Artificial neural networks reveal sex differences in gene methylation, and connections between maternal risk factors and symptom severity in autism spectrum disorder.

Aim and methods: Artificial neural networks were used to unravel connections among blood gene methylation levels, sex, maternal risk factors and symptom severity evaluated using the Autism Diagnostic Observation Schedule 2 (ADOS-2) score in 58 children with autism spectrum disorder (ASD). Results: Methylation levels of MECP2, HTR1A and OXTR genes were connected to females, and those of EN2, BCL2 and RELN genes to males. High gestational weight gain, lack of folic acid supplements, advanced maternal age, preterm birth, low birthweight and living in rural context were the best predictors of a high ADOS-2 score. Conclusion: Artificial neural networks revealed links among ASD maternal risk factors, symptom severity, gene methylation levels and sex differences in methylation that warrant further investigation in ASD.

Correlation among maternal risk factors, gene methylation and disease severity in females with autism spectrum disorder.

Aim: To detect early-life environmental factors leading to DNA methylation changes of autism spectrum disorder (ASD)-related genes in young ASD females and reveal epigenetic biomarkers of disease severity. Materials & methods: We investigated blood methylation levels of MECP2, OXTR, BDNF, RELN, BCL2, EN2 and HTR1A genes in 42 ASD females. Results: Maternal gestational weight gain correlated with BDNF methylation levels (Bonferroni-corrected p = 0.034), and lack of folic acid supplementation at periconception resulted in higher disease severity in the ASD children (Bonferroni-corrected p = 0.048). RELN methylation levels were inversely correlated with disease severity (Bonferroni corrected p = 0.042). Conclusion: The present study revealed gene-environment interactions and potential epigenetic biomarkers of disease severity in ASD females.

Early-life maternal factors can leave marks on the DNA of the developing fetus, including changes in DNA methylation that regulate gene expression levels. These marks can pose an increased risk for several diseases, such as autism spectrum disorder (ASD) and other developmental disorders. In the present study, we searched for links between early-life maternal factors and the methylation levels of ASD-related genes in blood DNA samples of young ASD diagnosed females. We found that high maternal gestational weight gain resulted in increased methylation levels of the BDNF gene, one of the most important genes for brain development. Moreover, lack of maternal folic acid supplementation and low RELN methylation levels resulted in higher disease severity in ASD females.

Behavioral and emotional problems of toddlers with autism spectrum disorder: Effects of parents' sociocultural level and individual factors.

BACKGROUND: Toddlers with autism spectrum disorder (ASD) show higher prevalence and severity of Behavioral and Emotional Problems (BEP) than their peers without ASD. AIMS: Investigating the effects of parental factors, i.e., mothers' and fathers' age and Sociocultural Level (Socioeconomic Status, Cultural Capital, and Social Capital), and individual factors, i.e., toddles' age, birth order, general development, autism symptom severity, and adaptive behavior, on the expression of BEP in toddlers with ASD. METHODS: Participants were 148 toddlers with ASD (aged 18-37 months) and both their parents. BEP were measured with the Child Behavior Checklist 1½-5 (CBCL) Syndrome and Pervasive developmental problems (PDD) DSM-oriented scales, general development with the Griffiths Mental Development Scales (GMDS), autism symptom severity with the Autism Diagnostic Observation Schedule-2 (ADOS-2), and adaptive behavior with the Vineland-II Adaptive behavior composite. RESULTS: Vineland-IIAdaptive behavior composite was negatively associated with the majority of the CBCL scales. In contrast, the ADOS-2 Restrictive and repetitive behavior was negatively and the ADOS-2 Social affect, toddlers' age, and birth order were positively associated with only a few of the CBCL scales (e.g., PDD). GMDS scores were not associated with any CBCL scales. Mothers' age and fathers' Cultural Capital and Social Capital dimensions were negatively associated with specific CBCL scales, even when considered in addition to individuals' factors. CONCLUSIONS: Individual and parental factors simultaneously affect the expression of BEP and should be considered for clinical decisions.

Individual and Environmental Factors Affecting Adaptive Behavior of Toddlers with Autism Spectrum Disorder: Role of Parents' Socio-cultural Level.

The effects of environmental factors [including Socio-Economic Status, Cultural Capital, and Social Capital (Socio-Cultural Level) of both parents] on the Vineland-II adaptive behavior dimensions of toddlers with autism spectrum disorder (ASD), in addition to individual factors, was investigated in 148 Italian toddlers (82% males), aged 18 to 37 months with ASD. Toddlers' age and Griffiths Mental Development Scales general development affected all of the adaptive behavior dimensions, with negative and positive associations, respectively. The Child Behavior Checklist comorbid conditions were negatively associated with some adaptive behavior dimensions while the ADOS-2 Social affect only with the communication dimension. Mothers' and fathers' specific Socio-Cultural Level dimensions were positively associated with toddlers' specific adaptive behavior dimensions with the same magnitude as comorbid conditions.

Focusing on Autism Spectrum Disorder in Xia-Gibbs Syndrome: Description of a Female with High Functioning Autism and Literature Review.

BACKGROUND: Xia-Gibbs syndrome (XGS) is a rare disorder caused by de novo mutations in the AT-Hook DNA binding motif Containing 1 (AHDC1) gene, which is characterised by a wide spectrum of clinical manifestations, including global developmental delay, intellectual disability, structural abnormalities of the brain, global hypotonia, feeding problems, sleep difficulties and apnoea, facial dysmorphisms, and short stature. METHODS: Here, we report on a girl patient who shows a peculiar cognitive and behavioural profile including high-functioning autism spectrum disorder (ASD) without intellectual disability and provide information on her developmental trajectory with the aim of expanding knowledge of the XGS clinical spectrum. On the basis of the current clinical case and the literature review, we also attempt to deepen understanding of behavioural and psychiatric manifestations associated with XGS. RESULTS: In addition to the patient we described, a considerable rate of individuals with XGS display autistic symptoms or have been diagnosed with an autistic spectrum disorder. Moreover, the analysis of the few psychopathological profiles of patients with XGS described in the literature shows a frequent presence of aggressive and self-injurious behaviours that could be either an expression of autistic functioning or an additional symptom of the ASD evolution. A careful investigation of the abovementioned symptoms is therefore required, since they could represent a "red flag" for ASD.

Evaluation of Chromosome Microarray Analysis in a Large Cohort of Females with Autism Spectrum Disorders: A Single Center Italian Study.

Autism spectrum disorders (ASD) encompass a heterogeneous group of neurodevelopmental disorders resulting from the complex interaction between genetic and environmental factors. Thanks to the chromosome microarray analysis (CMA) in clinical practice, the accurate identification and characterization of submicroscopic deletions/duplications (copy number variants, CNVs) associated with ASD was made possible. However, the widely acknowledged excess of males on the autism spectrum reflects on a paucity of CMA studies specifically focused on females with ASD (f-ASD). In this framework, we aim to evaluate the frequency of causative CNVs in a single-center cohort of idiopathic f-ASD. Among the 90 f-ASD analyzed, we found 20 patients with one or two potentially pathogenic CNVs, including those previously associated with ASD (located at 16p13.2 16p11.2, 15q11.2, and 22q11.21 regions). An exploratory genotype/phenotype analysis revealed that the f-ASD with causative CNVs had statistically significantly lower restrictive and repetitive behaviors than those without CNVs or with non-causative CNVs. Future work should focus on further understanding of f-ASD genetic underpinnings, taking advantage of next-generation sequencing technologies, with the ultimate goal of contributing to precision medicine in ASD.