title: Branchiootorenal syndrome and oculoauriculovertebral spectrum features associated with duplication of SIX1, SIX6, and OTX2 resulting from a complex chromosomal rearrangement.
abstract: We report on a 26-month-old boy with developmental delay and multiple congenital anomalies, including many features suggestive of either branchiootorenal syndrome (BOR) or oculoauriculovertebral spectrum (OAVS). Chromosomal microarray analysis (CMA) initially revealed a copy-number gain with a single BAC clone (RP11-79M1) mapping to 14q23.1. FISH analysis showed that the third copy of this genomic region was inserted into the long arm of one chromosome 13. The same pattern was also seen in the chromosomes of the father, who has mental retardation, short stature, hypernasal speech, and minor craniofacial anomalies, including tall forehead, and crowded dentition. Subsequent whole genome oligonucleotide microarray analysis revealed an approximately 11.79 Mb duplication of chromosome 14q22.3-q23.3 and a loss of an approximately 4.38 Mb sequence in 13q21.31-q21.32 in both the propositus and his father and FISH supported the apparent association of the two events. Chromosome 14q22.3-q23.3 contains 51 genes, including SIX1, SIX6, and OTX2. A locus for branchiootic syndrome (BOS) has been mapped to 14q21.3-q24.3, and designated as branchiootic syndrome 3 (BOS3). Interestingly, mutations in SIX1 have been reported in patients with BOR/BOS3. We propose that the increased dosage of SIX1, SIX6, or OTX2 may be responsible for the BOR and OAVS-like features in this family.
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas 77030, USA.
authors.forename: Zhishuo
authors.initials: Z
authors.lastname: Ou
authors.forename: Donna M
authors.initials: DM
authors.lastname: Martin
authors.forename: Jirair K
authors.initials: JK
authors.lastname: Bedoyan
authors.forename: M Lance
authors.initials: ML
authors.lastname: Cooper
authors.forename: A Craig
authors.initials: AC
authors.lastname: Chinault
authors.forename: Pawel
authors.initials: P
authors.lastname: Stankiewicz
authors.forename: Sau W
authors.initials: SW
authors.lastname: Cheung
mesh_terms: D019280:Branchio-Oto-Renal Syndrome / Q000235:genetics*; D002675:Child, Preschool; D002882:Chromosomes, Human, Pair 13; D002883:Chromosomes, Human, Pair 14; D020440:Gene Duplication; D006053:Goldenhar Syndrome / Q000235:genetics*; D018398:Homeodomain Proteins / Q000235:genetics*; D006801:Humans; D007621:Karyotyping; D008297:Male; D025202:Molecular Diagnostic Techniques; D051857:Otx Transcription Factors / Q000235:genetics*; D015534:Trans-Activators / Q000235:genetics*; D014178:Translocation, Genetic; D014314:Trisomy
chemical_list: D018398:Homeodomain Proteins; C497659:OTX2 protein, human; D051857:Otx Transcription Factors; C099236:SIX1 protein, human; C491945:SIX6 protein, human; D015534:Trans-Activators