Challenges in screening for de novo noncoding variants contributing to genetically complex phenotypes.

Understanding the genetic basis for complex, heterogeneous disorders, such as autism spectrum disorder (ASD), is a persistent challenge in human medicine. Owing to their phenotypic complexity, the genetic mechanisms underlying these disorders may be highly variable across individual patients. Furthermore, much of their heritability is unexplained by known regulatory or coding variants. Indeed, there is evidence that much of the causal genetic variation stems from rare and de novo variants arising from ongoing mutation. These variants occur mostly in noncoding regions, likely affecting regulatory processes for genes linked to the phenotype of interest. However, because there is no uniform code for assessing regulatory function, it is difficult to separate these mutations into likely functional and nonfunctional subsets. This makes finding associations between complex diseases and potentially causal de novo single-nucleotide variants (dnSNVs) a difficult task. To date, most published studies have struggled to find any significant associations between dnSNVs from ASD patients and any class of known regulatory elements. We sought to identify the underlying reasons for this and present strategies for overcoming these challenges. We show that, contrary to previous claims, the main reason for failure to find robust statistical enrichments is not only the number of families sampled, but also the quality and relevance to ASD of the annotations used to prioritize dnSNVs, and the reliability of the set of dnSNVs itself. We present a list of recommendations for designing future studies of this sort that will help researchers avoid common pitfalls.

Early Life Experiences Moderate the Relationship Between Genetic Risk of Autism and Current and Lifetime Mental Health.

Although individuals with autism are at greater risk of mental health challenges than others, we know little about the relationship between the mental health of older adults (50+) and autism because they are less likely to be diagnosed. Identifying the risk and protective factors that are associated with mental health can increase educational awareness, inform clinical practice, and provide information to help diagnose and treat older adults with autism. This study used longitudinal panel data of the 2008-2016 waves of the Health and Retirement Study. It estimated individual random-effect models by interacting a genetic propensity toward autism and early life experiences to test whether the latter has a moderating effect on the relationships between genetics and the Center for Epidemiologic Studies Depression (CES-D) score, self-reported depression, and history of psychiatric problems. Results suggest that individuals with a higher genetic propensity for autism are less likely to develop psychiatric problems if they report a positive maternal relationship early in life. Further, a combined effect of police encounters early in life and genetic risk for autism is associated with higher CES-D scores, increased odds of self-reported depression, and a history of psychiatric problems. Clinical applications of these findings include the need to establish and support high-quality relationships by addressing both child and caregiver needs. Further, these findings support the need to design and implement proactive interventions to teach police and autistic individuals how to successfully navigate these encounters.

Next-Generation Sequencing in Korean Children With Autism Spectrum Disorder and Comorbid Epilepsy.

Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by impairments in social communication and restricted and repetitive behaviors and interests. Identifying the genetic background may be one of the key features for the future diagnosis and treatment of ASD. With the tremendous development in genetic diagnosis techniques, next-generation sequencing (NGS) can be used to analyze multiple genes simultaneously with a single test in laboratory and clinical settings and is well suited for investigating autism genetics. According to previous studies, there are two types of genetic variants in ASD, rare variants and common variants, and both are important in explaining pathogenesis. In this study, NGS data from 137 participants with ASD were reviewed retrospectively with consideration for comorbid epilepsy. Diagnostic yield was 17.51% (24/137), and pathogenic/likely pathogenic variants were seen more frequently in female participants. Fourteen participants were diagnosed with comorbid epilepsy, six of them had pathogenic/likely pathogenic variants (43%). Genes with variants of unknown significance (VOUS) which have one or more evidence of pathogenicity following the American College of Medical Genetics (ACMG) criteria were also reviewed in both ASD and ASD with comorbid epilepsy groups. We found that most frequently found VOUS genes have previously been reported as genes related to ASD or other developmental disorders. These results suggest that when interpreting the NGS results in the clinical setting, careful observation of VOUS with some pathological evidence might contribute to the discovery of genetic pathogenesis of neurodevelopmental disorders such as ASD and epilepsy.

Aspectos genéticos y neuroendocrinos en el trastorno del espectro autista / Genetic and neuroendocrine aspects in autism spectrum disorder

El autismo, hoy en día definido como trastornos del espectro autista, fue descrito inicialmente en 1943. Se caracteriza por alteraciones en la comunicación, la interacción social y un espectro restringido de intereses del paciente. Generalmente se identifica en etapas tempranas del desarrollo a partir de los 18 meses de edad. Actualmente el autismo se considera un desorden neurológico con un espectro que abarca diferentes grados que se asocian con factores genéticos, no genéticos y del medio ambiente. Dentro de los factores genéticos se han referido diversos síndromes relacionados con este trastorno. Asimismo, el autismo se ha estudiado a nivel genético, neurofisiológico, neuroquímico y neuropatológico. Las técnicas de neuroimagen han mostrado múltiples anormalidades estructurales en estos pacientes. También se han observado alteraciones relacionadas en los sistemas serotoninérgico, GABAérgico, catecolaminérgico y colinérgico. En este trabajo se presenta una actualización de la información de los aspectos genéticos y neuroendocrinos del trastorno del espectro autista.

The autism spectrum disorder (ASD) was described in 1943 and is defined as a developmental disorder that affects social interaction and communication. It is usually identified in early stages of development from 18 months of age. Currently, autism is considered a neurological disorder with a spectrum covering cases of different degrees, which is associated with genetic factors, not genetic and environmental. Among the genetic factors, various syndromes have been described that are associated with this disorder. Also, the neurobiology of autism has been studied at the genetic, neurophysiological, neurochemical and neuropathological levels. Neuroimaging techniques have shown multiple structural abnormalities in these patients. There have also been changes in the serotonergic, GABAergic, catecholaminergic and cholinergic systems related to this disorder. This paper presents an update of the information presented in the genetic and neuroendocrine aspects of autism spectrum disorder.

[Genetic and neuroendocrine aspects in autism spectrum disorder]. / Aspectos genéticos y neuroendocrinos en el trastorno del espectro autista.

The autism spectrum disorder (ASD) was described in 1943 and is defined as a developmental disorder that affects social interaction and communication. It is usually identified in early stages of development from 18 months of age. Currently, autism is considered a neurological disorder with a spectrum covering cases of different degrees, which is associated with genetic factors, not genetic and environmental. Among the genetic factors, various syndromes have been described that are associated with this disorder. Also, the neurobiology of autism has been studied at the genetic, neurophysiological, neurochemical and neuropathological levels. Neuroimaging techniques have shown multiple structural abnormalities in these patients. There have also been changes in the serotonergic, GABAergic, catecholaminergic and cholinergic systems related to this disorder. This paper presents an update of the information presented in the genetic and neuroendocrine aspects of autism spectrum disorder.

A de novo convergence of autism genetics and molecular neuroscience.

Autism spectrum disorder (ASD) and intellectual disability (ID) are neurodevelopmental disorders with large genetic components, but identification of pathogenic genes has proceeded slowly because hundreds of loci are involved. New exome sequencing technology has identified novel rare variants and has found that sporadic cases of ASD/ID are enriched for disruptive de novo mutations. Targeted large-scale resequencing studies have confirmed the significance of specific loci, including chromodomain helicase DNA binding protein 8 (CHD8), sodium channel, voltage-gated, type II, alpha subunit (SCN2A), dual specificity tyrosine-phosphorylation-regulated kinase 1A (DYRK1A), and catenin (cadherin-associated protein), beta 1, 88 kDa (CTNNB1, beta-catenin). We review recent studies and suggest that they have led to a convergence on three functional pathways: (i) chromatin remodeling; (ii) wnt signaling during development; and (iii) synaptic function. These pathways and genes significantly expand the neurobiological targets for study, and suggest a path for future genetic and functional studies.