Characterization of intellectual disability and autism comorbidity through gene panel sequencing.

Intellectual disability (ID) and autism spectrum disorder (ASD) are clinically and genetically heterogeneous diseases. Recent whole exome sequencing studies indicated that genes associated with different neurological diseases are shared across disorders and converge on common functional pathways. Using the Ion Torrent platform, we developed a low-cost next-generation sequencing gene panel that has been transferred into clinical practice, replacing single disease-gene analyses for the early diagnosis of individuals with ID/ASD. The gene panel was designed using an innovative in silico approach based on disease networks and mining data from public resources to score disease-gene associations. We analyzed 150 unrelated individuals with ID and/or ASD and a confident diagnosis has been reached in 26 cases (17%). Likely pathogenic mutations have been identified in another 15 patients, reaching a total diagnostic yield of 27%. Our data also support the pathogenic role of genes recently proposed to be involved in ASD. Although many of the identified variants need further investigation to be considered disease-causing, our results indicate the efficiency of the targeted gene panel on the identification of novel and rare variants in patients with ID and ASD.

Contribution of SNP arrays in diagnosis of deletion 2p11.2-p12.

Deletions of the short arm of chromosome 2 are exceedingly rare, having been reported in few patients. Furthermore most cases with deletion in 2p11.2-p12 have been studied using standard karyotype and so it is not possible to delineate the precise size of deletions. Here, we describe a 9-year-old girl with a 9.4 Mb de novo interstitial deletion of region 2p11.2-p12 identified by SNP array analysis. The deleted region encompasses over 40 known genes, including LRRTM1, CTNNA2 and REEP1, haploinsufficiency of which could explain some clinical features of this patient such as mental retardation, speech delay and gait abnormalities. A comparison of our case with previously reported patients who present deletions in 2p11.2-p12 was carried out. Our case adds new information to the deletion of 2p11.2-p12, improving the knowledge on this rearrangement.

COMT Val158Met polymorphism and socioeconomic status interact to predict attention deficit/hyperactivity problems in children aged 10-14.

The functional Val158Met COMT polymorphism appears to affect a host of behaviours mediated by the pre-frontal cortex, and has been found associated to the risk for disruptive behaviours including ADHD. Parental socioeconomic status (SES) has also been reported as a predictor for the same childhood disorders. In a general population sample of 575 Italian pre-adolescents aged 10-14, we examined the association of the functional Val158Met COMT polymorphism and SES-both as linear and interactive effects-with oppositional defiant problems, conduct problems, and attention deficit/hyperactivity problems, as defined by the newly established Child Behaviour Check-List/6-18 DSM oriented scales. Multivariate- and subsequent univariate-analysis of covariance showed a significant association of COMT x SES interaction with CBCL 6/18 DOS attention deficit/hyperactivity problems (p = 0.004), and revealed higher scores among those children with Val/Val COMT genotype who belonged to low-SES families. We also found a significant association of SES with attention deficit/hyperactivity problems and conduct problems DOS (p = 0.04 and 0.01, respectively). Our data are consistent with a bulk of recent literature suggesting a role of environmental factors in moderating the contribution of specific genetic polymorphisms to human variability in ADHD. While future investigations will refine and better clarify which specific environmental and genetic mechanisms are at work in influencing the individual risk to ADHD in pre-adolescence, these data may contribute to identify/prevent the risk for ADHD problems in childhood.

Prevalence and correlates of mental disorders among adolescents in Italy: the PrISMA study.

BACKGROUND: While in the last 5 years several studies have been conducted in Italy on the prevalence of mental disorders in adults, to date no epidemiological study has been targeted on mental disorders in adolescents. METHOD: A two-phase study was conducted on 3,418 participants using the child behavior checklist/6-18 (CBCL) and the development and well-being assessment (DAWBA), a structured interview with verbatim reports reviewed by clinicians. RESULTS: The prevalence of CBCL caseness and DSM-IV disorders was 9.8% (CI 8.8-10.8%) and 8.2% (CI 4.2-12.3%), respectively. DSM-IV Emotional disorders were more frequently observed (6.5% CI 2.2-10.8%) than externalizing disorders (1.2% CI 0.2-2.3%). In girls, prevalence estimates increased significantly with age; furthermore, living with a single parent, low level of maternal education, and low family income were associated with a higher likelihood of suffering from emotional or behavioral problems. CONCLUSIONS: Approximately one in ten adolescents has psychological problems. Teachers and clinicians should focus on boys and girls living with a single parent and/or in disadvantaged socioeconomic conditions.

The influence of family structure, the TPH2 G-703T and the 5-HTTLPR serotonergic genes upon affective problems in children aged 10-14 years.

BACKGROUND: Both genetic and psychosocial risk factors influence the risk for depression in development. While the impacts of family structure and of serotonergic polymorphisms upon individual differences for affective problems have been investigated separately, they have never been considered together in a gene-environment interplay perspective. METHODS: We examined the effects of family structure and two serotonergic polymorphisms (the TPH2 G-703T and the 5-HTTLPR) upon depressive symptoms assessed by the new CBCL/6-18 DSM-oriented Affective Problems scale in a general population sample of 607 Italian children aged 10-14 years. RESULTS: Belonging to 'one-parent' families, the TPH2 G-703T 'G variant', and the 5-HTTLPR 'short' alleles were associated - both alone and in apparent gene-by-environment interaction - with higher Affective Problems scores. As predicted by quantitative genetics theory, both polymorphisms contributed with a small effect size, while 'family structure' had a moderate effect size. CONCLUSIONS: A putative hazard factor impinging on individual risk at the family-wide level, namely family structure, appears to act interactively with two pivotal serotonergic genes in heightening risk for Affective Problems. Although it remains to be demonstrated that belonging to a one- rather than a two-parent family has true environmental causal effects on Affective Problems, these data may contribute to identify/prevent risk for depression in childhood.

Socioeconomic status mediates the genetic contribution of the dopamine receptor D4 and serotonin transporter linked promoter region repeat polymorphisms to externalization in preadolescence.

The impact of socioeconomic status (SES) and genetic polymorphisms on individual differences for externalized behaviors have often been investigated separately in studies of children and adults. In a general population sample of 607 Italian preadolescents, we examined the independent and joint effects of SES and the dopamine receptor D4 (DRD4) and serotonin transporter linked promoter region (5-HTTLPR) polymorphisms upon rule-breaking and aggressive behaviors measured with the Child Behavior CheckList/6-18. We found evidence, which was based on both one locus and two-loci genotype analyses, that low SES and DRD4 long and 5-HTTLPR long alleles, both alone and in interaction, are associated with higher aggressive behavior scores. The effects were similar but more modest and limited to one locus genotype analyses for rule-breaking behavior. Consistent with studies that showed the effects of societal moderators on the heritability of externalized behaviors across different segments of the population, we suggest that diminished social constraints associated with low parental SES may act as enhancers of the genetic influence of specific DRD4 and 5-HTTLPR alleles over aggressive behaviors in preadolescence.

The Italian preadolescent mental health project (PrISMA): rationale and methods.

The Italian preadolescent mental health project (PrISMA--Progetto Italiano Salute Mentale Adolescenti) is the first Italian study designed to estimate the prevalence of mental disorders in preadolescents (10-14 years old) living in urban areas, and to analyse the demographic and biological correlates of emotional and behavioural problems. This paper describes the rationale, methods and the analysis plan of the project. The design of the study used a two-stage sampling procedure, one screening stage of emotional and behavioural problems in a large sample of subjects attending public and private schools and a second stage of diagnostic assessment in a sample including all high scorers and a proportion of low scorers. In the screening stage, parents of preadolescents were asked to fill in the Child Behavior Checklist (CBCL), whereas in the second stage preadolescents and their parents were administered the Development and Well Being Assessment for the assessment of mental disorders together with the Strengths and Difficulties Questionnaire and two scales (C-GAS and HoNOSCA) designed to evaluate the functioning of the preadolescent in different areas. Genetic samples were collected during the screening stage, after parents gave their informed written consent. The findings of this study are expected to allow an adequate planning of interventions for the prevention and the treatment of mental disorders in preadolescence as well as efficient health services.