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

a Dc Paulussen (1) , Connie Schrander-Stumpel (1) , D Tserpelis (1) , K Spee (1) , Sander Stegmann (1) , Grazia Maria Stefania Mancini (1) , Alice S Brooks (1) , J M Collée (1) , Anneke Maat-Kievit (1) , M Eh Simon (1) , Yolande van Bever (1) , Irene Stolte-Dijkstra (1) , W S Kerstjens-Frederikse (1) , J C Herkert (1) , Ton J. van Essen (1) , K D Lichtenbelt (1) , Arie van Haeringen (1) , Mei Lan Kwee (1) , A. M.A. Lachmeijer (1) , M.B. Tan-Sindhunata (1) , Merel van Maarle (1) , y H Arens (1) , Eric Smeets (1) , Christine E.M. de Die-Smulders (1) , John J Engelen (1) , Bert Smeets (1) , J Herbergs (1)

1 Department of Clinical Genetics

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 1:16000. The aetiology 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 1.45 Mb deletion including SIX2/SIX3 genes. The mutation percentage (24%) is comparable to previous reports, but we detected significantly less mutations in SHH: 3.5%vs10.7% (p=0.043) and significantly more in SIX3: 10.5%vs4.3% (p=0.018). For TGIF1 and ZIC2 mutation rate was conform earlier reports. About half of the mutations was de novo, one was a germ line mozaic. The familial mutations displayed extensive heterogeneity in clinical manifestation. Of 7 familial index patients only 2 parental carriers showed minor HPE signs, 5 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.

Mots clés: Holoprosencephaly; genotype-phenotype; mutations

a Dc Paulussen, Connie Schrander-Stumpel, D Tserpelis, K Spee, Sander Stegmann, et al.. The unfolding clinical spectrum of holoprosencephaly due to mutations in SHH, ZIC2, SIX3 and TGIF genes. European Journal of Human Genetics, 2010, ⟨10.1038/ejhg.2010.70⟩. ⟨hal-00544822⟩