Mercier et al. (2011) reported the clinical and molecular features of a large European series of 645 HPE probands (51% fetuses) and 699 relatives in order to examine genotype/phenotype correlations. The facial features were assigned to 4 categories: ... Mercier et al. (2011) reported the clinical and molecular features of a large European series of 645 HPE probands (51% fetuses) and 699 relatives in order to examine genotype/phenotype correlations. The facial features were assigned to 4 categories: categories 1 and 2 had severe facial defects, whereas microforms were listed as 3 and 4. TGIF mutations were found in 11 (1.7%) probands and tended to be associated with a severe phenotype, with alobar HPE and severe facial defects. About 27% of patients had extracraniofacial defects, mostly visceral. Mutations were 100% heritable, but 5 parents had no HPE spectrum disorder. Statistical analysis showed a positive correlation between the severity of the brain malformation and facial features for mutations in TGIF. Based on these results, Mercier et al. (2011) proposed an algorithm for molecular analysis in HPE.
By FISH analysis, Gripp et al. (2000) demonstrated that the TGIF gene resides within the HPE4 minimal critical region. Mutation analysis of the TGIF gene in 268 DNA samples of patients with HPE detected 4 heterozygous missense mutations ... By FISH analysis, Gripp et al. (2000) demonstrated that the TGIF gene resides within the HPE4 minimal critical region. Mutation analysis of the TGIF gene in 268 DNA samples of patients with HPE detected 4 heterozygous missense mutations in the coding region, 1 of which was identified in familial HPE and 3 of which were identified in clinically sporadic cases. Among 94 fetuses with HPE and a normal karyotype, Bendavid et al. (2006) used quantitative multiplex PCR of short fluorescent fragments (QMPSF) to screen for microdeletions in the 4 major HPE genes, SHH, SIX3 (603714), ZIC2 (603073), and TGIF. Microdeletions were identified in 8 (8.5%) fetuses: 2 in SHH, 2 in SIX3, 3 in ZIC2, and 1 in TGIF. Further analysis showed that the entire gene was missing in each case. Point mutations in 1 of the 4 genes were identified in 13 of the fetuses. Combining the instances of point mutations and microdeletions for the 94 cases yielded the following percentages: SHH (6.3%), ZIC2 (8.5%), SIX3 (5.3%), and TGIF (2%). Bendavid et al. (2006) reported the use of 2 complementary assays for HPE-associated submicroscopic deletions: a multicolor fluorescence in situ hybridization (FISH) assay using probes for the 4 major HPE genes and 2 candidate genes (DISP1, 607502 and FOXA2, 600288) followed by quantitative PCR to selected samples. Microdeletions for SHH, ZIC2, SIX3, or TGIF were found in 16 of 339 severe HPE cases (i.e., with CNF findings; 4.7%). In contrast, no deletions were found in 85 patients at the mildest end of the HPE spectrum. Based on their data, Bendavid et al. (2006) suggested that microdeletion testing should be considered as part of an evaluation of holoprosencephaly, especially in severe HPE cases.