We report the identification of a recurrent 520-kbp 16p12.1 microdeletion significantly associated with childhood developmental delay. The microdeletion was detected in 20/11,873 cases vs. 2/8,540 controls (p=0.0009, OR=7.2) and replicated in a second series of 22/9,254 cases vs. 6/6,299 controls (p=0.028, OR=2.5). Most deletions were inherited with carrier parents likely to manifest neuropsychiatric phenotypes (p=0.037, OR=6). Probands were more likely to carry an additional large CNV when compared to matched controls (10/42 cases, p=5.7×10-5, OR=6.65). Clinical features of cases with two mutations were distinct from and/or more severe than clinical features of patients carrying only the co-occurring mutation. Our data suggest a two-hit model in which the 16p12.1 microdeletion both predisposes to neuropsychiatric phenotypes as a single event and exacerbates neurodevelopmental phenotypes in association with other large deletions or duplications. Analysis of other microdeletions with variable expressivity suggests that this two-hit model may be more generally applicable to neuropsychiatric disease.

The Health Belief Model (HBM) was developed as an attempt to explain an individual's decision regarding obtaining preventive health care. This model was applied to predict the decisions of women of advanced maternal age regarding their obtaining amniocentesis in a one-year study conducted in Toledo, Ohio. A questionnaire based on the HBM was administered to a sample of 98 pregnant women of advanced maternal age. A total of 96 questionnaires were eligible for inclusion in the study. Sixty-one women reported that they would have amniocentesis, 22 would not, and 13 were unsure. A multivariate analysis of variance among amniocentesis decision groups was performed using the health belief components (perceived susceptibility, perceived seriousness, perceived benefit, perceived barrier) and knowledge as variables. There was a significant difference (Wilks' criterion, p less than .0001) among the three decision groups, but the differences were in the health belief components and not in knowledge. A stepwise discriminant function analysis was used to classify subjects on the amniocentesis decision. Of the variables examined, only the HBM component perceived benefit factor was a significant discriminant (p = .0001). It is not necessarily the lack of knowledge that prevents women who are at risk because of advanced maternal age from having amniocentesis but their perceptions regarding amniocentesis. Genetic counselors need to focus more on exploring the perceptions of amniocentesis benefits in this population to facilitate the decision making process.

Non-allelic homologous recombination (NAHR) between segmental duplications in proximal chromosome 15q breakpoint (BP) regions can lead to microdeletions and microduplications. Several individuals with deletions flanked by BP3 and BP4 on 15q13, immediately distal to, and not including the Prader-Willi/Angelman syndrome (PW/AS) critical region and proximal to the BP4-BP5 15q13.3 microdeletion syndrome region, have been reported; however, because the deletion has also been found in normal relatives, the significance of these alterations is unclear. We have identified six individuals with deletions limited to the BP3-BP4 interval and an additional four individuals with deletions of the BP3-BP5 interval from 34 046 samples submitted for clinical testing by microarray-based comparative genomic hybridization (aCGH). Of four individuals with BP3-BP4 deletions for whom parental testing was conducted, two were apparently de novo and two were maternally inherited. A comparison of clinical features, available for five individuals in our study (four with deletions within BP3-BP4 and one with a BP3-BP5 deletion), with those in the literature show common features of short stature and/or failure to thrive, microcephaly, hypotonia, and premature breast development in some individuals. Although the BP3-BP4 deletion does not yet demonstrate statistically significant enrichment in abnormal populations compared with control populations, the presence of common clinical features among probands and the presence of genes with roles in development and nervous system function in the deletion region suggest that this deletion may have a role in abnormal phenotypes in some individuals.

Here we report on a boy who died at 16 1/2 months with hemihypertrophy, eye abnormalities, macrodactyly, hamartomas, pigmented nevi, cerebral involvement, and other anomalies compatible with the Proteus syndrome. In addition, he also had abnormalities previously unreported in the Proteus syndrome including craniosynostosis and complex congenital heart defects. He seems to represent an extremely severe form of the Proteus syndrome and expands the already broad range of the phenotype.

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