Holoprosencephaly (HPE; see 236100) is the most common structural anomaly of the human brain and is one of the anomalies seen in patients with deletions and duplications of chromosome 13. On the basis of molecular analysis of a ... Holoprosencephaly (HPE; see 236100) is the most common structural anomaly of the human brain and is one of the anomalies seen in patients with deletions and duplications of chromosome 13. On the basis of molecular analysis of a series of patients with hemizygous deletions of the long arm of chromosome 13, Brown et al. (1993, 1995) defined a discrete 1-Mb region in band 13q32 where a deletion leads to major developmental anomalies (the 13q32 deletion syndrome). Patients in whom this region is deleted usually have major congenital malformations, including brain anomalies such as HPE or exencephaly, as well as digital anomalies such as absent thumbs. Brown et al. (2001) reported that central nervous system malformations seen in patients with ZIC2 mutations ranged from alobar HPE (most common) to middle interhemispheric fusion defect (1 case). Additionally, all of the patients with ZIC2 mutations had relatively normal faces, suggesting that ZIC2 mutations represent a large proportion of HPE cases without facial malformation. Solomon et al. (2010) retrospectively reviewed the clinical features of 157 individuals from 119 unrelated kindreds with HPE5, including 141 patients with intragenic ZIC2 mutations and 16 with deletions involving the ZIC2 gene. The alobar and semilobar types of HPE were the most common among those with point mutations, occurring in 20% and 34% of patients, respectively. A majority (67%) of patients did not display typical HPE facial features, such as the combination of hypotelorism, midface hypoplasia, cleft palate, and single maxillary central incisor, and none had features at the severe end of the spectrum, including cyclopia, synophthalmia, or a proboscis. Instead, patients with HPE5 had a more subtle common facial phenotype consisting of bitemporal narrowing (53%), upslanting palpebral fissures (97%), a flat nasal bridge (33%), a short nose with anteverted nares (73%), a broad and deep philtrum (43%), and a subjective appearance of large ears (37%). Facial clefts were described in 10%, while 17% had high-arched palates. Hydrocephalus was present in 12%, neural tube defects in 4%, and skeletal anomalies in 14%. There was no consistent pattern of extraneurologic features. In 2 half sisters with holoprosencephaly and partial rhombencephalosynapsis, Ramocki et al. (2011) identified a heterozygous truncating mutation in the ZIC2 gene (603073.0006). One of the girls had macrocephaly and scaphocephaly, and the other had microcephaly. Both had severe mental retardation and motor disability. The mother did not carry the deletion in her peripheral blood, suggesting germline mosaicism. Although these findings suggested that rhombencephalosynapsis may be related to HPE, no ZIC2 mutations were identified in 11 additional cases of rhombencephalosynapsis. Guleria (2011) disagreed with the diagnosis of partial rhombencephalosynapsis in the patients reported by Ramocki et al. (2011), and suggested that the appearance of the contiguous cerebellar folial pattern likely resulted from a small posterior fossa and crowding of the structures. Ramocki et al. (2011) responded that the interpretation of neuroimaging regarding the diagnosis of partial rhombencephalosynapsis is controversial, and maintained that their patients were correctly diagnosed. By detailed ophthalmologic examination of a 5-year-old girl with genetically confirmed HPE5, Pineda-Alvarez et al. (2011) found hyperopia, astigmatism, and microcornea. The patient was part of a cohort of 10 patients with genetically confirmed HPE. All had at least 2 ophthalmologic anomalies, including refractive errors, microcornea, microphthalmia, blepharoptosis, exotropia, and coloboma. The findings contributed to the understanding of the phenotypic variability of the HPE spectrum and showed that subtle intraocular abnormalities can occur in HPE.
Among 34 patients with holoprosencephaly, Dubourg et al. (2004) observed that mutation in ZIC2 was associated with anencephaly.
Mercier et al. (2011) reported the clinical and molecular features of a large European series of 645 HPE ... Among 34 patients with holoprosencephaly, Dubourg et al. (2004) observed that mutation in ZIC2 was associated with anencephaly. 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. ZIC2 mutations were found in 53 (8.2%) probands, and the phenotype tended to include severe alobar or semilobar HPE with few facial features. Other associated findings included neural tube defects (9%) and neuronal migration abnormalities (15%). Two patients had rachischisis. There was a high proportion of associated extracraniofacial malformations (40%), mostly visceral abnormalities and abnormalities of the extremities; 8 cases had multiple congenital malformations. There was a high ratio of female:male affected (1.8:1), suggesting that ZIC2 mutations may be embryonically lethal in males. Although heritability was low (30%), microforms were reported in 36% of parents with ZIC2 mutations. Statistical analysis did not show a positive correlation between the severity of the brain malformation and facial features for those with ZIC2 mutations, and those with ZIC2 mutations tended to have the most severe HPE types compared to those with mutations in other genes. Based on these results, Mercier et al. (2011) proposed an algorithm for molecular analysis in HPE.
Brown et al. (1998) reported that heterozygous mutations in the human ZIC2 gene, a homolog of the Drosophila 'odd-paired' (opa) gene, are associated with HPE. Haploinsufficiency of ZIC2 is likely to cause the brain malformation seen in 13q ... Brown et al. (1998) reported that heterozygous mutations in the human ZIC2 gene, a homolog of the Drosophila 'odd-paired' (opa) gene, are associated with HPE. Haploinsufficiency of ZIC2 is likely to cause the brain malformation seen in 13q deletion patients. Brown et al. (1998) used SSCP to screen for ZIC2 mutations in DNA samples from 150 patients with sporadic HPE and 63 patients with familial HPE. One sporadic patient showed a 56-bp head-to-tail repeat insertion in the first exon of the gene (603073.0001). In a second sporadic case, a 1-bp C insertion caused a frameshift that altered the last 90 amino acids, or approximately 20%, of the protein (603073.0002). In a third family with 2 sibs affected with HPE, Brown et al. (1998) determined that both had a 30-bp insertion in the third exon of ZIC2 (603073.0003). This insertion was a head-to-tail repeat and expanded the alanine tract normally present at that position from 15 to 25 alanine residues. In a fourth family with a single child affected with HPE, Brown et al. (1998) found a 7-bp deletion in the zinc finger region that destroyed the reading frame (603073.0004). Brown et al. (2001) found 15 ZIC2 mutations within a cohort of 509 isolated holoprosencephaly cases. Seven mutations were frameshifts that were predicted to result in loss of function, further supporting the idea that ZIC2 haploinsufficiency can result in HPE. One mutation, an alanine tract expansion which is caused by the expansion of an imperfect trinucleotide repeat, occurred in 7 patients from 6 different families. In 3 of those families, the father was found to be apparently mosaic for the mutation. The authors hypothesized that this mutation may arise through errors in somatic recombination, an extremely unusual mutation mechanism. In 30 unrelated children with holoprosencephaly, Orioli et al. (2001) analyzed for mutations in the SIX3 (603714), SHH (600725), TGIF (602630), and ZIC2 genes. They identified 3 novel mutations, 2 in the SHH gene and 1 in the ZIC2 gene. Their results explained 8% (2 of 26 newborn samples) of the HPE cases in the South American population studied. 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, ZIC2, 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. Solomon et al. (2010) found ZIC2 mutations in 49 (8.4%) of 582 probands with HPE. These results were combined with other reports of ZIC2-related HPE from testing areas. In a cohort of 65 families with ZIC2 mutations in whom parents were available for testing, ZIC2 mutations occurred de novo in 72%. The majority of mutations (98%) were predicted or proven to result in loss of function.
In a targeted screening study of 4 genes in 86 Dutch patients with holoprosencephaly, Paulussen et al. (2010) found that 21 (24%) had heterozygous mutations in 1 of 3 of the genes. Three (3.5%) had mutations in the ... In a targeted screening study of 4 genes in 86 Dutch patients with holoprosencephaly, Paulussen et al. (2010) found that 21 (24%) had heterozygous mutations in 1 of 3 of the genes. Three (3.5%) had mutations in the SHH gene (600725), 9 (10.5%) had mutations in the ZIC2 gene, and 9 (10.5%) had mutations in the SIX3 gene (603714). None had mutations in the TGIF gene (602630). Two deletions were detected, 1 encompassing the ZIC2 gene and another encompassing the SIX3 gene. About half of the mutations were de novo; 1 was germline mosaic. There was marked clinical variability, but those with ZIC2 mutations tended to have less severe facial malformations. Five of 7 parental carriers were asymptomatic, and 2 had minor HPE signs.