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      Chromosomal microarray analysis in a cohort of underrepresented population identifies SERINC2 as a novel candidate gene for autism spectrum disorder

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          Abstract

          Chromosomal microarray (CMA) is now recognized as the first-tier genetic test for detection of copy number variations (CNVs) in patients with autism spectrum disorder (ASD). The aims of this study were to identify known and novel ASD associated-CNVs and to evaluate the diagnostic yield of CMA in Thai patients with ASD. The Infinium CytoSNP-850K BeadChip was used to detect CNVs in 114 Thai patients comprised of 68 retrospective ASD patients (group 1) with the use of CMA as a second line test and 46 prospective ASD and developmental delay patients (group 2) with the use of CMA as the first-tier test. We identified 7 (6.1%) pathogenic CNVs and 22 (19.3%) variants of uncertain clinical significance (VOUS). A total of 29 patients with pathogenic CNVs and VOUS were found in 22% (15/68) and 30.4% (14/46) of the patients in groups 1 and 2, respectively. The difference in detected CNV frequencies between the 2 groups was not statistically significant (Chi square = 1.02, df = 1, P = 0.31). In addition, we propose one novel ASD candidate gene, SERINC2, which warrants further investigation. Our findings provide supportive evidence that CMA studies using population-specific reference databases in underrepresented populations are useful for identification of novel candidate genes.

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          Structural variation of chromosomes in autism spectrum disorder.

          Structural variation (copy number variation [CNV] including deletion and duplication, translocation, inversion) of chromosomes has been identified in some individuals with autism spectrum disorder (ASD), but the full etiologic role is unknown. We performed genome-wide assessment for structural abnormalities in 427 unrelated ASD cases via single-nucleotide polymorphism microarrays and karyotyping. With microarrays, we discovered 277 unbalanced CNVs in 44% of ASD families not present in 500 controls (and re-examined in another 1152 controls). Karyotyping detected additional balanced changes. Although most variants were inherited, we found a total of 27 cases with de novo alterations, and in three (11%) of these individuals, two or more new variants were observed. De novo CNVs were found in approximately 7% and approximately 2% of idiopathic families having one child, or two or more ASD siblings, respectively. We also detected 13 loci with recurrent/overlapping CNV in unrelated cases, and at these sites, deletions and duplications affecting the same gene(s) in different individuals and sometimes in asymptomatic carriers were also found. Notwithstanding complexities, our results further implicate the SHANK3-NLGN4-NRXN1 postsynaptic density genes and also identify novel loci at DPP6-DPP10-PCDH9 (synapse complex), ANKRD11, DPYD, PTCHD1, 15q24, among others, for a role in ASD susceptibility. Our most compelling result discovered CNV at 16p11.2 (p = 0.002) (with characteristics of a genomic disorder) at approximately 1% frequency. Some of the ASD regions were also common to mental retardation loci. Structural variants were found in sufficiently high frequency influencing ASD to suggest that cytogenetic and microarray analyses be considered in routine clinical workup.
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            Comorbidity of mental disorders with alcohol and other drug abuse. Results from the Epidemiologic Catchment Area (ECA) Study.

            The prevalence of comorbid alcohol, other drug, and mental disorders in the US total community and institutional population was determined from 20,291 persons interviewed in the National Institute of Mental Health Epidemiologic Catchment Area Program. Estimated US population lifetime prevalence rates were 22.5% for any non-substance abuse mental disorder, 13.5% for alcohol dependence-abuse, and 6.1% for other drug dependence-abuse. Among those with a mental disorder, the odds ratio of having some addictive disorder was 2.7, with a lifetime prevalence of about 29% (including an overlapping 22% with an alcohol and 15% with another drug disorder). For those with either an alcohol or other drug disorder, the odds of having the other addictive disorder were seven times greater than in the rest of the population. Among those with an alcohol disorder, 37% had a comorbid mental disorder. The highest mental-addictive disorder comorbidity rate was found for those with drug (other than alcohol) disorders, among whom more than half (53%) were found to have a mental disorder with an odds ratio of 4.5. Individuals treated in specialty mental health and addictive disorder clinical settings have significantly higher odds of having comorbid disorders. Among the institutional settings, comorbidity of addictive and severe mental disorders was highest in the prison population, most notably with antisocial personality, schizophrenia, and bipolar disorders.
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              A recurrent 16p12.1 microdeletion suggests a two-hit model for severe developmental delay

              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.
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                Author and article information

                Contributors
                lpornpro@yahoo.com
                jnatini@hotmail.com
                Journal
                Sci Rep
                Sci Rep
                Scientific Reports
                Nature Publishing Group UK (London )
                2045-2322
                21 September 2017
                21 September 2017
                2017
                : 7
                : 12096
                Affiliations
                [1 ]ISNI 0000 0004 0470 1162, GRID grid.7130.5, Graduate Program in Biomedical Sciences, Prince of Songkla University, ; Songkhla, Thailand
                [2 ]ISNI 0000 0004 1937 0490, GRID grid.10223.32, Program in Translational Medicine, Faculty of Medicine Ramathibodi Hospital, Mahidol University, ; Bangkok, Thailand
                [3 ]ISNI 0000 0004 1937 0490, GRID grid.10223.32, Division of Medical Genetics, Department of Pediatrics, Faculty of Medicine Ramathibodi Hospital, Mahidol University, ; Bangkok, Thailand
                [4 ]Division of Medical Genetics, Department of Pediatrics, Faculty of Medicine, Thammasart University, Pathumthani, Thailand
                [5 ]Division of Child Development, Department of Pediatrics, Faculty of Medicine, Thammasart University, Pathumthani, Thailand
                [6 ]ISNI 0000 0004 1937 0490, GRID grid.10223.32, Division of Developmental-Behavioral Pediatrics, Department of Pediatrics, Faculty of Medicine Ramathibodi Hospital, Mahidol University, ; Bangkok, Thailand
                [7 ]ISNI 0000 0004 0470 1162, GRID grid.7130.5, Division of Child Development, Department of Pediatrics, Faculty of Medicine, Prince of Songkla University, ; Songkhla, Thailand
                [8 ]ISNI 0000 0004 1937 0490, GRID grid.10223.32, Thalassemia Research Center, Institute of Molecular Biosciences, Mahidol University, ; Salaya, Nakhon Pathom Thailand
                [9 ]ISNI 0000 0004 0470 1162, GRID grid.7130.5, Division of Human Genetics, Department of Pathology, Faculty of Medicine, Prince of Songkla University, ; Songkhla, Thailand
                [10 ]ISNI 0000 0004 1937 0490, GRID grid.10223.32, Integrative Computational Bioscience Center, Mahidol University, ; Salaya, Nakhon Pathom Thailand
                Author information
                http://orcid.org/0000-0001-8044-7993
                http://orcid.org/0000-0003-2329-2176
                Article
                12317
                10.1038/s41598-017-12317-3
                5608768
                28935972
                799cfd5e-27eb-445a-917d-b14de76e955d
                © The Author(s) 2017

                Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

                History
                : 10 January 2017
                : 7 September 2017
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