The terminal ends of most human chromosomes are G-band negative and are usually gene-rich, containing a higher than average density of genes [Niimura and Gojobori, 2002]. Microscopically discernible deletions of the terminal band of a chromosome are usually associated with significant clinical abnormality. For example, chromosome 4p deletion (Wolf-Hirschhorn syndrome) and chromosome 5p deletion (cri du chat syndrome) have critical regions in the most distal 4p16 and 5p15 band, respectively [de Grouchy and Turleau, 1984]. Since the terminal band of 3p26 is an exception as it is G-band positive, one can predict that a deletion of 3p26 might be accompanied by milder clinical symptoms than those resulting from deletion of the terminal bands of other chromosomes. We report here clinical findings in a boy with concurrent 3p26 deletion and 8q24.3 duplication, whose only clinical symptom is deficient cognitive skills. We suggest that his reduced cognitive skills are more likely the result of duplication of genes on terminal 8q, rather than deletion of genes on terminal 3p.Our patient was born at term after an uneventful pregnancy with a birth weight of 3,450 g and a length of 50 cm. His developmental milestones were normal. He sat at 6 months, crawled at 9 months, and walked independently at 14 months. Psychological testing (Stanford Binet Intelligence Scale) at 3 years of age revealed a composite IQ score of 97 (range 91-103). Subsequent developmental assessments, in conjunction with his enrollment in kindergarten, showed a definitive delay in cognitive skills, speech and language skills, and fine motor skills. He was categorized as multiply disabled. His Peabody Picture Vocabulary Test III scores were at the 39th centile at 4½ years and the 35th centile at 5½ years. He scored solidly in the 36-41 months range but had some scattered scores in the 42-47 months range of the test. He was first seen at the genetics clinic at 5½ years of age. He was quiet, but answered simple questions himself. He had occasional staring spells and absent-mindedness. A seizure disorder was ruled out. He wore glasses for hypermetropia. He was not able to write his own name. His weight and height were between 25th and 50th centile, and head circumference was at the 75th centile. No dysmorphic feature was noted. A year later, the staring spells subsided. He needed extra help in kindergarten and was placed in a special education class in the first grade. A chromosome study was subsequently requested to rule out the possibility of a sex chromosome aberration. He was last seen at 9½ years of age; he remained a friendly and enthusiastic boy, but had become more talkative over the years and stuttering had become apparent. He continued to receive physical, occupational, and speech/language therapies. Cytogenetic StudyThe only cytogenetic abnormality detected was a small terminal aberration of distal 3p [Fig. 1a]. The subsequent chromosomal studies on the parents

The small eye (Sey) mouse is a model of PAX6-aniridia syndrome (aniridia). Aniridia, a congenital ocular disorder caused by heterozygous loss-of-function mutations in PAX6, needs new vision saving therapies. However, high phenotypic variability in Sey mice makes development of such therapies challenging. We hypothesize that genetic background is a major source of undesirable variability in Sey mice. Here we performed a systematic quantitative examination of anatomical, histological, and molecular phenotypes on the inbred C57BL/6J, hybrid B6129F1, and inbred 129S1/SvImJ backgrounds. The Sey allele significantly reduced eye weight, corneal thickness, PAX6 mRNA and protein levels, and elevated blood glucose levels. Surprisingly, Pax6Sey/Sey brains had significantly elevated Pax6 transcripts compared to Pax6+/+ embryos. Genetic background significantly influenced 12/24 measurements, with inbred strains introducing severe ocular and blood sugar phenotypes not observed in hybrid mice. Additionally, significant interactions (epistasis) between Pax6 genotype and genetic background were detected in measurements of eye weight, cornea epithelial thickness and cell count, retinal mRNA levels, and blood glucose levels. The number of epistatic interactions was reduced in hybrid mice. In conclusion, severe phenotypes in the unnatural inbred strains reinforce the value of more naturalistic F1 hybrid mice for the development of therapies for aniridia and other disorders.

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