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.

(1). Characteristic morphological lesions of diabetic nephropathy initially present in the renal glomerulus; these include glomerular hypertrophy, thickening of the basement membrane, and mesangial expansion (2). Several interventions have been shown to slow the progression of diabetic nephropathy, including tight glucose and blood pressure control and the blockade of the renin-angiotensin system (3-5). However, none of these can cure or prevent the development of diabetic nephropathy.Recent observations indicate important roles for glomerular epithelial cells (podocytes) in the pathogenesis of diabetic nephropathy (6 -9). The density of glomerular visceral epithelial cells is reduced in kidneys of individuals with diabetic nephropathy. Among various glomerular morphological characteristics, the decreased podocyte density is one of the strongest predictors of disease progression (10). Apoptosis and detachment of podocytes have been implicated as a potential mechanism of podocyte loss in animal models of diabetic nephropathy (7,11). We recently reported increased apoptosis of podocytes in type 1 diabetic Akita and type 2 diabetic Lepr db/db mice at the time of development of hyperglycemia. In vitro treatment of podocytes with high glucose also leads to increased apoptosis rate (7,12). Podocyte apoptosis seems to contribute significantly to the development of diabetic nephropathy, as prevention of podocyte apoptosis in vivo was associated with a decrease in albuminuria and mesangial expansion in the Lepr db/db model of type 2 diabetes. Brownlee (13) has pioneered the concept that hyperglycemia-induced overproduction of superoxide is the single unifying link to diabetes complications, including cellular activation of protein kinase C, hexosamine pathway, and advanced glycation formation, which are the major pathways of hyperglycemic damage in endothelial cells. This process occurs via inhibition of glyceraldehyde-3-phosphate dehydrogenase activity, which is likely to be the consequence of poly(ADP) ribosylation of the enzyme by active poly(ADP-ribose) polymerase (PARP)-1 (14). Since uncoupling protein 1 or manganese superoxide dismutase overexpressions blocked the activation of PARP-1, it has been hypothesized that the high-glucose-induced PARP-1 activation is the consequence of the increased intracellular reactive oxygen species (ROS) and subsequent DNA breakage in endothelial cells (14).PARP-1 is one of the most abundant nuclear proteins. The catalytic function of PARP-1 relates to its role as a DNA damage sensor and signaling molecule. The zinc C.S. is a stockholder of Inotek Pharmaceuticals, a firm involved in the development of PARP inhibitors.Additional information for this article can be found in an online appendix at http://diabetes.diabetesjournals.org.ELISA, enzyme-linked immunosorbent assay; IB␣, inhibitor of B␣; NFB; nuclear factor-B; PARP, poly(ADP-ribose) polymerase; PAS, periodic acid Schiff; ROS, reactive oxygen species.

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