title: Molecular screening of SHH, ZIC2, SIX3, and TGIF genes in patients with features of holoprosencephaly spectrum: Mutation review and genotype-phenotype correlations.
abstract: Holoprosencephaly (HPE; 1 out of 16,000 live births; 1 out of 250 conceptuses) is a complex brain malformation resulting from incomplete cleavage of the prosencephalon, affecting both the forebrain and the face. Clinical expressivity is variable, ranging from a single cerebral ventricle and cyclopia to clinically unaffected carriers in familial dominant autosomic HPE. The disease is genetically heterogeneous, but additional environmental agents also contribute to the etiology of HPE. In our cohort of 200 patients, 34 heterozygous mutations were identified, 24 of them being novel ones: 13 out of 17 in the Sonic hedgehog gene (SHH); 4 out of 7 in ZIC2; and 7 out of 8 in SIX3. The two mutations identified in TGIF have already been reported. Novel phenotypes associated with a mutation have been described, such as abnormalities of the pituitary gland and corpus callosum, colobomatous microphthalmia, choanal aperture stenosis, and isolated cleft lip. This study confirms the great genetic heterogeneity of the disease, the important phenotypic variability in HPE families, and the difficulty to establish genotype-phenotype correlations.
authors.affiliation: Laboratoire de Génétique Moléculaire, CHU Pontchaillou, Rennes, France. christele.dubourg@chu-rennes.fr
authors.forename: Christèle
authors.initials: C
authors.lastname: Dubourg
authors.forename: Leïla
authors.initials: L
authors.lastname: Lazaro
authors.forename: Laurent
authors.initials: L
authors.lastname: Pasquier
authors.forename: Claude
authors.initials: C
authors.lastname: Bendavid
authors.forename: Martine
authors.initials: M
authors.lastname: Blayau
authors.forename: Franck
authors.initials: F
authors.lastname: Le Duff
authors.forename: Marie-Renée
authors.initials: MR
authors.lastname: Durou
authors.forename: Sylvie
authors.initials: S
authors.lastname: Odent
authors.forename: Véronique
authors.initials: V
authors.lastname: David
mesh_terms: D000328:Adult; D002648:Child; D002675:Child, Preschool; D002872:Chromosome Deletion; D018389:Codon, Nonsense / Q000235:genetics; D015331:Cohort Studies; D004252:DNA Mutational Analysis / Q000379:methods*; D005091:Exons / Q000235:genetics; D005136:Eye Proteins; D005260:Female; D005315:Fetal Diseases / Q000235:genetics; D018740:Genetic Heterogeneity; D005838:Genotype; D053823:Hedgehog Proteins; D016142:Holoprosencephaly / Q000235:genetics*; D018398:Homeodomain Proteins / Q000235:genetics*; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D009154:Mutation / Q000235:genetics*; D009419:Nerve Tissue Proteins / Q000235:genetics*; D009687:Nuclear Proteins; D010641:Phenotype; D011247:Pregnancy; D011256:Pregnancy Outcome; D012097:Repressor Proteins / Q000235:genetics*; D015534:Trans-Activators / Q000235:genetics*; D014157:Transcription Factors / Q000235:genetics*; D000097607:Homeobox Protein SIX3
chemical_list: D018389:Codon, Nonsense; D005136:Eye Proteins; D053823:Hedgehog Proteins; D018398:Homeodomain Proteins; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D012097:Repressor Proteins; D015534:Trans-Activators; D014157:Transcription Factors; D000097607:Homeobox Protein SIX3; C509239:SHH protein, human; C097504:TGIF1 protein, human; C491812:ZIC2 protein, human