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Br J Psychiatry ; 212(5): 287-294, 2018 May.
Artigo em Inglês | MEDLINE | ID: mdl-29693535


BACKGROUND: Copy number variants (CNVs) are established risk factors for neurodevelopmental disorders. To date the study of CNVs in psychiatric illness has focused on single disorder populations. The role of CNVs in individuals with intellectual disabilities and psychiatric comorbidities are less well characterised.AimsTo determine the type and frequency of CNVs in adults with intellectual disabilities and comorbid psychiatric disorders. METHOD: A chromosomal microarray analysis of 599 adults recruited from intellectual disabilities psychiatry services at three European sites. RESULTS: The yield of pathogenic CNVs was high - 13%. Focusing on established neurodevelopmental disorder risk loci we find a significantly higher frequency in individuals with intellectual disabilities and comorbid psychiatric disorder (10%) compared with healthy controls (1.2%, P<0.0001), schizophrenia (3.1%, P<0.0001) and intellectual disability/autism spectrum disorder (6.5%, P < 0.00084) populations. CONCLUSIONS: In the largest sample of adults with intellectual disabilities and comorbid psychiatric disorders to date, we find a high rate of pathogenic CNVs. This has clinical implications for the use of genetic investigations in intellectual disability psychiatry.Declaration of interestNone.

Eur J Med Genet ; 59(9): 436-43, 2016 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-27519580


BACKGROUND: Catatonia is a motor dysregulation syndrome co-occurring with a variety of psychiatric and medical disorders. Response to treatment with benzodiazepines and electroconvulsive therapy suggests a neurobiological background. The genetic etiology however remains largely unexplored. Copy Number Variants (CNV), known to predispose to neurodevelopmental disorders, may play a role in the etiology of catatonia. METHODS: This study is exploring the genetic field of catatonia through CNV analysis in a cohort of psychiatric patients featuring intellectual disability and catatonia. Fifteen adults admitted to a psychiatric inpatient unit and diagnosed with catatonia were selected for array Comparative Genomic Hybridization analysis at 200 kb resolution. We introduced a CNV interpretation algorithm to define detected CNVs as benign, unclassified, likely pathogenic or causal with regard to catatonia. RESULTS: Co-morbid psychiatric diagnoses in these patients were autism, psychotic or mood disorders. Eight patients were found to carry rare CNVs, which could not be classified as benign, comprising 6 duplications and 2 deletions. Microdeletions on 22q13.3, considered causal for catatonia, were detected in 2 patients. Duplications on 16p11.2 and 22q11.2 were previously implicated in psychiatric disorders, but not in catatonia, and were therefore considered likely pathogenic. Driven by the identification of a rare 14q11.2 duplication in one catatonic patient, additional patients with overlapping duplications were gathered to delineate a novel susceptibility locus for intellectual disability and psychiatric disorders on 14q11.2, harboring the gene SUPT16H. Three remaining variants respectively on 2q36.1, 16p13.13 and 17p13.3 were considered variants of unknown significance. CONCLUSION: The identification of catatonia-related copy number changes in this study, underscores the importance of genetic research in patients with catatonia. We confirmed that 22q13.3 deletions, affecting the gene SHANK3, predispose to catatonia, and we uncover 14q11.2 duplications as a novel susceptibility factor for intellectual and psychiatric disorders.

Catatonia/genética , Variações do Número de Cópias de DNA , Proteínas do Tecido Nervoso/genética , Adolescente , Criança , Pré-Escolar , Aberrações Cromossômicas , Cromossomos Humanos Par 14 , Cromossomos Humanos Par 22 , Feminino , Predisposição Genética para Doença , Haploinsuficiência/genética , Humanos , Deficiência Intelectual/genética , Masculino , Pessoa de Meia-Idade , Adulto Jovem
Eur J Med Genet ; 57(4): 157-62, 2014 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-24576609


A definitive molecular diagnosis of 22q11 Deletion Syndrome (22q11DS) even if occurring later in life, has important genetic, medical and emotional impact on the patients and their families. The aim of this study is to describe presenting symptoms and age at diagnosis in an adult 22q11DS population. A retrospective study was performed on 65 individuals diagnosed with 22q11DS at adult age. Data were collected on adults referred to the genetic clinic or actively recruited through systematic diagnostic examination in both institutions and a psychiatric unit for intellectually disabled. Presenting symptoms were categorized into seven groups: familial occurrence, intellectual disability, cardiac anomalies, palatal anomalies, facial dysmorphic features, psychiatric problems and 'other' (comprising all other features associated with 22q11DS). Age at diagnosis was defined as the age at which the 22q11.2 deletion was detected by fluorescence in situ hybridization or comparative genomic hybridization. Ascertainment subgroups were different in presenting symptoms and age at diagnosis. Adults were referred to the genetic clinic mainly because of familial occurrence, cardiac defects and psychiatric disorders whereas adults diagnosed in institutions for intellectually disabled presented mainly with moderate to severe intellectual disability and psychotic disorders. Adults diagnosed at the psychiatric unit for intellectually disabled had a variety of psychiatric disorders but none of them had additional physical features. This emphasizes the need to stay alert for presenting symptoms such as conotruncal heart defects or moderate to severe intellectual disability in combination with a history of psychiatric disorders, even in the absence of obvious physical features.

Síndrome da Deleção 22q11/genética , Anormalidades Múltiplas/genética , Síndrome da Deleção 22q11/diagnóstico , Adolescente , Adulto , Hibridização Genômica Comparativa , Face/anormalidades , Feminino , Cardiopatias Congênitas/genética , Humanos , Hibridização in Situ Fluorescente , Deficiência Intelectual/genética , Masculino , Pessoa de Meia-Idade , Palato/anormalidades , Transtornos Psicóticos/genética , Estudos Retrospectivos , Adulto Jovem