Martin et al. (1977) described a kindred with 7 persons affected with a syndrome manifested by cleft lip and anterior cleft palate, hypotelorism, microcephaly, mental retardation, scoliosis, and chronic constipation. The disorder bore similarities to familial holoprosencephaly. Three ... Martin et al. (1977) described a kindred with 7 persons affected with a syndrome manifested by cleft lip and anterior cleft palate, hypotelorism, microcephaly, mental retardation, scoliosis, and chronic constipation. The disorder bore similarities to familial holoprosencephaly. Three of 4 affected males survived past 20 years of age. All 3 affected females died early in infancy. Although no affected male begot an affected son, 2 presumed carrier males had an affected son. Ardinger and Bartley (1988) interpreted a family they studied as suggesting autosomal dominant inheritance. Three individuals in 3 successive generations had severe brain anomalies and 12 individuals had minor manifestations, mainly microcephaly. Other findings in the family included single central incisor and hypotelorism, which have been suggested as mild manifestations of autosomal dominant familial holoprosencephaly. Jaramillo et al. (1988) described a family in which several persons had variable combinations of craniofacial defects. The most severely affected relatives had holoprosencephaly, whereas others had only mild facial dysmorphism and decreased bitemporal diameters. One member of the family had a single central maxillary incisor. Male-to-male transmission occurred. Berry et al. (1984) and Johnson (1989) provided information on a family in which holoprosencephaly occurred in 3 first cousins who were offspring of parents with single central maxillary incisor. Johnson (1989) reported a second patient with full-blown holoprosencephaly whose mother and sister had only single central maxillary incisor. Johnson (1989) suggested that holoprosencephaly is a developmental field defect of which the mild forms can be single median incisor, hypotelorism, bifid uvula, or pituitary deficiency. Hennekam et al. (1991) described a family in which 1 sib had holoprosencephaly and microcephaly, a second sib had microcephaly alone, and the mother had microcephaly with single central maxillary incisor, submucous cleft palate, absence of the nasal septal cartilage, and hypotelorism. Solomon et al. (2009) reported a large kindred in which at least 15 individuals spanning 5 generations had a variable severity of holoprosencephaly. The proband was ascertained at birth because of alobar HPE, macrocephaly, severe hypotelorism, short nose with upturned nares, hypoplastic philtrum, and low-set ears. In a family review, 2 deceased individuals had full HPE as observed in the proposita, 5 had died in early infancy from unknown causes, and at least 9 had a subtle facial microform with short angular nose with hypotelorism or narrow nasal bridge. Genetic analysis identified a heterozygous mutation (W113C; 603714.0007) in the SIX3 gene in 6 affected individuals. Solomon et al. (2009) commented that the studies of this family spanned 15 years, and that the analysis was complicated by reduced penetrance, variable expressivity, and phenocopies. By detailed ophthalmologic examination of 3 patients with genetically confirmed HPE2, Pineda-Alvarez et al. (2011) found several subtle abnormalities, including refractory errors, small corneal diameter, astigmatism, cataracts, fine nystagmus, strabismus, and dysplastic optic nerve. 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 mutation in the SIX3 gene was associated with atelencephaly.
Lacbawan et al. (2009) identified SIX3 mutations in 4.7% of 800 probands and relatives with HPE. ... Among 34 patients with holoprosencephaly, Dubourg et al. (2004) observed that mutation in the SIX3 gene was associated with atelencephaly. Lacbawan et al. (2009) identified SIX3 mutations in 4.7% of 800 probands and relatives with HPE. In total, 138 cases of HPE were identified, 59 of whom had not previously been reported. Mutations in SIX3 resulted in more severe HPE than in other cases of nonchromosomal, nonsyndromic HPE. An overrepresentation of severe HPE was found in patients whose mutations conferred greater loss of protein function, as measured by an in vitro assay. The gender ratio in this combined set of patients was 1.5:1 (F:M), and maternal inheritance was almost twice as common as paternal. About 14% of SIX3 mutations in probands occurred de novo. There was a wide intrafamilial clinical range of features, and penetrance was estimated to be at least 62% from diagnosis on clinical grounds alone. The data suggested that SIX3 mutations result in relatively severe HPE, but also indicated that variability may be due to a multi-hit mechanism. 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. SIX3 mutations were found in 5.1% of probands, and most (57%) had severe HPE, including atelencephaly/aprosencephaly, as well as severe facial and ophthalmologic defects. About 24% had extracraniofacial defects, mostly visceral, skeletal, and of the extremities. The sex ratio favored females, suggesting that SIX3 mutations may be embryonically lethal in males. SIX3 mutations were highly heritable (88%), but only 3 of 17 parents had a microform. Statistical analysis showed a positive correlation between the severity of the brain malformation and facial features for SIX3 mutations, and those with SIX3 mutations had a more severe HPE type compared to those with other mutations. Based on these results, Mercier et al. (2011) proposed an algorithm for molecular analysis in HPE.
Wallis et al. (1999) demonstrated mutations in the SIX3 gene (603714.0001-603714.0003) in patients with holoprosencephaly.
In 6 Brazilian patients with HPE2, Ribeiro et al. (2006) identified 5 missense mutations and 2 frameshift mutations in the SIX3 ... Wallis et al. (1999) demonstrated mutations in the SIX3 gene (603714.0001-603714.0003) in patients with holoprosencephaly. In 6 Brazilian patients with HPE2, Ribeiro et al. (2006) identified 5 missense mutations and 2 frameshift mutations in the SIX3 gene. Comparison of patients with missense versus frameshift mutations showed essentially no difference. Experience with these patients suggested that SIX3 mutations result in a more severe phenotype than other gene mutations for holoprosencephaly. One patient had a double heterozygosity for SIX3 mutation (603714.0005 and 603714.0006). Three mutations were paternally transmitted, 2 were maternal, and 1 was a de novo event. The 5 parental mutation carriers appeared normal. 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 (600725), SIX3, ZIC2 (603073), and TGIF (602630). 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.
In a targeted screening study of 4 genes in 186 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 186 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 (603073), and 9 (10.5%) had mutations in the SIX3 gene. 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.