The studies on genotype-phenotype analysis show that in most cases the phenotype was similar in patients with deletions and in those with truncating mutations [11
]. Patients with large deletions may have a more severe phenotype and additional features [11
]. Facial gestalt and the psychomotor development delay, particularly of language, are constant. The frequent and severe malformations (HSCR, congenital heart defect, agenesis of the corpus callosum) and seizures may lead to suspicion of the diagnosis, but their presence is variable [5
The comparison between clinical data concerning the associated malformations of one of the patients with a R695X mutation and those of the other eight patients with the same mutation, demonstrated the phenotypic variability of a single mutation in MWS [4
]. This variability is remarkable not only in the same mutation but also in the same family. In fact, two siblings (sister and brother) with characteristic face, HSCR and agenesis of the corpus callosum were discordant for congenital heart disease and ocular coloboma [17
]. On the other hand, the phenotypic expression in two affected sisters was very similar for a/hypoplasia of corpus callosum, HSCR, congenital heart defect, seizures and microcephaly [18
]. These features might be controlled by common familial genetic modifiers [18
Few data are available about the parental origin of deletions. The origin of the deleted chromosome is paternal in 17 out of 19 patients examined so far [11
]. The investigation of four patients showed that agenesis of corpus callosum (present in two patients and absent in two others) and seizures (present in one patient and absent in three others) showed no correlation with paternal origin of the deletion [11
HSCR, when present, is a strong cross reference marker, even in the neonatal period, but it is not constant. It is noteworthy that at first the patients were selected among those with syndromic HSCR. As the number of described patients with ZEB2
mutations rises, the percentage of patients with HSCR decreases: 70% of 30 patients [11
], 62% of 45 [9
], 63.8% of 47 [12
], 62.8% of 70 [4
], 62,6% of 97 [18
], 57.2% of 159 [22
] and 57% of 170. Therefore, there was a bias of ascertainment.
Also the male preponderance of HSCR in general populations (4:1) [43
] can cause a bias of ascertainment and explain the male excess in MWS [9
]. In fact, the male/female ratio decreases from 2.13/1 out of 47 patients (M/F 32/15) [12
] to 1.92/1 out of 70 patients (M/F 46/24) [4
], to 1.49/1 out of 97 patients (M/F 58/39) (personal data), to 1.37/1 out of 159 patients (M/F 92/67) [22
] and today 1.42/1 out of 170 patients (M/F 100/70).
The manifestation of HSCR is not influenced by deletion size [11
]. Moreover, Zfhx1b
knockout mice do not exhibit HSCR [44
], therefore a non-allelic modifier might contribute to the manifestation of HSCR [11
Unusual mutations can lead to an atypical phenotype. The first person reported was a 48-year-old woman with severe constipation and mild mental retardation in the absence of specific facial anomalies, seizures, and other malformations caused by non-truncating mutations with a 3 bp in frame deletion [27
Three patients with ZEB2
missense mutations showed a clinical severity as variable as expected. The first was a boy with Down syndrome and typical facial features of trisomy 21, HSCR (rarer in Down syndrome than in MWS), myopia, and ocular coloboma affecting iris and retina [28
]. The child showed some dysmorphism compatible with MWS but not the facial gestalt. The importance of ocular anomalies that differs and are more severe than those observed in Down syndrome is underlined.
Another boy with a missense mutation [20
] showed HSCR, corpus callosum hypoplasia, epilepsy and severe mental retardation, but also other anomalies such as cleft lip and palate, brachytelephalangy, and broad thumbs and halluces. Facial phenotype was similar to MWS but differed by the presence of bilateral cleft lip and palate, and eyebrows that were not typical of MWS.
The third missense mutation was found in a young child with typical MWS including HSCR who died at age of 3 years [22
An exceptionally mild phenotype, caused by a novel and unusual splice site mutation in the 5'UTR, was reported by Zweier et al
(2006) in a 5-year-old child. He showed a mild motor and speech delay but, by age 5 years, he spoke in full sentences. The phenotype was not typical but facial features resembled the facial gestalt of MWS. Clinical features were mild in comparison with these associated with truncating mutations, no malformations or seizures were present. The mild phenotype could be due to the conservation of all known functional domains of the protein: in fact, this mutation only results in loss of exon 2 [21
]. The authors suggested that exon 2 might contain important determinants of the facial phenotype in MWS [21
]. Three other splice site mutations [10
] have been identified in patients with typical phenotypes.
The confirmation of the diagnosis based on the presence of a mutation, deletion or translocation in the ZEB2 gene will allow the knowledge on genotype-phenotype correlation to be increased.