Holoprosencephaly 4

A number sign (#) is used with this entry because of evidence that holoprosencephaly-4 (HPE4) is caused by heterozygous mutation in the TGIF gene (602630) on chromosome 18p11.

For phenotypic information and a general discussion of genetic heterogeneity in holoprosencephaly, see HPE1 (236100).


Johnson and Bachman (1976) described a normal female who appeared to have a nonreciprocal translocation from the short arm of one chromosome 18 to the long arm of a chromosome 12. She gave birth to a cebocephalic child whose karyotype included an 18p- chromosome. The association of loss of 18p with holoprosencephaly was suggested by the patient reported by Munke et al. (1988); cytogenetic and molecular studies indicated a Y/18 translocation with loss of 18p and distal Yq material in a holoprosencephalic fetus.

As a first step toward positional cloning of the HPE4 gene, Overhauser et al. (1995) narrowed the assignment of the gene to 18p by characterizing the 18p deletions and clinical features of 6 patients by using a combination of somatic cell hybrid analysis and fluorescence in situ hybridization. By using a set of 27 chromosome 18p-specific markers, the deletion in each patient was characterized. The HPE minimal critical region was defined as 18p11.3. They pictured one of their patients with ocular hypotelorism, microcephaly, and a single central maxillary incisor (147250).

Nanni et al. (1999) described 2 families with mutations in the Sonic hedgehog gene (SHH; 600725), which is mutant in HPE3 (142945), who also had mutations in the TGIF gene. They suggested that such combinations of mutations may account for the intrafamilial variability frequently observed in holoprosencephaly.


Odent et al. (1998) reviewed 258 HPE records involving at least 1 affected child and found 97 cases in 79 families with nonsyndromic, nonchromosomal HPE. A high degree of familial aggregation was found in 29% of families. By segregation analysis, Odent et al. (1998) concluded that autosomal dominant inheritance with incomplete penetrance (82% for major and 88% for major and minor) was the most likely mode of inheritance. Sporadic cases accounted for 68%, and the recurrence risk after an isolated case was predicted to be 13 to 14%.

Molecular Genetics

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 (602630.0001-602630.0004), 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.

Genotype/Phenotype Correlations

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.