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Molecular evaluation of foetuses with holoprosencephaly shows high incidence of microdeletions in the HPE genes

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Abstract

Holoprosencephaly (HPE), the most common structural malformation of the forebrain in humans, can be detected early during pregnancy using prenatal ultrasonography . Among foetuses with a normal karyotype, 14% have mutations in the four main HPE genes (SHH, ZIC2, SIX3 and TGIF). Genomic rearrangements have now been implicated in many genetic diseases, so we hypothesized that microdeletions in the major HPE genes may also be common in HPE foetuses with severe phenotype or other associated malformations. We screened the DNA obtained from 94 HPE foetuses with a normal karyotype for the presence of microdeletions involving the four major HPE genes (SHH, ZIC2, SIX3 and TGIF). Thirteen of the foetuses had a point mutation in one of the 4 genes and 81 had no known mutations. Quantitative multiplex PCR of short fluorescent fragments (QMPSF) analysis was used for rapid determination of HPE genes copy numbers and the identified microdeletions were confirmed by real time quantitative PCR, or fluorescent in situ hybridization (FISH) (if a cell line was available). Microdeletions were detected in 8 of 94 foetuses (8.5%) (2 in SHH, 2 in SIX3, 3 in ZIC2 and 1 in TGIF genes), and only among the 81 foetuses with a normal karyotype and no point mutations. These data suggest that microdeletions in the four main HPE genes are a common cause of prenatal HPE, as well as point mutations, and increase the total diagnosis rate close to ≈22.3% of foetuses with normal karyotype. Detection can be achieved by the QMPSF testing method that proved to be efficient for testing several genes in a single assay.

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References

  • Ariyurek Y, Lantinga-van Leeuwen I, Spruit L, Ravine D, Breuning MH, Peters DJ (2004) Large deletions in the polycystic kidney disease 1 (PKD1) gene. Hum Mutat 23: 99

    Article  PubMed  Google Scholar 

  • Audrezet MP, Chen JM, Raguenes O, Chuzhanova N, Giteau K, Le Marechal C, Quere I, Cooper DN, Ferec C (2004) Genomic rearrangements in the CFTR gene: extensive allelic heterogeneity and diverse mutational mechanisms. Hum Mutat 23:343–357

    Article  PubMed  CAS  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

    Article  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

    Article  PubMed  CAS  Google Scholar 

  • Bendavid C, Haddad BR, Griffin A, Huizing M, Dubourg C, Gicquel I, Cavalli LR, Pasquier L, Long R, Ouspenskaia M, Odent S, Lacbawan F, David V, Muenke M (2005) Multicolor FISH and quantitative PCR can detect submicroscopic deletions in holoprosencephaly patients with a normal karyotype. J Med Genet Sep 30-Epub ahead of print

  • Bendavid C, Kleta R, Long R, Ouspenskaia M, Muenke M, Haddad BR, Gahl WA (2004) FISH diagnosis of the common 57-kb deletion in CTNS causing cystinosis. Hum Genet 115:510–514

    Article  PubMed  CAS  Google Scholar 

  • Bougeard G, Brugieres L, Chompret A, Gesta P, Charbonnier F, Valent A, Martin C, Raux G, Feunteun J, Bressac-de Paillerets B, Frebourg T (2003) Screening for TP53 rearrangements in families with the Li-Fraumeni syndrome reveals a complete deletion of the TP53 gene. Oncogene 22:840–846

    Article  PubMed  CAS  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

    Article  PubMed  CAS  Google Scholar 

  • Byrne PJ, Silver MM, Gilbert JM, Cadera W, Tanswell AK (1987) Cyclopia and congenital cytomegalovirus infection. Am J Med Genet 28:61–65

    Article  PubMed  CAS  Google Scholar 

  • Casilli F, Di Rocco ZC, Gad S, Tournier I, Stoppa-Lyonnet D, Frebourg T, Tosi M (2002) Rapid detection of novel BRCA1 rearrangements in high-risk breast-ovarian cancer families using multiplex PCR of short fluorescent fragments. Hum Mutat 20:218–226

    Article  PubMed  CAS  Google Scholar 

  • Charbonnier F, Olschwang S, Wang Q, Boisson C, Martin C, Buisine MP, Puisieux A, Frebourg T (2002) MSH2 in contrast to MLH1 and MSH6 is frequently inactivated by exonic and promoter rearrangements in hereditary nonpolyposis colorectal cancer. Cancer Res 62:848–853

    PubMed  CAS  Google Scholar 

  • Charbonnier F, Raux G, Wang Q, Drouot N, Cordier F, Limacher JM, Saurin JC, Puisieux A, Olschwang S, Frebourg T (2000) Detection of exon deletions and duplications of the mismatch repair genes in hereditary nonpolyposis colorectal cancer families using multiplex polymerase chain reaction of short fluorescent fragments. Cancer Res 60:2760–2763

    PubMed  CAS  Google Scholar 

  • Chung DC, Smith AP, Louis DN, Graeme-Cook F, Warshaw AL, Arnold A (1997) Analysis of the retinoblastoma tumour suppressor gene in pancreatic endocrine tumours. Clin Endocrinol (Oxf) 47:523–528

    Article  CAS  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

    Article  PubMed  CAS  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

    PubMed  CAS  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

    Article  PubMed  CAS  Google Scholar 

  • Edison R, Muenke M (2003) The interplay of genetic and environmental factors in craniofacial morphogenesis: holoprosencephaly and the role of cholesterol. Congenit Anom (Kyoto) 43:1–21

    Article  CAS  Google Scholar 

  • Edison RJ, Muenke M (2004) Central nervous system and limb anomalies in case reports of first-trimester statin exposure. N Engl J Med 350:1579–1582

    Article  PubMed  CAS  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

    Article  PubMed  CAS  Google Scholar 

  • Haddad B, Pabon-Pena CR, Young H, Sun WH (1998) Assignment1 of STAT1 to human chromosome 2q32 by FISH and radiation hybrids. Cytogenet Cell Genet 83:58–59

    Article  PubMed  CAS  Google Scholar 

  • Iafrate AJ, Feuk L, Rivera MN, Listewnik ML, Donahoe PK, Qi Y, Scherer SW, Lee C (2004) Detection of large-scale variation in the human genome. Nat Genet 36:949–951

    Article  PubMed  CAS  Google Scholar 

  • Lammer EJ, Chen DT, Hoar RM, Agnish ND, Benke PJ, Braun JT, Curry CJ, Fernhoff PM, Grix AW Jr, Lott IT, et al (1985) Retinoic acid embryopathy. N Engl J Med 313:837–841

    Article  PubMed  CAS  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 129:21–24

    Article  PubMed  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  • Muenke M, Beachy PA (2001) Holoprosencephaly, 8th edn. McGraw Hill, New York

  • 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

    Article  PubMed  CAS  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

    Article  PubMed  CAS  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

    Article  PubMed  CAS  Google Scholar 

  • Roessler E, Muenke M (1998) Holoprosencephaly: a paradigm for the complex genetics of brain development. J Inherit Metab Dis 21: 481–497

    Article  PubMed  CAS  Google Scholar 

  • Ronen GM, Andrews WL (1991) Holoprosencephaly as a possible embryonic alcohol effect. Am J Med Genet 40: 151–154

    Article  PubMed  CAS  Google Scholar 

  • Rosa F (1995) Holoprosencephaly and antiepileptic exposures. Teratology 51:230

    Article  PubMed  CAS  Google Scholar 

  • Schmidt C, Vester U, Wagner CA, Lahme S, Hesse A, Hoyer P, Lang F, Zerres K, Eggermann T (2003) Significant contribution of genomic rearrangements in SLC3A1 and SLC7A9 to the etiology of cystinuria. Kidney Int 64:1564–1572

    Article  PubMed  CAS  Google Scholar 

  • Sebat J, Lakshmi B, Troge J, Alexander J, Young J, Lundin P, Maner S, Massa H, Walker M, Chi M, Navin N, Lucito R, Healy J, Hicks J, Ye K, Reiner A, Gilliam TC, Trask B, Patterson N, Zetterberg A, Wigler M (2004) Large-scale copy number polymorphism in the human genome. Science 305:525–528

    Article  PubMed  CAS  Google Scholar 

  • Sonigo PC, Rypens FF, Carteret M, Delezoide AL, Brunelle FO (1998) MR imaging of fetal cerebral anomalies. Pediatr Radiol 28:212–222

    Article  PubMed  CAS  Google Scholar 

  • Toma P, Costa A, Magnano GM, Cariati M, Lituania M (1990) Holoprosencephaly: prenatal diagnosis by sonography and magnetic resonance imaging. Prenat Diagn 10:429–436

    Article  PubMed  CAS  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

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

This research was supported by grants from the Region Bretagne (A2CAL8), Centre Hospitalier et Universitaire de Rennes (Concours post Internat), GIS Institut des Maladies rares and PHRC Région Bretagne.

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Correspondence to Véronique David.

Additional information

Databases: SHH - OMIM: 600725; GenBank: NM_000193.2, ZIC2 - OMIM: 603073; GenBank: AF104902.1, SIX3 - OMIM: 603714; GenBank: NM_005413.1, TGIF - OMIM: 602630; GenBank: NM_003244.2, On-line Mendelian Inheritance in Man (OMIM), http://www.ncbi.nlm.nih.gov/omim/, UCSC (http://www.genome.ucsc.edu/), Ensembl (http://www.ensembl.org/), Database of genomic variants (http://projects.tcag.ca/variation/genomeView.html)

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Bendavid, C., Dubourg, C., Gicquel, I. et al. Molecular evaluation of foetuses with holoprosencephaly shows high incidence of microdeletions in the HPE genes. Hum Genet 119, 1–8 (2006). https://doi.org/10.1007/s00439-005-0097-6

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  • DOI: https://doi.org/10.1007/s00439-005-0097-6

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