title: Recurrent partial rhombencephalosynapsis and holoprosencephaly in siblings with a mutation of ZIC2.
abstract: Rhombencephalosynapsis (RES) is a rare congenital brain malformation typically identified by magnetic resonance imaging and characterized by fusion of the cerebellar hemispheres and dentate nuclei and vermian agenesis or hypogenesis. Although RES is frequently found in conjunction with other brain malformations and/or congenital anomalies, no specific molecular etiology has been discovered to date and no animal models exist. We identified two half sisters with alobar or semi-lobar holoprosencephaly (HPE) and partial RES, suggesting that genes linked to HPE may also contribute to RES. A deletion of seven base pairs in exon one of the ZIC2 gene (c.392_98del7) was identified in each of the two half sisters with HPE and partial RES. To identify genetic causes of RES and to assess whether genes identified in HPE have a role in RES, we tested 11 additional individuals with RES by high-resolution chromosome analysis, chromosomal microarray analysis, and sequencing of four HPE genes. No mutations in ZIC2 or in other genes that cause HPE were identified, suggesting that mutation of ZIC2 is a rare cause of, or contributor to, RES associated with HPE. In addition, an individual with a complex rearrangement of chromosome 22q13.3 and RES was identified, suggesting the presence of a dosage-sensitive gene that may contribute to RES in this region.
authors.affiliation: Division of Pediatric Neurology and Developmental Neuroscience, Department of Pediatrics, Baylor College of Medicine, Houston, Texas, USA. mramocki@bcm.edu
authors.forename: Melissa B
authors.initials: MB
authors.lastname: Ramocki
authors.forename: Fernando
authors.initials: F
authors.lastname: Scaglia
authors.forename: Pawel
authors.initials: P
authors.lastname: Stankiewicz
authors.forename: John W
authors.initials: JW
authors.lastname: Belmont
authors.forename: Jeremy Y
authors.initials: JY
authors.lastname: Jones
authors.forename: Gary D
authors.initials: GD
authors.lastname: Clark
mesh_terms: D000293:Adolescent; D002648:Child; D002675:Child, Preschool; D002871:Chromosome Banding; D055028:Comparative Genomic Hybridization; D005260:Female; D016142:Holoprosencephaly / Q000175:diagnosis / Q000235:genetics*; D006801:Humans; D007223:Infant; D008297:Male; D009154:Mutation / Q000235:genetics*; D009687:Nuclear Proteins / Q000235:genetics*; D012249:Rhombencephalon / Q000002:abnormalities* / Q000473:pathology*; D035781:Siblings; D014157:Transcription Factors / Q000235:genetics*
chemical_list: D009687:Nuclear Proteins; D014157:Transcription Factors; C491812:ZIC2 protein, human