Human Genetics

, Volume 119, Issue 1–2, pp 1–8

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

  • Claude Bendavid
  • Christèle Dubourg
  • Isabelle Gicquel
  • Laurent Pasquier
  • Pascale Saugier-Veber
  • Marie-Renée Durou
  • Sylvie Jaillard
  • Thierry Frébourg
  • Bassem R. Haddad
  • Catherine Henry
  • Sylvie Odent
  • Véronique David
Original Investigation

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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Copyright information

© Springer-Verlag 2005

Authors and Affiliations

  • Claude Bendavid
    • 1
    • 2
    • 3
  • Christèle Dubourg
    • 1
    • 3
  • Isabelle Gicquel
    • 1
  • Laurent Pasquier
    • 4
  • Pascale Saugier-Veber
    • 5
  • Marie-Renée Durou
    • 3
  • Sylvie Jaillard
    • 4
  • Thierry Frébourg
    • 5
  • Bassem R. Haddad
    • 2
  • Catherine Henry
    • 6
  • Sylvie Odent
    • 4
  • Véronique David
    • 1
    • 3
  1. 1.Groupe Génétique Humaine, IFR140 GFAS, CNRS UMR 6061Université de Rennes1Rennes CedexFrance
  2. 2.Institute for Molecular and Human Genetics/Lombardi Comprehensive Cancer Center, and Departments of Oncology and Obstetrics and GynecologyGeorgetown University Medical CenterWashingtonUSA
  3. 3.Laboratoire de Génétique Moléculaire et HormonologieCentre Hospitalier et Universitaire de PontchaillouRennesFrance
  4. 4.Service de Génétique MédicaleCentre Hospitalier et Universitaire de PontchaillouRennesFrance
  5. 5.Laboratoire de Génétique, INSERM U614Centre Hospitalier et UniversitaireRouenFrance
  6. 6.Laboratoire de CytogénétiqueCentre Hospitalier et Universitaire de PontchaillouRennesFrance

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