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Kishnani P.S.,Duke University | Heller J.H.,Duke University | Spiridigliozzi G.A.,Duke University | Lott I.,University of California at Irvine | And 4 more authors.
American Journal of Medical Genetics, Part A

The objective of this 10-week, randomized, double-blind, placebo-controlled multicenter study was to assess the efficacy and safety of donepezil for the treatment of cognitive dysfunction exhibited by children with Down syndrome (DS). Intervention comprised donepezil (2.5-10-mg/day) in children (aged 10-17 years) with DS of mild-to-moderate severity. The primary measures were the Vineland-II Adaptive Behavior Scales (VABS-II) Parent/Caregiver Rating Form (PCRF) the sum of nine subdomain standardized scores and standard safety measures. Secondary measures included the VABS-II/PCRF scores on the following domains and their respective individual subdomains: Communication (receptive, expressive, and written); Daily Living Skills (personal, domestic, and community); Socialization (interpersonal relationships, play and leisure time, and coping skills), and scores on the Test of Verbal Expression and Reasoning, a subject-performance-based measure of expressive language. At baseline, 129 participants were assigned treatment with donepezil or placebo. During the double-blind phase, VABS II/PCRF sum of the nine subdomain standardized scores, called v-scores, improved significantly from baseline in both groups (P-<-0.0001), with no significant between-group differences. This trial failed to demonstrate any benefit for donepezil versus placebo in children and adolescents with DS, although donepezil appeared to be well tolerated. © 2010 Wiley-Liss, Inc. Source

Dabell M.P.,Perkin Elmer Corporation | Rosenfeld J.A.,Perkin Elmer Corporation | Bader P.,Northeast Indiana Genetic Counseling Center | Escobar L.F.,Medical Genetics and Neurodevelopmental Center | And 29 more authors.
American Journal of Medical Genetics, Part A

Deletions at 2p16.3 involving exons of NRXN1 are associated with susceptibility for autism and schizophrenia, and similar deletions have been identified in individuals with developmental delay and dysmorphic features. We have identified 34 probands with exonic NRXN1 deletions following referral for clinical microarray-based comparative genomic hybridization. To more firmly establish the full phenotypic spectrum associated with exonic NRXN1 deletions, we report the clinical features of 27 individuals with NRXN1 deletions, who represent 23 of these 34 families. The frequency of exonic NRXN1 deletions among our postnatally diagnosed patients (0.11%) is significantly higher than the frequency among reported controls (0.02%; P=6.08×10-7), supporting a role for these deletions in the development of abnormal phenotypes. Generally, most individuals with NRXN1 exonic deletions have developmental delay (particularly speech), abnormal behaviors, and mild dysmorphic features. In our cohort, autism spectrum disorders were diagnosed in 43% (10/23), and 16% (4/25) had epilepsy. The presence of NRXN1 deletions in normal parents and siblings suggests reduced penetrance and/or variable expressivity, which may be influenced by genetic, environmental, and/or stochastic factors. The pathogenicity of these deletions may also be affected by the location of the deletion within the gene. Counseling should appropriately represent this spectrum of possibilities when discussing recurrence risks or expectations for a child found to have a deletion in NRXN1. © 2013 Wiley Periodicals, Inc. Source

Girirajan S.,University of Washington | Rosenfeld J.A.,Signature | Cooper G.M.,University of Washington | Antonacci F.,University of Washington | And 58 more authors.
Nature Genetics

We report the identification of a recurrent, 520-kb 16p12.1 microdeletion associated with childhood developmental delay. The microdeletion was detected in 20 of 11,873 cases compared with 2 of 8,540 controls (P = 0.0009, OR = 7.2) and replicated in a second series of 22 of 9,254 cases compared with 6 of 6,299 controls (P = 0.028, OR = 2.5). Most deletions were inherited, with carrier parents likely to manifest neuropsychiatric phenotypes compared to non-carrier parents (P = 0.037, OR = 6). Probands were more likely to carry an additional large copy-number variant when compared to matched controls (10 of 42 cases, P = 5.7 × 10 5, OR = 6.6). The clinical features of individuals with two mutations were distinct from and/or more severe than those of individuals carrying only the co-occurring mutation. Our data support 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 indicates that this two-hit model might be more generally applicable to neuropsychiatric disease. © 2010 Nature America, Inc. All rights reserved. Source

Soster E.L.,Indiana University | Tucker M.,Medical Genetics and Neurodevelopmental Center | Escobar L.F.,Medical Genetics and Neurodevelopmental Center | Vance G.H.,Indiana University
Birth Defects Research Part A - Clinical and Molecular Teratology

Background: Hydranencephaly is a relatively rare but severe structural brain abnormality that often results in perinatal death. Although several factors including infection and multiple births have been reported to be associated with this birth defect, the underlying etiology is not well understood. Recently, FLVCR2 gene mutations have been implicated in a subset of hydranencephaly cases, following an autosomal recessive pattern of inheritance. Case: We report a male infant with hydranencephaly found to have a previously unreported six amino acid deletion in one copy of the FLVCR2 gene following a pregnancy complicated by poor prenatal care and maternal cocaine use. Although our patient currently presents with developmental delays, he is showing progress and gaining some skills. Conclusion: We discuss the possibility of a synergistic effect between the FLVCR2 genetic mutation and environmental cocaine exposure, creating a susceptible brain, as an explanation for this infant's phenotype. This case demonstrates the potential clinical utility of testing for mutations in FLVCR2 for patients with hydranencephaly after other possible etiologies, such as congenital infection, have been reasonably eliminated. Current literature on FLVCR2 is relatively sparse; identifying additional patients with similar mutations will aid in defining the clinical significance of a gene mutation and the contribution to the etiology of hydranencephaly. © 2014 Wiley Periodicals, Inc. Source

Handrigan G.R.,University of Toronto | Chitayat D.,Hospital for Sick Children | Chitayat D.,University of Toronto | Lionel A.C.,Applied Genomics | And 21 more authors.
Journal of Medical Genetics

Background The contribution of copy-number variation (CNV) to disease has been highlighted with the widespread adoption of array-based comparative genomic hybridisation (aCGH) and microarray technology. Contiguous gene deletions involving ANKRD11 in 16q24.3 are associated with autism spectrum disorder (ASD) and intellectual disability (ID), while 16q24.1 deletions affecting FOXF1 are associated with congenital renal malformations, alveolar capillary dysplasia, and various other abnormalities. The disease associations of deletions in the intervening region, 16q24.2, have only been defined to a limited extent. Aim To determine whether deletions affecting 16q24.2 are correlated with congenital anomalies. Methods 35 individuals, each having a deletion in 16q24.2, were characterised clinically and by aCGH and/ or SNP-genotyping microarray. Results Several of the 35 16q24.2 deletions identified here closely abut or overlap the coding regions of FOXF1 and ANKRD11, two genes that have been previously associated with the disease. 25 patients were reported to have ASD/ID, and three were found to have bilateral hydronephrosis. 14 of the deletions associated with ASD/ ID overlap the coding regions of FBXO31 and MAP1LC3B. These same genes and two others, C16orf95 and ZCCHC14, are also included in the area of minimal overlap of the three deletions associated with hydronephrosis. Conclusions Our data highlight 16q24.2 as a region of interest for ASD, ID and congenital renal malformations. These conditions are associated, albeit without complete penetrance, with deletions affecting C16orf95, ZCCHC14, MAP1LC3B and FBXO31. The function of each gene in development and disease warrants further investigation. Source

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