Abstract
Holoprosencephaly (HPE) is the most common developmental defect affecting the forebrain and midface in humans. The aetiology of HPE is highly heterogeneous and includes both environmental and genetic factors. Here we report on a boy with mild mental retardation, lobar HPE, epilepsy, mild pyramidal syndrome of the legs, ventricular septal defect, vesicoureteral reflux, preaxial polydactyly, and facial dysmorphisms. Genome-wide tiling path resolution array based comparative genomic hybridisation (array CGH) revealed a de novo copy-number gain at 5q35.1 of 1.24 Mb. Additional multiplex ligation-dependent probe amplification screening of a cohort of 31 patients with HPE for copy-number changes at the 5q35.1 locus did not reveal any additional genomic anomalies. This report defines a novel 1.24 Mb critical interval for HPE and preaxial polydactyly at 5q35.1. The duplicated region encompasses seven genes: RANBP17, TLX3, NPM1, FGF18, FBXW11, STK10, and DC-UbP. Since FBXW11 is relatively highly expressed in fetal brain and is directly involved in proteolytic processing of GLI3, we propose FBXW11 as the most likely candidate gene for the HPE and prexial polydactyly phenotype. Additional research is needed to further establish the role of genes from the 5q35.1 region in brain and limb development and to determine the prevalence of copy number gain in the 5q35.1 region among HPE patients.
Log in or create a free account to read this content
Gain free access to this article, as well as selected content from this journal and more on nature.com
or
References
Aza-Blanc P, Ramirez-Weber FA, Laget MP, Schwartz C, Kornberg TB (1997) Proteolysis that is inhibited by hedgehog targets Cubitus interruptus protein to the nucleus and converts it to a repressor. Cell 89:1043–1053
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
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 (2006) Multicolor FISH and quantitative PCR can detect submicroscopic deletions in holoprosencephaly patients with a normal karyotype. J Med Genet (in press) Published Online First: 30 September 2005. doi:10.1136/jmg.2005.037176
De Vries BB, Pfundt R, Leisink M, Koolen DA, Vissers LE, Janssen IM, Reijmersdal S, Nillesen WM, Huys EH, Leeuw N, Smeets D, Sistermans EA, Feuth T, van Ravenswaaij-Arts CM, van Kessel AG, Schoenmakers EF, Brunner HG, Veltman JA (2005) Diagnostic genome profiling in mental retardation. Am J Hum Genet 77:606–616
De Mollerat X, Gurrieri F, Morgan CT, Sangiorgi E, Everman DB, Gaspari P, Amiel J, Bamshad MJ, Lyle R, Blouin JL, Allanson JE, Le MB, Wilson M, Braverman NE, Radhakrishna U, ozier-Blanchet C, Abbott A, Elghouzzi V, Antonarakis S, Stevenson RE, Munnich A, Neri G, Schwartz CE (2003) A genomic rearrangement resulting in a tandem duplication is associated with split hand-split foot malformation 3 (SHFM3) at 10q24. Hum Mol Genet 12:1959–1971
Dubourg C, Lazaro L, Pasquier L, Bendavid C, Blayau M, Le DF, 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
Groen SE, Drewes JG, de Boer EG, Hoovers JM, Hennekam RC (1998) Repeated unbalanced offspring due to a familial translocation involving chromosomes 5 and 6. Am J Med Genet 80:448–453
Kipreos ET, Pagano M (2000) The F-box protein family. Genome Biol 1:3002.1–3002.7
Koolen DA, Nillesen WM, Versteeg MH, Merkx GF, Knoers NV, Kets M, Vermeer S, van Ravenswaaij CM, de Kovel CG, Brunner HG, Smeets D, De Vries BB, Sistermans EA (2004) Screening for subtelomeric rearrangements in 210 patients with unexplained mental retardation using multiplex ligation dependent probe amplification (MLPA). J Med Genet 41:892–899
Lazjuk GI, Lurie IW, Kirillova IA, Zaletajev DV, Gurevich DB, Shved IA, Ostrovskaya TI (1985) Partial trisomy 5q and partial monosomy 5q within the same family. Clin Genet 28:122–129
Lettice LA, Horikoshi T, Heaney SJ, van Baren MJ, van der Linde HC, Breedveld GJ, Joosse M, Akarsu N, Oostra BA, Endo N, Shibata M, Suzuki M, Takahashi E, Shinka T, Nakahori Y, Ayusawa D, Nakabayashi K, Scherer SW, Heutink P, Hill RE, Noji S (2002) Disruption of a long-range cis-acting regulator for Shh causes preaxial polydactyly. Proc Natl Acad Sci USA 99:7548–7553
Levy B, Dunn TM, Kern JH, Hirschhorn K, Kardon NB (2002) Delineation of the dup5q phenotype by molecular cytogenetic analysis in a patient with dup5q/del 5p (cri du chat). Am J Med Genet 108:192–197
Ming JE, Roessler E, Muenke M (1998) Human developmental disorders and the Sonic hedgehog pathway. Mol Med Today 4:343–349
Rodewald A, Zankl M, Gley EO, Zang KD (1980) Partial trisomy 5q: three different phenotypes depending on different duplication segments. Hum Genet 55:191–198
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
Roessler E, Du YZ, Mullor JL, Casas E, Allen WP, Gillessen-Kaesbach G, Roeder ER, Ming JE, 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
Schinzel A (2003) Catalogue of unbalanced chromosome aberrations in Man, 2nd edn. de Gruyter, Berlin
Schouten JP, McElgunn CJ, Waaijer R, Zwijnenburg D, Diepvens F, Pals G (2002) Relative quantification of 40 nucleic acid sequences by multiplex ligation-dependent probe amplification. Nucleic Acids Res 30:e57
Schroeder HW Jr, Forbes S, Mack L, Davis S, Norwood TH (1986) Recombination aneusomy of chromosome 5 associated with multiple severe congenital malformations. Clin Genet 30:285–292
Te Welscher P, Zuniga A, Kuijper S, Drenth T, Goedemans HJ, Meijlink F, Zeller R (2002) Progression of vertebrate limb development through SHH-mediated counteraction of GLI3. Science 298:827–830
Villavicencio EH, Walterhouse DO, Iannaccone PM (2000) The sonic hedgehog-patched-gli pathway in human development and disease. Am J Hum Genet 67:1047–1054
Wallis D, Muenke M (2000) Mutations in holoprosencephaly. Hum Mutat 16:99–108
Wang B, Li Y (2006) Evidence for the direct involvement of {beta}TrCP in Gli3 protein processing. Proc Natl Acad Sci USA 103:33–38
Acknowledgements
We thank the patient and his parents for their cooperation. We also thank M.H.A. Ruiterkamp–Versteeg for skilled technical assistance. This work was supported by grants from The Netherlands Organisation for Health Research and Development [ZonMW 907-00-058 (B.B.A.dV.); ZonMW 920-03-338 (D.A.K.); ZonMW 912-04-047 (H.G.B. & J.A.V.)].
Author information
Authors and Affiliations
Corresponding author
Electronic supplementary material
Rights and permissions
About this article
Cite this article
Koolen, D.A., Herbergs, J., Veltman, J.A. et al. Holoprosencephaly and preaxial polydactyly associated with a 1.24 Mb duplication encompassing FBXW11 at 5q35.1. J Hum Genet 51, 721–726 (2006). https://doi.org/10.1007/s10038-006-0010-8
Received:
Accepted:
Published:
Issue date:
DOI: https://doi.org/10.1007/s10038-006-0010-8
