Behavioral characterization of a white-throated sparrow homozygous for the ZAL2(m) chromosomal rearrangement.

The white-throated sparrow is rapidly becoming an important model in the genetics of social behavior because of a chromosomal rearrangement that segregates with a behavioral phenotype. Within a population, 50 % of individuals are heterozygous for a rearranged chromosome 2 (ZAL2(m)). These birds sing more and are more aggressive than the other 50 %, who lack the rearrangement. A disassortative mating system, in which heterozygotes almost never interbreed, ensures that ZAL2(m)/2(m) homozygotes are extremely rare. Here, we provide the first systematic characterization of such a homozygote, a hatch-year female. Her plumage was atypical of her age and sex, resembling that of an adult male. She was extremely vocal and aggressive, dominating her opponents in behavioral tests. Her phenotype was thus an exaggerated version of a typical ZAL2/2(m) heterozygote, supporting the hypothesis that alleles inside the ZAL2(m) rearrangement confer high aggression and further emphasizing this species' value as a model of social behavior.

Cleft palate in a multigenerational family with a microdeletion of 20p12.3 involving BMP2.

Cleft palate (CP) is a frequent and recognizable birth defect attributed to a variety of etiologies including genetic abnormalities and environmental exposures. Bone morphogenetic proteins (BMPs) are involved in embryonic signaling important for a number of developmental processes including bone formation and palate morphogenesis. Recently, haploinsufficiency of BMP2 was associated with syndromic forms of CP. Here, we report on a multigenerational family with a history of CP as a result of a 2.3 Mb deletion of chromosome 20p12.3, including the BMP2 gene. In addition to a submucous CP, the proband's clinical phenotype included failure to thrive (FTT), global developmental delays (DD), and dysmorphic features. The affected father exhibited an overt CP, with a facial gestalt and minor dysmorphic features similar to the proband. The father was otherwise healthy with no history of FTT or DD, suggesting high penetrance, yet variable expressivity for haploinsufficiency of BMP2. The findings presented here provide further evidence for the role of BMP2 in syndromic forms of CP.

Enhanced detection of clinically relevant genomic imbalances using a targeted plus whole genome oligonucleotide microarray.

PURPOSE: Array comparative genomic hybridization is rapidly becoming an integral part of cytogenetic diagnostics. We report the design, validation, and clinical utility of an oligonucleotide array which combines genome-wide coverage with targeted enhancement at known clinically relevant regions. METHODS: Probes were placed every 75 kb across the entire euchromatic genome to establish a chromosomal "backbone" with a resolution of approximately 500 kb, which is increased to approximately 50 kb in targeted regions. RESULTS: For validation, 30 samples showed 100% concordance with previous G-banding and/or fluorescence in situ hybridization results. Prospective array analysis of 211 clinical samples identified 33 (15.6%) cases with clinically significant abnormalities. Of these, 23 (10.9%) were detected by the "targeted" coverage and 10 (4.7%) by the genome-wide coverage (average size of 3.7 Mb). All abnormalities were verified by fluorescence in situ hybridization, using commercially available or homebrew probes using the 32K bacterial artificial chromosome set. Four (1.9%) cases had previously reported imbalances of uncertain clinical significance. Five (2.4%) cases required parental studies for interpretation and all were benign familial variants. CONCLUSIONS: Our results highlight the enhanced diagnostic utility of a genome-wide plus targeted array design, as the use of only a targeted array would have failed to detect 4.7% of the clinically relevant imbalances.