Expanded Insights Into Mechanisms of Gene Expression and Disease Related Disruptions

Definitive molecular diagnoses in disorders apparently due to genetic or genomic defects are still lacking in a significant number of investigated cases, despite use of studies designed to discover defects in the protein coding regions of the genome. Increasingly studies are being designed to search for defects in the non-protein coding genome, and for alterations in gene expression. Here we review new insights into genomic elements involved in control of gene expression, including methods to analyze chromatin that is accessible for transcription factor binding, enhancers, chromatin looping, transcription, RNA binding proteins, and alternative splicing. We review new studies on levels of genome organization, including the occurrence of transcriptional domains and their boundary elements. Information is presented on specific malformation syndromes that arise due to structural genomic changes that impact the non-protein coding genome and sometimes impact specific transcriptional domains. We also review convergence of genome-wide association with studies of gene expression, discoveries related to expression quantitative trait loci and splicing quantitative trait loci and the relevance of these to specific complex common diseases. Aspects of epigenetic mechanisms and clinical applications of analyses of methylation signatures are also discussed

A case of autism with an interstitial deletion on 4q leading to hemizygosity for genes encoding for glutamine and glycine neurotransmitter receptor sub-units (AMPA 2, GLRA3, GLRB) and neuropeptide receptors NPY1R, NPY5R

BACKGROUND: Autism is a pervasive developmental disorder characterized by a triad of deficits: qualitative impairments in social interactions, communication deficits, and repetitive and stereotyped patterns of behavior. Although autism is etiologically heterogeneous, family and twin studies have established a definite genetic basis. The inheritance of idiopathic autism is presumed to be complex, with many genes involved; environmental factors are also possibly contributory. The analysis of chromosome abnormalities associated with autism contributes greatly to the identification of autism candidate genes. CASE PRESENTATION: We describe a child with autistic disorder and an interstitial deletion on chromosome 4q. This child first presented at 12 months of age with developmental delay and minor dysmorphic features. At 4 years of age a diagnosis of Pervasive Developmental Disorder was made. At 11 years of age he met diagnostic criteria for autism. Cytogenetic studies revealed a chromosome 4q deletion. The karyotype was 46, XY del 4 (q31.3-q33). Here we report the clinical phenotype of the child and the molecular characterization of the deletion using molecular cytogenetic techniques and analysis of polymorphic markers. These studies revealed a 19 megabase deletion spanning 4q32 to 4q34. Analysis of existing polymorphic markers and new markers developed in this study revealed that the deletion arose on a paternally derived chromosome. To date 33 genes of known or inferred function are deleted as a consequence of the deletion. Among these are the AMPA 2 gene that encodes the glutamate receptor GluR2 sub-unit, GLRA3 and GLRB genes that encode glycine receptor subunits and neuropeptide Y receptor genes NPY1R and NPY5R. CONCLUSIONS: The deletion in this autistic subject serves to highlight specific autism candidate genes. He is hemizygous for AMPA 2, GLRA3, GLRB, NPY1R and NPY5R. GluR2 is the major determinant of AMPA receptor structure. Glutamate receptors maintain structural and functional plasticity of synapses. Neuropeptide Y and its receptors NPY1R and NPY5R play a role in hippocampal learning and memory. Glycine receptors are expressed in very early cortical development. Molecular cytogenetic studies and DNA sequence analysis in other patients with autism will be necessary to confirm that these genes are involved in autism

Rightward hemispheric asymmetries in auditory language cortex in children with autistic disorder: an MRI investigation

Purpose: determine if language disorder in children with autistic disorder (AD) corresponds to abnormalities in hemispheric asymmetries in auditory language cortex. Methods: MRI morphometric study in children with AD (n = 50) to assess hemispheric asymmetries in auditory language cortex. A key region of interest was the planum temporale (PT), which is larger in the left hemisphere in most healthy individuals. Results: (i) Heschl’s gyrus and planum polare showed typical hemisphere asymmetry patterns; (ii) posterior Superior Temporal Gyrus (pSTG) showed significant rightward asymmetry; and (iii) PT showed a trend for rightward asymmetry that was significant when constrained to right-handed boys (n = 30). For right-handed boys, symmetry indices for pSTG were significantly positively correlated with those for PT. PT asymmetry was age dependent, with greater rightward asymmetry with age. Conclusions: results provide evidence for rightward asymmetry in auditory association areas (pSTG and PT) known to subserve language processing. Cumulatively, our data provide evidence for a differing maturational path for PT for lower functioning children with AD, with both pre- and post-natal experience likely playing a role in PT asymmetry

Nuclear and mitochondrial genome defects in autisms.

In this review we will evaluate evidence that altered gene dosage and structure impacts neurodevelopment and neural connectivity through deleterious effects on synaptic structure and function, and evidence that the latter are key contributors to the risk for autism. We will review information on alterations of structure of mitochondrial DNA and abnormal mitochondrial function in autism and indications that interactions of the nuclear and mitochondrial genomes may play a role in autism pathogenesis. In a final section we will present data derived using Affymetrix SNP 6.0 microarray analysis of DNA of a number of subjects and parents recruited to our autism spectrum disorders project. We include data on two sets of monozygotic twins. Collectively these data provide additional evidence of nuclear and mitochondrial genome imbalance in autism and evidence of specific candidate genes in autism. We present data on dosage changes in genes that map on the X chromosomes and the Y chromosome. Precise analyses of Y located genes are often difficult because of the high degree of homology of X- and Y-related genes. However, continued efforts to analyze the latter are important, given the consistent evidence for a 4:1 ratio of males to females affected by autism. It is also important to consider whether environmental factors play a role in generating the nuclear and mitochondrial genomic instability we have observed. The study of autism will benefit from a move to analysis of pathways and multigene clusters for identification of subtypes that share a specific genetic etiology

Nuclear and mitochondrial genome defects in autisms.

In this review we will evaluate evidence that altered gene dosage and structure impacts neurodevelopment and neural connectivity through deleterious effects on synaptic structure and function, and evidence that the latter are key contributors to the risk for autism. We will review information on alterations of structure of mitochondrial DNA and abnormal mitochondrial function in autism and indications that interactions of the nuclear and mitochondrial genomes may play a role in autism pathogenesis. In a final section we will present data derived using Affymetrix SNP 6.0 microarray analysis of DNA of a number of subjects and parents recruited to our autism spectrum disorders project. We include data on two sets of monozygotic twins. Collectively these data provide additional evidence of nuclear and mitochondrial genome imbalance in autism and evidence of specific candidate genes in autism. We present data on dosage changes in genes that map on the X chromosomes and the Y chromosome. Precise analyses of Y located genes are often difficult because of the high degree of homology of X- and Y-related genes. However, continued efforts to analyze the latter are important, given the consistent evidence for a 4:1 ratio of males to females affected by autism. It is also important to consider whether environmental factors play a role in generating the nuclear and mitochondrial genomic instability we have observed. The study of autism will benefit from a move to analysis of pathways and multigene clusters for identification of subtypes that share a specific genetic etiology

Mixture model based group inference in fused genotype and phenotype data

The analysis of genetic diseases has classically been directed towards establishing direct links between cause, a genetic variation, and effect, the observable deviation of phenotype. For complex diseases which are caused by multiple factors and which show a wide spread of variations in the phenotypes this is unlikely to succeed. One example is the Attention Deficit Hyperactivity Disorder (ADHD), where it is expected that phenotypic variations will be caused by the overlapping effects of several distinct genetic mechanisms. The classical statistical models to cope with overlapping subgroups are mixture models, essentially convex combinations of density functions, which allow inference of descriptive models from data as well as the deduction of groups. An extension of conventional mixtures with attractive properties for clustering is the context-specific independence (CSI) framework. CSI allows for an automatic adaption of model complexity to avoid overfitting and yields a highly descriptive model

A comparative study of patients’ perceptions of genetic and genomic medicine services in California and Malaysia

In the era of personalized and genomic medicine, awareness of patients with rare diseases is increasing as new approaches to diagnosis and treatment are developed. This study examined perceived barriers experienced by families with rare diseases and explored possible differences between participants in Malaysia and California, USA. The study involved N = 108 participants recruited in genetics clinic appointments at the University of Malaya Medical Center and three sites in Southern California. Participants completed a survey involving multiple choice and Likert scale items pertaining to perceived barriers to access genetics-related healthcare. Results from this study provide evidence of similar perceived barriers, despite differences in the two populations. Participants selected the expansion of healthcare provider knowledge of rare diseases to be the most beneficial approach to overcome perceived barriers. In both locations, it was also noted that travel distance to clinic was not perceived as a large stress factor. Taking these observations together, a healthcare model with a central location of providers well-versed in medical genetics may be considered if further data support our findings. The data from this study support a need for improving healthcare provider knowledge of genetics. Future studies exploring how these perceived stress factors are impacting families as well as different methods of educating providers are suggested by findings from the study, as well as studies querying the opinions of those who are unable to access genetics services. © 2018, Springer-Verlag GmbH Germany, part of Springer Nature