Identification of novel mutations in SHH and ZIC2 in a South American (ECLAMC) population with holoprosencephaly

Holoprosencephaly (HPE) is genetically heterogeneous with four genes, SIX3, SHH, TGIF, and ZIC2 that have been identified to date and that are altered in 12% of patients. To analyze this prevalence in a South American populat ion-based sample (57 HPE cases in 244,511 live and still births or 1 in 430 0), we performed a mutational study of these genes in 30 unrelated children (26 newborns and 4 non-newborns) with HPE being ascertained by ECLAMC (Lat in American Collaborative Study of Congenital Malformations). We identified three novel mutations: two were missense mutations of the SHH gene (Cys183 --->Phe; His140->Pro); the third mutation was a 2-bp deletion in the zinc-f inger region of the ZIC2 gene. These molecular results explained 8% (2/26 n ewborn samples) of the HPE cases in this South American population-based sa mple, a proportion similar to our previously published data from a collecti on of cases.