM Jr (1989a) Perspectives on holoprosencephaly: part I. Epidemiology, genetics, and syndromology. Teratology 40:211–235

    PubMed  Google Scholar 

  • Cohen MM Jr (1989b) Perspectives on holoprosencephaly: part III. Spectra, distinctions, continuities, and discontinuities. Am J Med Genet 34:271–288

    PubMed  Google Scholar 

  • Cohen MM Jr (2006) Holoprosencephaly: clinical, anatomic, and molecular dimensions. Birth Defects Res A Clin Mol Teratol 76:658–673

    CAS  PubMed  Google Scholar 

  • Cotarelo RP, Valero MC, Prados B, Pena A, Rodriguez L, Fano O, Marco JJ, Martinez-Frias ML, Cruces J (2008) Two new patients bearing mutations in the fukutin gene confirm the relevance of this gene in Walker-Warburg syndrome. Clin Genet 73:139–145

    CAS  PubMed  Google Scholar 

  • Croen LA, Shaw GM, Lammer EJ (1996) Holoprosencephaly: epidemiologic and clinical characteristics of a California population. Am J Med Genet 64:465–472

    CAS  PubMed  Google Scholar 

  • de la Cruz JM, Bamford RN, Burdine RD, Roessler E, Barkovich AJ, Donnai D, Schier AF, Muenke M (2002) A loss-of-function mutation in the CFC domain of TDGF1 is associated with human forebrain defects. Hum Genet 110:422–428

    Google Scholar 

  • Del Bene F, Tessmar-Raible K, Wittbrodt J (2004) Direct interaction of geminin and Six3 in eye development. Nature 427:745–749

    CAS  PubMed  Google Scholar 

  • Demyer W (1977) Holoprosencephaly (Cyclopia-arhinencephaly). In: Vinken PJ, Bruyn GW, Myrianthopoulos NC (eds) Congenital malformations of the brain and skull: part I, vol 30. North-Holland, Amsterdam, pp 431–478

    Google Scholar 

  • Demyer W, Zeman W (1963) Alobar holoprosencephaly (arhinencephaly) with median cleft lip and palate: clinical, electroencephalographic and nosologic considerations. Confin Neurol 23:1–36

    CAS  PubMed  Google Scholar 

  • Demyer W, Zeman W, Palmer CG (1964) The face predicts the brain: diagnostic significance of median facial anomalies for holoprosencephaly (Arhinencephaly). Pediatrics 34:256–263

    CAS  PubMed  Google Scholar 

  • Devriendt K, Fryns JP, Chen CP (1998) Holoprosencephaly in deletions of proximal chromosome 14q. J Med Genet 35:612

    CAS  PubMed  Google Scholar 

  • Dubourg C, Lazaro L, Pasquier L, Bendavid C, Blayau M, Le Duff F, Durou MR, Odent S, David V (2004) Molecular screening of SHH, ZIC2, SIX3, and TGIF genes in patients with features of holoprosencephaly spectrum: mutation review and genotype–phenotype correlations. Hum Mutat 24:43–51

    CAS  PubMed  Google Scholar 

  • Dubourg C, Bendavid C, Pasquier L, Henry C, Odent S, David V (2007) Holoprosencephaly. Orphanet J Rare Dis 2:8

    PubMed  Google Scholar 

  • Falardeau J, Chung WC, Beenken A, Raivio T, Plummer L, Sidis Y, Jacobson-Dickman EE, Eliseenkova AV, Ma J, Dwyer A, Quinton R, Na S, Hall JE, Huot C, Alois N, Pearce SH, Cole LW, Hughes V, Mohammadi M, Tsai P, Pitteloud N (2008) Decreased FGF8 signaling causes deficiency of gonadotropin-releasing hormone in humans and mice. J Clin Invest 118:2822–2831

    CAS  PubMed  Google Scholar 

  • Forsythe ME, Love DC, Lazarus BD, Kim EJ, Prinz WA, Ashwell G, Krause MW, Hanover JA (2006) Caenorhabditis elegans ortholog of a diabetes susceptibility locus: oga-1 (O-GlcNAcase) knockout impacts O-GlcNAc cycling, metabolism, and dauer. Proc Natl Acad Sci USA 103:11952–11957

    CAS  PubMed  Google Scholar 

  • Frame S, Cohen P (2001) GSK3 takes centre stage more than 20 years after its discovery. Biochem J 359:1–16

    CAS  PubMed  Google Scholar 

  • Galasso C, Lo-Castro A, Lalli C, Nardone AM, Gullotta F, Curatolo P (2008) Deletion 2q37: an identifiable clinical syndrome with mental retardation and autism. J Child Neurol 23:802–806

    PubMed  Google Scholar 

  • Gamerdinger U, Bosse K, Eggermann T, Kalscheuer V, Schwanitz G, Engels H (2006) First report of a partial trisomy 3q12-q23 de novo–FISH breakpoint determination and phenotypic characterization. Eur J Med Genet 49:225–234

    PubMed  Google Scholar 

  • Geng X, Speirs C, Lagutin O, Inbal A, Liu W, Solnica-Krezel L, Jeong Y, Epstein DJ, Oliver G (2008) Haploinsufficiency of Six3 fails to activate Sonic hedgehog expression in the ventral forebrain and causes holoprosencephaly. Dev Cell 15:236–247

    CAS  PubMed  Google Scholar 

  • Gripp KW, Wotton D, Edwards MC, Roessler E, Ades L, Meinecke P, Richieri-Costa A, Zackai EH, Massague J, Muenke M, Elledge SJ (2000) Mutations in TGIF cause holoprosencephaly and link NODAL signalling to human neural axis determination. Nat Genet 25:205–208

    CAS  PubMed  Google Scholar 

  • Hall JG, Pallister PD, Clarren SK, Beckwith JB, Wiglesworth FW, Fraser FC, Cho S, Benke PJ, Reed SD (1980) Congenital hypothalamic hamartoblastoma, hypopituitarism, imperforate anus and postaxial polydactyly—a new syndrome? Part I: clinical, causal, and pathogenetic considerations. Am J Med Genet 7:47–74

    CAS  PubMed  Google Scholar 

  • Han C, Lin X (2005) Shifted from Wnt to Hedgehog signaling pathways. Mol Cell 17:321–322

    CAS  PubMed  Google Scholar 

  • Hayhurst M, Gore BB, Tessier-Lavigne M, McConnell SK (2008) Ongoing sonic hedgehog signaling is required for dorsal midline formation in the developing forebrain. Dev Neurobiol 68:83–100

    PubMed  Google Scholar 

  • Houart C, Caneparo L, Heisenberg C, Barth K, Take-Uchi M, Wilson S (2002) Establishment of the telencephalon during gastrulation by local antagonism of Wnt signaling. Neuron 35:255–265

    CAS  PubMed  Google Scholar 

  • Hu YA, Gu X, Liu J, Yang Y, Yan Y, Zhao C (2008) Expression pattern of Wnt inhibitor factor 1(Wif1) during the development in mouse CNS. Gene Expr Patterns 8:515–522

    CAS  PubMed  Google Scholar 

  • Huffman KJ, Garel S, Rubenstein JL (2004) Fgf8 regulates the development of intra-neocortical projections. J Neurosci 24:8917–8923

    CAS  PubMed  Google Scholar 

  • Iwatani N, Mabe H, Devriendt K, Kodama M, Miike T (2000) Deletion of NKX2.1 gene encoding thyroid transcription factor-1 in two siblings with hypothyroidism and respiratory failure. J Pediatr 137:272–276

    CAS  PubMed  Google Scholar 

  • Jeong Y, Leskow FC, El-Jaick K, Roessler E, Muenke M, Yocum A, Dubourg C, Li X, Geng X, Oliver G, Epstein DJ (2008) Regulation of a remote Shh forebrain enhancer by the Six3 homeoprotein. Nat Genet 40:1348–1353

    CAS  PubMed  Google Scholar 

  • Jin O, Harpal K, Ang SL, Rossant J (2001) Otx2 and HNF3beta genetically interact in anterior patterning. Int J Dev Biol 45:357–365

    CAS  PubMed  Google Scholar 

  • Kamnasaran D, Chen CP, Devriendt K, Mehta L, Cox DW (2005) Defining a holoprosencephaly locus on human chromosome 14q13 and characterization of potential candidate genes. Genomics 85:608–621

    CAS  PubMed  Google Scholar 

  • Karkera JD, Izraeli S, Roessler E, Dutra A, Kirsch I, Muenke M (2002) The genomic structure, chromosomal localization, and analysis of SIL as a candidate gene for holoprosencephaly. Cytogenet Genome Res 97:62–67

    CAS  PubMed  Google Scholar 

  • Kasai K, Inaguma S, Yoneyama A, Yoshikawa K, Ikeda H (2008) SCL/TAL1 interrupting locus derepresses GLI1 from the negative control of suppressor-of-fused in pancreatic cancer cell. Cancer Res 68:7723–7729

    CAS  PubMed  Google Scholar 

  • Kelley RL, Roessler E, Hennekam RC, Feldman GL, Kosaki K, Jones MC, Palumbos JC, Muenke M (1996) Holoprosencephaly in RSH/Smith-Lemli-Opitz syndrome: does abnormal cholesterol metabolism affect the function of Sonic Hedgehog? Am J Med Genet 66:478–484

    CAS  PubMed  Google Scholar 

  • Kimura-Yoshida C, Nakano H, Okamura D, Nakao K, Yonemura S, Belo JA, Aizawa S, Matsui Y, Matsuo I (2005) Canonical Wnt signaling and its antagonist regulate anterior-posterior axis polarization by guiding cell migration in mouse visceral endoderm. Dev Cell 9:639–650

    CAS  PubMed  Google Scholar 

  • Kirchhoff M, Bisgaard AM, Stoeva R, Dimitrov B, Gillessen-Kaesbach G, Fryns JP, Rose H, Grozdanova L, Ivanov I, Keymolen K, Fagerberg C, Tranebjaerg L, Skovby F, Stefanova M (2009) Phenotype and 244 k array-CGH characterization of chromosome 13q deletions: an update of the phenotypic map of 13q21.1-qter. Am J Med Genet A 149A:894–905

    CAS  PubMed  Google Scholar 

  • Krude H, Schutz B, Biebermann H, von Moers A, Schnabel D, Neitzel H, Tonnies H, Weise D, Lafferty A, Schwarz S, DeFelice M, von Deimling A, van Landeghem F, DiLauro R, Gruters A (2002) Choreoathetosis, hypothyroidism, and pulmonary alterations due to human NKX2-1 haploinsufficiency. J Clin Invest 109:475–480

    CAS  PubMed  Google Scholar 

  • Lacbawan F, Solomon BD, Roessler E, El-Jaick K, Domene S, Velez JI, Zhou N, Hadley D, Balog JZ, Long R, Fryer A, Smith W, Omar S, McLean SD, Clarkson K, Lichty A, Clegg NJ, Delgado MR, Levey E, Stashinko E, Potocki L, Van Allen MI, Clayton-Smith J, Donnai D, Bianchi DW, Juliusson PB, Njolstad PR, Brunner HG, Carey JC, Hehr U, Musebeck J, Wieacker PF, Polstra A, Hennekam RC, van den Boogaard MJ, van Haeringen A, Paulussen A, Herbergs J, Schrander-Stumpel CT, Janecke AR, Chitayat D, Hahn J, McDonald-McGinn DM, Zackai EH, Dobyns WB, Muenke M (2009) Clinical spectrum of SIX3-associated mutations in holoprosencephaly: correlation between genotype, phenotype, and function. J Med Genet 46:389–395

    Google Scholar 

  • Lazaro L, Dubourg C, Pasquier L, Le Duff F, Blayau M, Durou MR, de la Pintiere AT, Aguilella C, David V, Odent S (2004) Phenotypic and molecular variability of the holoprosencephalic spectrum. Am J Med Genet A 129A:21–24

    PubMed  Google Scholar 

  • Lehman NL, Zaleski DH, Sanger WG, Adickes ED (2001) Holoprosencephaly associated with an apparent isolated 2q37.1→2q37.3 deletion. Am J Med Genet 100:179–181

    CAS  PubMed  Google Scholar 

  • Leoncini E, Baranello G, Orioli IM, Anneren G, Bakker M, Bianchi F, Bower C, Canfield MA, Castilla EE, Cocchi G, Correa A, De Vigan C, Doray B, Feldkamp ML, Gatt M, Irgens LM, Lowry RB, Maraschini A, Mc Donnell R, Morgan M, Mutchinick O, Poetzsch S, Riley M, Ritvanen A, Gnansia ER, Scarano G, Sipek A, Tenconi R, Mastroiacovo P (2008) Frequency of holoprosencephaly in the International Clearinghouse Birth Defects Surveillance Systems: searching for population variations. Birth Defects Res A Clin Mol Teratol 82:585–591

    CAS  PubMed  Google Scholar 

  • Liu KJ, Arron JR, Stankunas K, Crabtree GR, Longaker MT (2007) Chemical rescue of cleft palate and midline defects in conditional GSK-3beta mice. Nature 446:79–82

    CAS  PubMed  Google Scholar 

  • Lo Muzio L (2008) Nevoid basal cell carcinoma syndrome (Gorlin syndrome). Orphanet J Rare Dis 3:32

    PubMed  Google Scholar 

  • Lucas JJ, Hernandez F, Gomez-Ramos P, Moran MA, Hen R, Avila J (2001) Decreased nuclear beta-catenin, tau hyperphosphorylation and neurodegeneration in GSK-3beta conditional transgenic mice. EMBO J 20:27–39

    CAS  PubMed  Google Scholar 

  • Ma Y, Erkner A, Gong R, Yao S, Taipale J, Basler K, Beachy PA (2002) Hedgehog-mediated patterning of the mammalian embryo requires transporter-like function of dispatched. Cell 111:63–75

    CAS  PubMed  Google Scholar 

  • Madan K, Menko FH (1992) Intrachromosomal insertions: a case report and a review. Hum Genet 89:1–9

    CAS  PubMed  Google Scholar 

  • Martinelli DC, Fan CM (2007) Gas1 extends the range of Hedgehog action by facilitating its signaling. Genes Dev 21:1231–1243

    CAS  PubMed  Google Scholar 

  • Matsunaga E, Shiota K (1977) Holoprosencephaly in human embryos: epidemiologic studies of 150 cases. Teratology 16:261–272

    CAS  PubMed  Google Scholar 

  • McCarthy RA, Barth JL, Chintalapudi MR, Knaak C, Argraves WS (2002) Megalin functions as an endocytic sonic hedgehog receptor. J Biol Chem 277:25660–25667

    CAS  PubMed  Google Scholar 

  • McCormack WM Jr, Shen JJ, Curry SM, Berend SA, Kashork C, Pinar H, Potocki L, Bejjani BA (2002) Partial deletions of the long arm of chromosome 13 associated with holoprosencephaly and the Dandy–Walker malformation. Am J Med Genet 112:384–389

    PubMed  Google Scholar 

  • McMahon JA, Takada S, Zimmerman LB, Fan CM, Harland RM, McMahon AP (1998) Noggin-mediated antagonism of BMP signaling is required for growth and patterning of the neural tube and somite. Genes Dev 12:1438–1452

    CAS  PubMed  Google Scholar 

  • Menten B, Buysse K, Zahir F, Hellemans J, Hamilton SJ, Costa T, Fagerstrom C, Anadiotis G, Kingsbury D, McGillivray BC, Marra MA, Friedman JM, Speleman F, Mortier G (2007) Osteopoikilosis, short stature and mental retardation as key features of a new microdeletion syndrome on 12q14. J Med Genet 44:264–268

    CAS  PubMed  Google Scholar 

  • Meyers EN, Lewandoski M, Martin GR (1998) An Fgf8 mutant allelic series generated by Cre- and Flp-mediated recombination. Nat Genet 18:136–141

    CAS  PubMed  Google Scholar 

  • Ming JE, Muenke M (2002) Multiple hits during early embryonic development: digenic diseases and holoprosencephaly. Am J Hum Genet 71:1017–1032

    CAS  PubMed  Google Scholar 

  • Ming JE, Kaupas ME, Roessler E, Brunner HG, Golabi M, Tekin M, Stratton RF, Sujansky E, Bale SJ, Muenke M (2002) Mutations in PATCHED-1, the receptor for SONIC HEDGEHOG, are associated with holoprosencephaly. Hum Genet 110:297–301

    CAS  PubMed  Google Scholar 

  • Monsoro-Burq A, Le Douarin NM (2001) BMP4 plays a key role in left–right patterning in chick embryos by maintaining Sonic Hedgehog asymmetry. Mol Cell 7:789–799

    CAS  PubMed  Google Scholar 

  • Muenke M, Beachy PA (2001) Holoprosencephaly. In: Scriver CR, Beaudet AL, Sly WS, Valle D (eds) The metabolic & molecular bases of inherited disease, 8th edn. McGraw-Hill, New York, pp 6203–6230

    Google Scholar 

  • Muenke M, Bone LJ, Mitchell HF, Hart I, Walton K, Hall-Johnson K, Ippel EF, Dietz-Band J, Kvaloy K, Fan CM et al (1995) Physical mapping of the holoprosencephaly critical region in 21q22.3, exclusion of SIM2 as a candidate gene for holoprosencephaly, and mapping of SIM2 to a region of chromosome 21 important for Down syndrome. Am J Hum Genet 57:1074–1079

    CAS  PubMed  Google Scholar 

  • Mulcahy MT, Pemberton PJ, Sprague P (1979) Trisomy 3q : two clinically similar but cytogenetically different cases. Ann Genet 22:217–220

    CAS  PubMed  Google Scholar 

  • Nanni L, Ming JE, Bocian M, Steinhaus K, Bianchi DW, Die-Smulders C, Giannotti A, Imaizumi K, Jones KL, Campo MD, Martin RA, Meinecke P, Pierpont ME, Robin NH, Young ID, Roessler E, Muenke M (1999) The mutational spectrum of the sonic hedgehog gene in holoprosencephaly: SHH mutations cause a significant proportion of autosomal dominant holoprosencephaly. Hum Mol Genet 8:2479–2488

    CAS  PubMed  Google Scholar 

  • Nomura M, Li E (1998) Smad2 role in mesoderm formation, left–right patterning and craniofacial development. Nature 393:786–790

    CAS  PubMed  Google Scholar 

  • Novy M, Pohn R, Andorfer P, Novy-Weiland T, Galos B, Schwarzmayr L, Rotheneder H (2005) EAPP, a novel E2F binding protein that modulates E2F-dependent transcription. Mol Biol Cell 16:2181–2190

    CAS  PubMed  Google Scholar 

  • Odent S, Le Marec B, Munnich A, Le Merrer M, Bonaiti-Pellie C (1998) Segregation analysis in nonsyndromic holoprosencephaly. Am J Med Genet 77:139–143

    CAS  PubMed  Google Scholar 

  • Okada T, Okumura Y, Motoyama J, Ogawa M (2008) FGF8 signaling patterns the telencephalic midline by regulating putative key factors of midline development. Dev Biol 320:92–101

    CAS  PubMed  Google Scholar 

  • Olsen CL, Hughes JP, Youngblood LG, Sharpe-Stimac M (1997) Epidemiology of holoprosencephaly and phenotypic characteristics of affected children: New York State, 1984–1989. Am J Med Genet 73:217–226

    CAS  PubMed  Google Scholar 

  • Parks WT, Frank DB, Huff C, Renfrew Haft C, Martin J, Meng X, de Caestecker MP, McNally JG, Reddi A, Taylor SI, Roberts AB, Wang T, Lechleider RJ (2001) Sorting nexin 6, a novel SNX, interacts with the transforming growth factor-beta family of receptor serine-threonine kinases. J Biol Chem 276:19332–19339

    CAS  PubMed  Google Scholar 

  • Pasquier L, Dubourg C, Blayau M, Lazaro L, Le Marec B, David V, Odent S (2000) A new mutation in the six-domain of SIX3 gene causes holoprosencephaly. Eur J Hum Genet 8:797–800

    CAS  PubMed  Google Scholar 

  • Petek E, Plecko-Startinig B, Windpassinger C, Egger H, Wagner K, Kroisel PM (2003) Molecular characterisation of a 3.5 Mb interstitial 14q deletion in a child with several phenotypic anomalies. J Med Genet 40:e47

    CAS  PubMed  Google Scholar 

  • Petryk A, Anderson RM, Jarcho MP, Leaf I, Carlson CS, Klingensmith J, Shawlot W, O’Connor MB (2004) The mammalian twisted gastrulation gene functions in foregut and craniofacial development. Dev Biol 267:374–386

    CAS  PubMed  Google Scholar 

  • Pires A, Ramos L, Venancio M, Rei AI, Castedo S, Saraiva J (2005) Prenatal foetal diagnosis of partial trisomy 3q and monosomy 13p due to a maternal balanced rearrangement. Prenat Diagn 25:292–295

    PubMed  Google Scholar 

  • Rahimov F, Ribeiro LA, de Miranda E, Richieri-Costa A, Murray JC (2006) GLI2 mutations in four Brazilian patients: how wide is the phenotypic spectrum? Am J Med Genet A 140:2571–2576

    PubMed  Google Scholar 

  • Rastegar S, Albert S, Le Roux I, Fischer N, Blader P, Muller F, Strahle U (2002) A floor plate enhancer of the zebrafish netrin1 gene requires Cyclops (Nodal) signalling and the winged helix transcription factor FoxA2. Dev Biol 252:1–14

    CAS  PubMed  Google Scholar 

  • Reiter JF, Skarnes WC (2006) Tectonic, a novel regulator of the Hedgehog pathway required for both activation and inhibition. Genes Dev 20:22–27

    CAS  PubMed  Google Scholar 

  • Riobo NA, Lu K, Ai X, Haines GM, Emerson CP Jr (2006) Phosphoinositide 3-kinase and Akt are essential for Sonic Hedgehog signaling. Proc Natl Acad Sci USA 103:4505–4510

    CAS  PubMed  Google Scholar 

  • Roessler E, Belloni E, Gaudenz K, Jay P, Berta P, Scherer SW, Tsui LC, Muenke M (1996) Mutations in the human Sonic Hedgehog gene cause holoprosencephaly. Nat Genet 14:357–360

    CAS  PubMed  Google Scholar 

  • Roessler E, Ward DE, Gaudenz K, Belloni E, Scherer SW, Donnai D, Siegel-Bartelt J, Tsui LC, Muenke M (1997) Cytogenetic rearrangements involving the loss of the Sonic Hedgehog gene at 7q36 cause holoprosencephaly. Hum Genet 100:172–181

    CAS  PubMed  Google Scholar 

  • Roessler E, Mittaz L, Du Y, Scott HS, Chang J, Rossier C, Guipponi M, Matsuda SP, Muenke M, Antonarakis SE (1999) Structure of the human Lanosterol synthase gene and its analysis as a candidate for holoprosencephaly (HPE1). Hum Genet 105:489–495

    CAS  PubMed  Google Scholar 

  • Roessler E, Du Y, Glinka A, Dutra A, Niehrs C, Muenke M (2000) The genomic structure, chromosome location, and analysis of the human DKK1 head inducer gene as a candidate for holoprosencephaly. Cytogenet Cell Genet 89:220–224

    CAS  PubMed  Google Scholar 

  • Roessler E, Du YZ, Mullor JL, Casas E, Allen WP, Gillessen-Kaesbach G, Roeder ER, Ming JE, Ruiz i Altaba A, Muenke M (2003) Loss-of-function mutations in the human GLI2 gene are associated with pituitary anomalies and holoprosencephaly-like features. Proc Natl Acad Sci USA 100:13424–13429

    CAS  PubMed  Google Scholar 

  • Roessler E, Ouspenskaia MV, Karkera JD, Velez JI, Kantipong A, Lacbawan F, Bowers P, Belmont JW, Towbin JA, Goldmuntz E, Feldman B, Muenke M (2008) Reduced NODAL signaling strength via mutation of several pathway members including FOXH1 is linked to human heart defects and holoprosencephaly. Am J Hum Genet 83:18–29

    CAS  PubMed  Google Scholar 

  • Roessler E, Ma Y, Ouspenskaia MV, Lacbawan F, Bendavid C, Dubourg C, Beachy PA, Muenke M (2009) Truncating loss-of-function mutations of DISP1 contribute to holoprosencephaly-like microform features in humans. Hum Genet 125:393–400

    Google Scholar 

  • Salazar D, Rosenfeld W, Verma RS, Jhaveri RC, Dosik H (1979) Partial trisomy of chromosome 3 (3q12 leads to qter) owing to 3q/18p translocation. A trisomy 3q syndrome. Am J Dis Child 133:1006–1008

    CAS  PubMed  Google Scholar 

  • Schinzel A (2001) Catalogue of unbalanced chromosome aberrations in man, 2nd edn. Walter de Gruyter, Berlin

    Google Scholar 

  • Seppala M, Depew MJ, Martinelli DC, Fan CM, Sharpe PT, Cobourne MT (2007) Gas1 is a modifier for holoprosencephaly and genetically interacts with sonic hedgehog. J Clin Invest 117:1575–1584

    CAS  PubMed  Google Scholar 

  • Shaffer LG, McCaskill C, Han JY, Choo KH, Cutillo DM, Donnenfeld AE, Weiss L, Van Dyke DL (1994) Molecular characterization of de novo secondary trisomy 13. Am J Hum Genet 55:968–974

    CAS  PubMed  Google Scholar 

  • Shaffer LG, Theisen A, Bejjani BA, Ballif BC, Aylsworth AS, Lim C, McDonald M, Ellison JW, Kostiner D, Saitta S, Shaikh T (2007) The discovery of microdeletion syndromes in the post-genomic era: review of the methodology and characterization of a new 1q41q42 microdeletion syndrome. Genet Med 9:607–616

    CAS  PubMed  Google Scholar 

  • Song J, Oh SP, Schrewe H, Nomura M, Lei H, Okano M, Gridley T, Li E (1999) The type II activin receptors are essential for egg cylinder growth, gastrulation, and rostral head development in mice. Dev Biol 213:157–169

    CAS  PubMed  Google Scholar 

  • Storm EE, Garel S, Borello U, Hebert JM, Martinez S, McConnell SK, Martin GR, Rubenstein JL (2006) Dose-dependent functions of Fgf8 in regulating telencephalic patterning centers. Development 133:1831–1844

    CAS  PubMed  Google Scholar 

  • Tian H, Jeong J, Harfe BD, Tabin CJ, McMahon AP (2005) Mouse Disp1 is required in sonic hedgehog-expressing cells for paracrine activity of the cholesterol-modified ligand. Development 132:133–142

    CAS  PubMed  Google Scholar 

  • van de Vooren MJ, Planteydt HT, Hagemeijer A, Peters-Slough MF, Timmerman MJ (1984) Familial balanced insertion (5;10) and monosomy and trisomy (10) (q24.2–q25.3). Clin Genet 25:52–58

    Article  PubMed  Google Scholar 

  • Wallis DE, Roessler E, Hehr U, Nanni L, Wiltshire T, Richieri-Costa A, Gillessen-Kaesbach G, Zackai EH, Rommens J, Muenke M (1999) Mutations in the homeodomain of the human SIX3 gene cause holoprosencephaly. Nat Genet 22:196–198

    CAS  PubMed  Google Scholar 

  • Warr N, Powles-Glover N, Chappell A, Robson J, Norris D, Arkell RM (2008) Zic2-associated holoprosencephaly is caused by a transient defect in the organizer region during gastrulation. Hum Mol Genet 17:2986–2996

    CAS  PubMed  Google Scholar 

  • Willnow TE, Hilpert J, Armstrong SA, Rohlmann A, Hammer RE, Burns DK, Herz J (1996) Defective forebrain development in mice lacking gp330/megalin. Proc Natl Acad Sci USA 93:8460–8464

    CAS  PubMed  Google Scholar 

  • Yamakawa K, Mitchell S, Hubert R, Chen XN, Colbern S, Huo YK, Gadomski C, Kim UJ, Korenberg JR (1995) Isolation and characterization of a candidate gene for progressive myoclonus epilepsy on 21q22.3. Hum Mol Genet 4:709–716

    CAS  PubMed  Google Scholar 

  • Zhang XM, Ramalho-Santos M, McMahon AP (2001) Smoothened mutants reveal redundant roles for Shh and Ihh signaling including regulation of L/R asymmetry by the mouse node. Cell 105:781–792

    CAS  PubMed  Google Scholar 

  • Zhang W, Kang JS, Cole F, Yi MJ, Krauss RS (2006) Cdo functions at multiple points in the Sonic Hedgehog pathway, and Cdo-deficient mice accurately model human holoprosencephaly. Dev Cell 10:657–665

    CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. Signature Genomic Laboratories, 2820 N. Astor St, Spokane, WA, 99207, USA

    Jill A. Rosenfeld, Blake C. Ballif, Bassem A. Bejjani, Beth S. Torchia & Lisa G. Shaffer

  2. Department of Pediatrics and Genetics, University of Michigan Medical Center, Ann Arbor, MI, USA

    Donna M. Martin

  3. Department of Pediatrics and Genetics, University of North Carolina, Chapel Hill, NC, USA

    Arthur S. Aylsworth

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  1. Jill A. Rosenfeld
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  2. Blake C. Ballif
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  3. Donna M. Martin
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  5. Bassem A. Bejjani
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  6. Beth S. Torchia
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  7. Lisa G. Shaffer
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Correspondence to Lisa G. Shaffer.

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Rosenfeld, J.A., Ballif, B.C., Martin, D.M. et al. Clinical characterization of individuals with deletions of genes in holoprosencephaly pathways by aCGH refines the phenotypic spectrum of HPE. Hum Genet 127, 421–440 (2010). https://doi.org/10.1007/s00439-009-0778-7

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