The unfolding clinical spectrum of holoprosencephaly due to mutations in SHH, ZIC2, SIX3 and TGIF genes

Aimee D. C. Paulussen*, Constance T. R. M. Schrander-Stumpel, Demis C. J. Tserpelis, Matteus K. M. Spee, Alexander P. A. Stegmann, Grazia M. S. Mancini, Alice S. Brooks, Margriet J. Collee, Anneke Maat-Kievit, Marleen E. H. Simon, Yolande van Bever, Irene Stolte-Dijkstra, Wilhelmina S. Kerstjens-Frederikse, Johanna C. Herkert, Anthonie J. van Essen, Klaske D. Lichtenbelt, Arie van Haeringen, Mei L. Kwee, Augusta M. A. Lachmeijer, Gita M. B. Tan-SindhunataMerel C. van Maarle, Yvonne H. J. M. Arens, Eric E. J. G. L. Smeets, Christine E. M. de Die-Smulders, John J. M. Engelen, Hubertus J. M. Smeets, Jos Herbergs

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review


Holoprosencephaly is a severe malformation of the brain characterized by abnormal formation and separation of the developing central nervous system. The prevalence is 1:250 during early embryogenesis, the live-born prevalence is 1:16 000. The etiology of HPE is extremely heterogeneous and can be teratogenic or genetic. We screened four known HPE genes in a Dutch cohort of 86 non-syndromic HPE index cases, including 53 family members. We detected 21 mutations (24.4%), 3 in SHH, 9 in ZIC2 and 9 in SIX3. Eight mutations involved amino-acid substitutions, 7 ins/del mutations, 1 frame-shift, 3 identical poly-alanine tract expansions and 2 gene deletions. Pathogenicity of mutations was presumed based on de novo character, predicted non-functionality of mutated proteins, segregation of mutations with affected family-members or combinations of these features. Two mutations were reported previously. SNP array confirmed detected deletions; one spanning the ZIC2/ZIC5 genes (approx. 100 kb) the other a 1.45Mb deletion including SIX2/SIX3 genes. The mutation percentage (24%) is comparable with previous reports, but we detected significantly less mutations in SHH: 3.5 vs 10.7% (P = 0.043) and significantly more in SIX3: 10.5 vs 4.3% (P = 0.018). For TGIF1 and ZIC2 mutation the rate was in conformity with earlier reports. About half of the mutations were de novo, one was a germ line mosaic. The familial mutations displayed extensive heterogeneity in clinical manifestation. Of seven familial index patients only two parental carriers showed minor HPE signs, five were completely asymptomatic. Therefore, each novel mutation should be considered as a risk factor for clinically manifest HPE, with the caveat of reduced clinical penetrance. European Journal of Human Genetics (2010) 18, 999-1005; doi:10.1038/ejhg.2010.70; published online 9 June 2010
Original languageEnglish
Pages (from-to)999-1005
JournalEuropean Journal of Human Genetics
Issue number9
Publication statusPublished - 10 Sept 2010


  • Holoprosencephaly
  • SHH
  • SIX3
  • ZIC2
  • TGIF
  • genotype-phenotype

Cite this