No abstract

In patients with the 3p-syndrome, hemizygous deletion of 3p25-pter is associated with profound growth failure, characteristic facial features, and mental retardation. We performed a molecular genetic analysis of 3p25 breakpoints in four patients with the 3p-syndrome, and a fifth patient with a more complex abnormality, 46,XY,der(3)t(3;?)(p25.3;?). EBV transformed lymphoblasts from each of the patients were initially characterised using fluorescent in situ hybridisation (FISH) and polymorphic microsatellite analyses. The 3p-chromosome from each patient was isolated from the normal chromosome 3 in somatic cell hybrid lines and subsequently analysed with polymorphic and monomorphic PCR amplifiable markers from 3p25. The analysis clearly shows that all five breakpoints are distinct. Furthermore, we have identified yeast artificial chromosomes that cross the 3p25 breakpoints of all four 3p-patients. Two of the patients were deleted for the von Hippel-Lindau (VHL) tumour suppressor gene, although neither has yet developed evidence of VHL disease. The patient with the most centromeric breakpoint, between D3S1585 and D3S1263, had the most severe clinical phenotype including an endocardial cushion defect that was not observed in any of the four patients who had more telomeric breakpoints. This study should provide useful insights into critical regions within 3p25 that are involved in normal human growth and development.

Quantitative trait loci (QTLs) associated with general cognitive ability ( g) were investigated for several groups of children selected for very high or for average cognitive functioning. A DNA marker in the gene for insulin-like growth factor-2 receptor (IGF2R) on Chromosome 6 yielded a significantly greater frequency of a particular form of the gene (allele) in a high- g group (.303; average IQ = 136, N = 51) than in a control group (.156; average IQ = 103, N = 51). This association was replicated in an extremely-high- g group (all estimated IQs > 160, N = 52) as compared with an independent control group (average IQ = 101, N = 50), with allelic frequencies of .340 and .169, respectively. Moreover, a high-mathematics-ability group ( N = 62) and a high-verbal-ability group ( N = 51) yielded results that were in the same direction but only marginally significant ( p = .06 and .08, respectively).

General cognitive ability (g), which is related to many aspects of brain functioning, is one of the most heritable traits in neuroscience. Similarly to other heritable quantitatively distributed traits, genetic influence on g is likely to be due to the combined action of many genes of small effect [quantitative trait loci (QTLs)], perhaps several on each chromosome. We used DNA pooling for the first time to search a chromosome systematically with a dense map of DNA markers for allelic associations with g. We screened 147 markers on chromosome 4 such that 85% of the chromosome were estimated to be within 1 cM of a marker. Comparing pooled DNA from 51 children of high g and from 51 controls of average g, 11 significant QTL associations emerged. The association with three of these 11 markers ( D4S2943, MSX1 and D4S1607 ) replicated using DNA pooling in independent samples of 50 children of extremely high g and 50 controls. Furthermore, all three associations were confirmed when each individual was genotyped separately ( D4S2943, P = 0. 00045; MSX1, P = 0.011; D4S1607, P = 0.019). Identifying specific genes responsible for such QTL associations will open new windows in cognitive neuroscience through which to observe pathways between genes and learning and memory.