Nanni et al. (1999) presented a panel of 12 photographs illustrating the range of severity in holoprosencephaly resulting from mutation in the SHH gene.
Nowaczyk et al. (2000) reported an infant with holoprosencephaly, sacral anomalies, and ... Nanni et al. (1999) presented a panel of 12 photographs illustrating the range of severity in holoprosencephaly resulting from mutation in the SHH gene. Nowaczyk et al. (2000) reported an infant with holoprosencephaly, sacral anomalies, and situs ambiguus associated with partial monosomy 7q/trisomy 2p, der(7)t(2;7)(p23.2;q36.1), as a result of an adjacent-1 segregation of a t(2;7) in the father. The chromosomal abnormality was diagnosed prenatally after sonographic detection of HPE in the fetus. The baby was born at 37 weeks' gestation and died in the neonatal period; he had dysmorphic features consistent with the HPE sequence. Postmortem examination showed semilobar HPE, abdominal situs ambiguus, multiple segments of bowel atresia, dilatation of the ureters, and bony sacral anomalies. Molecular analysis confirmed hemizygosity for the SHH and HLXB9 (142994) genes, which were thought to be responsible for the HPE and sacral phenotypes, respectively. Immunohistochemical studies showed intact dopaminergic pathways in the mesencephalon, suggesting that midbrain dopamine neuron induction requires only one functioning SHH allele. Marini et al. (2003) studied a family, previously described by Camera et al. (1992), in which the mother presented with a single central maxillary incisor and mild hypotelorism and her daughter and 2 fetuses were diagnosed with HPE. Sequencing of DNA in this family identified a nonsense mutation in the SHH gene (600725.0019). By detailed ophthalmologic examination of 5 patients with genetically confirmed HPE3, Pineda-Alvarez et al. (2011) found several subtle abnormalities, including refractory errors, small corneal diameter, coloboma, foveal hypoplasia, blepharoptosis, hyperopia, strabismus, and astigmatism. These findings occurred without brain malformations; the patients had single central incisors, microcephaly, hypotelorism, and depressed nasal bridge; 1 had hypoplasia of the left frontal lobe. The patients were part of a larger 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 mutations in the SHH gene were associated with choanal stenosis and ophthalmologic malformations.
Mercier et al. (2011) reported the clinical and molecular features of a ... Among 34 patients with holoprosencephaly, Dubourg et al. (2004) observed that mutations in the SHH gene were associated with choanal stenosis and ophthalmologic malformations. 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. SHH mutations were found in 67 (10.4%) probands. The patients had alobar (28%), semilobar (34%), lobar (4%), or microform (34%) HPE, but the 4 categories of facial defects were evenly distributed, although the proportion of coloboma was relatively high (15% for the series as a whole). Extracranial defects were found in 24%, mostly visceral or renal/urinary. The mutations showed high heritability (73%), and 23% of parents with mutations had a microform. Statistical analysis for the whole study showed a positive correlation between the severity of the brain malformation and facial features for those with mutations in the SHH gene, and that microforms were associated with SHH mutations. Based on these results, Mercier et al. (2011) proposed an algorithm for molecular analysis in HPE.
Roessler et al. (1996) identified SHH as the gene responsible for HPE3. They analyzed 30 autosomal dominant HPE families and found 5 families that segregated different heterozygous SHH mutations. Two of these mutations predict premature termination of SHH ... Roessler et al. (1996) identified SHH as the gene responsible for HPE3. They analyzed 30 autosomal dominant HPE families and found 5 families that segregated different heterozygous SHH mutations. Two of these mutations predict premature termination of SHH protein (600725.0002 and 600725.0003). The remaining 3 mutations altered highly conserved residues in the vicinity of the alpha helix-1 motif (600725.0004 and 600725.0005) or the signal cleavage site (600725.0001). Roessler et al. (1996) noted that in humans loss of one SHH allele is sufficient to cause HPE, whereas in the mouse both alleles need to be lost to produce a similar CNS phenotype. They observed that haploinsufficiency for SHH in human is sufficient to disturb ventral midline neurogenesis but is insufficient to cause ventralization defects of sclerotome or limb abnormalities. In 30 unrelated children with holoprosencephaly, Orioli et al. (2001) analyzed for mutations in the SIX3 (603714), SHH, TGIF (602630), and ZIC2 (603073) 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. - Modifier Genes Martinelli and Fan (2009) demonstrated that a constructed mouse Shh N116K mutant, which corresponds to the HPE3-associated SHH mutation N115K (600725.0020), caused markedly decreased binding to Gas1 (139185), resulting in decreased Shh signaling. These findings indicated that HPE due to the N115K mutation results from an inability of mutant SHH to bind to GAS1 normally, thus interrupting the positive regulatory effect of GAS1. Martinelli and Fan (2009) suggested that mutations in GAS1 may act as possible modifiers of HPE. In 4 Brazilian patients with HPE or HPE-like phenotype, Ribeiro et al. (2010) identified 4 different heterozygous nonsynonymous variants in the GAS1 gene that were predicted to be damaging. Two of 4 patients also carried heterozygous missense mutations in the SHH gene. The authors suggested that mutations in the GAS1 gene may confer susceptibility to the development of HPE or may act as a modifier locus for HPE in conjunction with mutations in other genes.
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, 9 (10.5%) had mutations in the ZIC2 gene (603073), 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.