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

Identifying Genes and Loci for Complex Diseases: Examples from Primary Open Angle Glaucoma and Schizophrenia.

This purpose of this dissertation is to progress towards identification of disease genes and loci for primary open-angle glaucoma (POAG) and schizophrenia. In studying schizophrenia, we conducted a genome-wide linkage scan in 479 subjects from 129 Afrikaner families; Afrikaners are a founder population from South Africa. Conducting a MOD score analysis, we were able to replicate a schizophrenia locus on chromosome 13q34 in subjects with broadly defined schizophrenia, which includes schizoaffective disorder- depressive subtype and schizoaffective disorder- bipolar subtype (MOD score = 3.76). We also detected a locus on chromosome 1p36 in subjects classified with a more narrowly defined form of schizophrenia that include schizoaffective disorder- depressive subtype, but not bipolar subtype (MOD score = 3.21). We conducted two separate studies looking for POAG genes and loci. In the first study, we replicated the GLC1I locus on chromosomes 15q11-13. We initially tested 167 European American individuals in 25 multiplex open-angle glaucoma families and detected a LOD score of 1.01 at 14.3 cM. However when we used ordered subset analysis, we found that by including only the 14 families with earlier average ages at diagnosis (average=50.6 years ±5.4 years), there is evidence for linkage to GLC1I (LOD score = 2.09; p-value = 0.021). In the third and final study, we tested whether glaucoma severity is associated with variants in the promoter region of a known glaucoma gene, myocilin (MYOC). There have been conflicting reports regarding the relationship between glaucoma severity and the -1000CG MYOC promoter SNP, also designated mt1. This study tested for an association in subjects from the Collaborative Initial Glaucoma Treatment Study (CIGTS); a longitudinal study where the subjects were reevaluated every six months. We found that there was not evidence for an association between -1000CG and visual field mean deviation (p=0.98) or intraocular pressure (p=0.52) across the study period in the CIGTS population. There was also no evidence of association between two other MYOC promoter SNPs, -1075GA and -1081AG, and mean deviation or intraocular pressure. In describing these studies, this dissertation illustrates methods and techniques that can be applied to the study of genetics of other complex diseases.PhDEpidemiological ScienceUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttp://deepblue.lib.umich.edu/bitstream/2027.42/63652/1/awoodrof_1.pd

Veterans Health Administration Mental Health Program Evaluation, Summary

This report summarizes a four-year evaluation of mental health services provided by the Veterans Administration (VA) for veterans with schizophrenia, bipolar disorder, posttraumatic stress disorder, major depression, and substance use disorders. The population of veterans with the diagnoses included in the study comprises a large and growing number of veterans with severe and complex general medical and mental disorders and accounts for a disproportionately large proportion of utilization and costs for the VA. Study veterans represented 15.4 percent of all veterans who used VA services in 2007 but accounted for 32.9 percent of the costs due to higher utilization of inpatient and outpatient services. Across the country, VA facilities report substantial capacity for treating seriously mentally ill veterans. Although capacity has increased since the implementation of the Mental Health Strategic Plan in 2005, important gaps remain. The proportion of veterans receiving recommended care varies widely, and there is variation in many of the performance indicators assessed with regard to specific populations, services, and locations. In most instances, VA care performance is as good as or better than that reported by other groups or shown by direct comparisons with other systems of care, but the level often does not meet implicit VA expectations. Most performance indicators did not show substantial improvement from FY 2004 through FY 2007, but recent structural enhancements and increased availability of services may yield improvements in the future, and the number of veterans in the study cohorts who were served during the study period increased annually. Veterans' perceptions of VA services were favorable, although they did not perceive significant improvement in their conditions. Opportunities for further investigation are identified, along with specific problem areas and strategies for improving performance and methods to enhance capacity for quality monitoring and improvement

Nogo receptor 1 (RTN4R) as a candidate gene for schizophrenia: Analysis using human and mouse genetic approaches

Background. NOGO Receptor 1 (RTN4R) regulates axonal growth, as well as axort regeneration after injury. The gene maps to the 22q11.2 schizophrenia susceptibility locus and is thus a strong functional and positional candidate gene. Methodology/Principal Findings. We evaluate evidence for genetic association between common RTN4R polymorphisms and schizophrenia in a large family sample of Afrikaner origin and screen the exonic sequence of RTN4R for rare variants in an independent sample from the U.S. We also employ animal model studies to assay a panel of schizophrenia-related behavioral tasks in an Rtn4r-deficient mouse model. We found weak sex-specific evidence for association between common RTN4R polymorphisms and schizophrenia in the Afrikaner patients. In the U.S. sample, we identified two novel non-conservative RTN4R coding variants in two patients with schizophrenia that were absent in 600 control chromosomes. In our complementary mouse model studies, we identified a haploinsufficient effect of Rtn4r on locomotor activity, but normal performance in schizophrenia-related behavioral tasks. We also provide evidence that Rtn4r deficiency can modulate the long-term behavioral effects of transient postnatal N-methyl-D-aspartate (NMDA) receptor hypofunction. Conclusions. Our results do not support a major role of RTN4R in susceptibility to schizophrenia or the cognitive and behavioral deficits observed in individuals with 22q11 microdeletions. However, they suggest that RTN4R may modulate the genetic risk or clinical expression of schizophrenia in a subset of patients and identify additional studies that will be necessary to clarify the role of RTN4R in psychiatric phenotypes. In addition, our results raise interesting issues about evaluating the significance of rare genetic variants in disease and their role in causation. © 2007 Hsu et al

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.

BackgroundAutism 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 presentationWe 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.ConclusionsThe 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

Nogo Receptor 1 (RTN4R) as a candidate gene for schizophrenia: analysis using human and mouse genetic approaches.

NOGO Receptor 1 (RTN4R) regulates axonal growth, as well as axon regeneration after injury. The gene maps to the 22q11.2 schizophrenia susceptibility locus and is thus a strong functional and positional candidate gene.We evaluate evidence for genetic association between common RTN4R polymorphisms and schizophrenia in a large family sample of Afrikaner origin and screen the exonic sequence of RTN4R for rare variants in an independent sample from the U.S. We also employ animal model studies to assay a panel of schizophrenia-related behavioral tasks in an Rtn4r-deficient mouse model. We found weak sex-specific evidence for association between common RTN4R polymorphisms and schizophrenia in the Afrikaner patients. In the U.S. sample, we identified two novel non-conservative RTN4R coding variants in two patients with schizophrenia that were absent in 600 control chromosomes. In our complementary mouse model studies, we identified a haploinsufficient effect of Rtn4r on locomotor activity, but normal performance in schizophrenia-related behavioral tasks. We also provide evidence that Rtn4r deficiency can modulate the long-term behavioral effects of transient postnatal N-methyl-D-aspartate (NMDA) receptor hypofunction.Our results do not support a major role of RTN4R in susceptibility to schizophrenia or the cognitive and behavioral deficits observed in individuals with 22q11 microdeletions. However, they suggest that RTN4R may modulate the genetic risk or clinical expression of schizophrenia in a subset of patients and identify additional studies that will be necessary to clarify the role of RTN4R in psychiatric phenotypes. In addition, our results raise interesting issues about evaluating the significance of rare genetic variants in disease and their role in causation