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Background: Autism spectrum disorder (ASD) is a heterogeneous group of neurodevelopmental disorders characterized by a complex, multifactorial etiology with a strong genetic contribution. Our study aimed to evaluate the link between the burden of rare genetic variants within a specific panel of ASD and intellectual disability-associated genes and phenotypic variability in a cohort of children with autism in Slovakia. Methods: Gene burden scores were calculated based on pathogenic, likely pathogenic, and uncertain significance rare DNA variants identified by whole-exome sequencing. We then assessed the effect of three different scoring methods on the variance across 15 psycho-behavioral parameters describing the phenotypic profiles of 117 ASD probands. Results: The burden score showed a significant multivariate effect on the combination of psycho-behavioral parameters. This score was associated with the social affect of ADOS-2, as well as with the socialization domain, and total adaptive behavior scores from the Vineland Adaptive Behavior Scales-3 (VABS). While a score based solely on count of pathogenic and likely pathogenic variants did not show a multivariate effect, incorporating variants of uncertain significance revealed a multivariate effect on two adaptive behavior parameters: daily living skills and total adaptive behavior score (VABS). Conclusions: Our findings partially explain the variability in phenotypic manifestation in our ASD patient cohort, highlighting the importance of considering the cumulative effect of rare genetic variants, including those of uncertain significance, in shaping the diverse clinical presentation of ASD.

Here, we present a case study of twin boys aged 2 and 7 years who both met the diagnostic criteria for autism spectrum disorders (ASDs) based on the standard diagnostic instruments ADOS-2 and ADI-R. The clinical indication for genetic diagnostics in the first boy was autism with high severity of symptoms, delayed speech development, and mild facial dysmorphia. The second boy’s indication was autism with moderate severity of symptoms, delayed speech development, mild facial features, slowed psychomotor development, and microcephaly. The microarray-based analysis of chromosome aberrations revealed a heterozygous 977,456 bp deletion of region 10q26.3 in both boys. The region includes 28 genes, some of these genes are important in the development of the central nervous and urogenital systems, and heterozygous deletions in this region have been associated with mental retardation, growth and development disorders, and craniofacial anomalies. The whole exome sequencing confirmed the presence of this deletion in both boys and, at the same time, led to the identification of a pathogenic SNV variant in the TRIO gene in the boy with microcephaly and delayed psychomotor development, which may explain the different phenotype of both boys. However, the segregation analysis of these variants in the family revealed that the microdeletion was inherited from the asymptomatic father, and the c.2149C > T variant in the TRIO gene was inherited from the asymptomatic mother, making the diagnostic finding uncertain. This case highlights that when pathogenic or likely pathogenic variants are inherited from unaffected parents, the clinical phenotype may result from a combined burden of multiple rare variants and polygenic risk, underscoring the importance of a comprehensive genomic analysis in complex cases. Thus, we emphasize the importance of utilizing available methods, such as whole exome sequencing besides microarray-based comparative genomic hybridization, in the genetic diagnosis of autism patients in Slovakia.

Autism spectrum disorders (ASD) diagnostic procedure still lacks a uniform biological marker. This review gathers the information on microRNAs (miRNAs) specifically as a possible source of biomarkers of ASD. Extracellular vesicles, and their subset of exosomes, are believed to be a tool of cell-to-cell communication, and they are increasingly considered to be carriers of such a marker. The interest in studying miRNAs in extracellular vesicles grows in all fields of study and therefore should not be omitted in the field of neurodevelopmental disorders. The summary of miRNAs associated with brain cells and ASD either studied directly in the tissue or biofluids are gathered in this review. The heterogeneity in findings from different studies points out the fact that unified methods should be established, beginning with the determination of the accurate patient and control groups, through to sample collection, processing, and storage conditions. This review, based on the available literature, proposes the standardized approach to obtain the results that would not be affected by technical factors. Nowadays, the method of high-throughput sequencing seems to be the most optimal to analyze miRNAs. This should be followed by the uniformed bioinformatics procedure to avoid misvalidation. At the end, the proper validation of the obtained results is needed. With such an approach as is described in this review, it would be possible to obtain a reliable biomarker that would characterize the presence of ASD.

Here, we present a case study of twin boys aged 2 and 7years who both met the diagnostic criteria for autism spectrum disorders (ASDs) based on the standard diagnostic instruments ADOS-2 and ADI-R. The clinical indication for genetic diagnostics in the first boy was autism with high severity of symptoms, delayed speech development, and mild facial dysmorphia. The second boy's indication was autism with moderate severity of symptoms, delayed speech development, mild facial features, slowed psychomotor development, and microcephaly. The microarray-based analysis of chromosome aberrations revealed a heterozygous 977,456bp deletion of region 10q26.3 in both boys. The region includes 28 genes, some of these genes are important in the development of the central nervous and urogenital systems, and heterozygous deletions in this region have been associated with mental retardation, growth and development disorders, and craniofacial anomalies. The whole exome sequencing confirmed the presence of this deletion in both boys and, at the same time, led to the identification of a pathogenic SNV variant in the TRIO gene in the boy with microcephaly and delayed psychomotor development, which may explain the different phenotype of both boys. However, the segregation analysis of these variants in the family revealed that the microdeletion was inherited from the asymptomatic father, and the c.2149C>T variant in the TRIO gene was inherited from the asymptomatic mother, making the diagnostic finding uncertain. This case highlights that when pathogenic or likely pathogenic variants are inherited from unaffected parents, the clinical phenotype may result from a combined burden of multiple rare variants and polygenic risk, underscoring the importance of a comprehensive genomic analysis in complex cases. Thus, we emphasize the importance of utilizing available methods, such as whole exome sequencing besides microarray-based comparative genomic hybridization, in the genetic diagnosis of autism patients in Slovakia.

Autism spectrum disorder (ASD) is a complex of neurodevelopmental conditions with increasing incidence. The microbiota of children with ASD is distinct from neurotypical children, their food habits are also different, and it is known that nutrient intake influences microbiota in a specific way. Thus, this study investigates the food habits of children with ASD and their association with the gut microbiota. Children with ASD had their dietary energy intakes similar to controls, but they more often demonstrated food selectivity, which seemed to result in deficiency of micronutrients such as vitamins K, B6, C, iron, cooper, docosahexaenoic and docosapentanoic acid. Using high-throughput sequencing, a DNA library of intestinal microbiota was performed. Core microbiota was similar in children with and without ASD, but Dichelobacter, Nitriliruptor and Constrictibacter were found to be putative markers of ASD. The changes in gut microbiota that we observed in connection to food selectivity, intake of fats and omega-3 in particular, fermented milk products and animal/plant protein consumption had similar character, independent of diagnosis. However, high fibre intake was connected with a decreased α-diversity only in children with ASD. High carbohydrate and fibre intake influenced β-diversity, changing the abundance of Bacteroides and other genera, many of them members of the Clostidiaceae. Modulating food habits of ASD children can influence their gut microbiota composition.

In children with autism spectrum disorder (ASD), sleep disturbances are a frequent comorbidity with an adverse effect on their behavior and functioning. It was suggested that melatonin deficit is at least partly responsible for the sleep problems. The study aimed to investigate, in a sample of 56 children with ASD aged 2.8–13.3 years, if the sleep problems and melatonin secretion can serve as predictors of adaptive functioning and severity of the ASD core symptoms. We demonstrated that, after adjustment for age, the Sleep score assessed by the Children’s Sleep Habits Questionnaire predicts the Adaptive behavior composite score only in children younger than 6 years, and the preferred predictive model is for the domain Socialization. The age-adjusted Sleep score predicted Externalizing and Internalizing maladaptive behavior, with a near-zero contribution of age to the relationship between the Internalizing maladaptive behavior and Sleep score. After adjustment for age, the reduced night-time melatonin secretion predicted a higher severity of ASD symptoms in the domain Social affect and the Calibrated Severity Score, but not the sleep problems. Our results emphasize the importance of assessing sleep problems as a modifiable predictor of behavior in children with ASD and support the hypothesis about the role of melatonin in pathophysiology of ASD.