Molecular diagnosis of a novel heterozygous 268C-->T (R90C) mutation in TGIF gene in a fetus with holoprosencephaly and premaxillary agenesis.

We report the sonographic diagnosis and molecular analysis of holoprosencephaly (HPE) and premaxillary agenesis in a second-trimester fetus with a 46,XY karyotype. Mutational sequence analyses for the entire coding region and exon-intron boundaries of SHH, ZIC2, SIX3 and TGIF genes identified a novel heterozygous missense TGIF mutation 268C-->T (CGC-->TGC change) that predicts an Arg90Cys substitution in the homeodomain region of TGIF. The proband's parents did not carry the mutation. The present case is an example of the heterogeneous entity of the HPE spectrum and demonstrates that adjunctive molecular analyses of distinct human genes for HPE can reassure genetic counselling by elucidating the genetic pathogenesis, especially in cytogenetically normal fetuses affected with HPE.