Structural Variations Contribute to the Genetic Etiology of Autism Spectrum Disorder and Language Impairments.

Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by restrictive interests and/or repetitive behaviors and deficits in social interaction and communication. ASD is a multifactorial disease with a complex polygenic genetic architecture. Its genetic contributing factors are not yet fully understood, especially large structural variations (SVs). In this study, we aimed to assess the contribution of SVs, including copy number variants (CNVs), insertions, deletions, duplications, and mobile element insertions, to ASD and related language impairments in the New Jersey Language and Autism Genetics Study (NJLAGS) cohort. Within the cohort, ~77% of the families contain SVs that followed expected segregation or de novo patterns and passed our filtering criteria. These SVs affected 344 brain-expressed genes and can potentially contribute to the genetic etiology of the disorders. Gene Ontology and protein-protein interaction network analysis suggested several clusters of genes in different functional categories, such as neuronal development and histone modification machinery. Genes and biological processes identified in this study contribute to the understanding of ASD and related neurodevelopment disorders.

Common genetic risk factors in ASD and ADHD co-occurring families.

Autism spectrum disorder (ASD) and attention-deficit/hyperactivity disorder (ADHD) are two major neurodevelopmental disorders that frequently co-occur. However, the genetic mechanism of the co-occurrence remains unclear. The New Jersey Language and Autism Genetics Study (NJLAGS) collected more than 100 families with at least one member affected by ASD. NJLAGS families show a high prevalence of ADHD and provide a good opportunity to study shared genetic risk factors for ASD and ADHD. The linkage study of the NJLAGS families revealed regions on chromosomes 12 and 17 that are significantly associated with ADHD. Using whole-genome sequencing data on 272 samples from 73 NJLAGS families, we identified potential risk genes for ASD and ADHD. Within the linkage regions, we identified 36 genes that are associated with ADHD using a pedigree-based gene prioritization approach. KDM6B (Lysine Demethylase 6B) is the highest-ranking gene, which is a known risk gene for neurodevelopmental disorders, including ASD and ADHD. At the whole-genome level, we identified 207 candidate genes from the analysis of both small variants and structure variants, including both known and novel genes. Using enrichment and protein-protein interaction network analyses, we identified gene ontology terms and pathways enriched for ASD and ADHD candidate genes, such as cilia function and cation channel activity. Candidate genes and pathways identified in our study improve the understanding of the genetic etiology of ASD and ADHD and will lead to new diagnostic or therapeutic interventions for ASD and ADHD in the future.

MicroRNA and MicroRNA-Target Variants Associated with Autism Spectrum Disorder and Related Disorders.

Autism spectrum disorder (ASD) is a childhood neurodevelopmental disorder with a complex and heterogeneous genetic etiology. MicroRNA (miRNA), a class of small non-coding RNAs, could regulate ASD risk genes post-transcriptionally and affect broad molecular pathways related to ASD and associated disorders. Using whole-genome sequencing, we analyzed 272 samples in 73 families in the New Jersey Language and Autism Genetics Study (NJLAGS) cohort. Families with at least one ASD patient were recruited and were further assessed for language impairment, reading impairment, and other associated phenotypes. A total of 5104 miRNA variants and 1,181,148 3' untranslated region (3' UTR) variants were identified in the dataset. After applying several filtering criteria, including population allele frequency, brain expression, miRNA functional regions, and inheritance patterns, we identified high-confidence variants in five brain-expressed miRNAs (targeting 326 genes) and 3' UTR miRNA target regions of 152 genes. Some genes, such as SCP2 and UCGC, were identified in multiple families. Using Gene Ontology overrepresentation analysis and protein-protein interaction network analysis, we identified clusters of genes and pathways that are important for neurodevelopment. The miRNAs and miRNA target genes identified in this study are potentially involved in neurodevelopmental disorders and should be considered for further functional studies.

RSMD-repeat searcher and motif detector.

The functionality of a gene or a protein depends on codon repeats occurring in it. As a consequence of their vitality in protein function and apparent involvement in causing diseases, an interest in these repeats has developed in recent years. The analysis of genomic and proteomic sequences to identify such repeats requires some algorithmic support from informatics level. Here, we proposed an offline stand-alone toolkit Repeat Searcher and Motif Detector (RSMD), which uncovers and employs few novel approaches in identification of sequence repeats and motifs to understand their functionality in sequence level and their disease causing tendency. The tool offers various features such as identifying motifs, repeats and identification of disease causing repeats. RSMD was designed to provide an easily understandable graphical user interface (GUI), for the tool will be predominantly accessed by biologists and various researchers in all platforms of life science. GUI was developed using the scripting language Perl and its graphical module PerlTK. RSMD covers algorithmic foundations of computational biology by combining theory with practice.