MRNA Transcription, Translation, and Defects in Developmental Cognitive and Behavioral Disorders.

The growth of expertise in molecular techniques, their application to clinical evaluations, and the establishment of databases with molecular genetic information has led to greater insights into the roles of molecular processes related to gene expression in neurodevelopment and functioning. The goal of this review is to examine new insights into messenger RNA transcription, translation, and cellular protein synthesis and the relevance of genetically determined alterations in these processes in neurodevelopmental, cognitive, and behavioral disorders.

Ethnic disparities in the frequency of cancer reported in family histories.

This study was designed to observe whether disparities exist between ethnicities in reporting a family history of cancer in a cancer genetic counseling clinic. Four hundred sixty-nine pedigrees collected between 2015 to 2017 from a cancer clinic at the University of California, Irvine, were analyzed. Pedigrees were separated by ethnicity into the following categories: non-Hispanic White, Hispanic, Asian, or Ashkenazi Jewish.

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.

Meta-analysis of genotype-phenotype analysis of OPA1 mutations in autosomal dominant optic atrophy.

Autosomal Dominant Optic Atrophy (ADOA) is a neuro-ophthalmic disease characterized by progressive bilateral vision loss, pallor of the optic disc, central vision loss, and impairment of color vision. Additionally, a small percentage of patients experience hearing loss and ataxia, while recent studies suggest disruption of cardiac and neuromuscular functions. In order to obtain a better understanding of the genotype-phenotype correlation of the various mutations in the optic atrophy 1 (OPA1) gene, we obtained both clinical and genetic information of ADOA patients from published reports.

DNA Sequence Analysis in Clinical Medicine, Proceeding Cautiously.

Delineation of underlying genomic and genetic factors in a specific disease may be valuable in establishing a definitive diagnosis and may guide patient management and counseling. In addition, genetic information may be useful in identification of at risk family members. Gene mapping and initial genome sequencing data enabled the development of microarrays to analyze genomic variants.

Mitochondrial and ion channel gene alterations in autism.

To evaluate the potential importance in autistic subjects of copy number variants (CNVs) that alter genes of relevance to bioenergetics, ionic metabolism, and synaptic function, we conducted a detailed microarray analysis of 69 autism probands and 35 parents, compared to 89 CEU HapMap controls. This revealed that the frequency CNVs of≥100kb and CNVs of≥10 Kb were markedly increased in probands over parents and in probands and parents over controls. Evaluation of CNVs≥1Mb by chromosomal FISH confirmed the molecular identity of a subset of the CNVs, some of which were associated with chromosomal rearrangements.

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.

The year in human and medical genetics. Highlights of 2007-2008.

The breadth and scope of new information makes difficult a selection of topics to be included in a limited review of highlights of the year. Admittedly, the choices are idiosyncratic. The eight topics presented here are (1) structural and copy number variants in the human genome; (2) progress in defining genetic factors in the etiology of schizophrenia; (3) microRNAs in central nervous system development and function; (4) progress in elucidation of risk factors for complex common disorders through large scale association studies; (5) epigenetics and the epigenomic era; (6) reprogramming of somatic cell nuclei to generate pluripotent stem cells; (7) new concepts regarding factors involved in sexual differentiation; and (8) Duffy blood group antigens: new concepts, and new discoveries on the role of these antigens in malaria and HIV-AIDS.

Mapping autism risk loci using genetic linkage and chromosomal rearrangements.

Autism spectrum disorders (ASDs) are common, heritable neurodevelopmental conditions. The genetic architecture of ASDs is complex, requiring large samples to overcome heterogeneity. Here we broaden coverage and sample size relative to other studies of ASDs by using Affymetrix 10K SNP arrays and 1,181 [corrected] families with at least two affected individuals, performing the largest linkage scan to date while also analyzing copy number variation in these families.

Evaluation of the chromosome 2q37.3 gene CENTG2 as an autism susceptibility gene.

Autism is a highly heritable neurodevelopmental syndrome with a complex genetic etiology for which no disease genes have yet been definitively identified. We ascertained three subjects with autism spectrum disorders and chromosome 2q37.3 terminal deletions, and refined the deletion breakpoint regions using polymorphism mapping and fluorescence in situ hybridization (FISH) probes.

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.

Alleles of a reelin CGG repeat do not convey liability to autism in a sample from the CPEA network.

A recent study by Persico et al. [2001: Mol Psychiatry 6:150-159] suggests alleles of a CGG polymorphism, just 5' of the reelin gene (RELN) initiator codon, confer liability for autism, especially alleles bearing 11 or more CGG repeats (long alleles). The association is consistent across both a case-control and family-based sample.

Mitochondrial dysfunction in autistic patients with 15q inverted duplication.

Two autistic children with a chromosome 15q11-q13 inverted duplication are presented. Both had uneventful perinatal courses, normal electroencephalogram and magnetic resonance imaging scans, moderate motor delay, lethargy, severe hypotonia, and modest lactic acidosis. Both had muscle mitochondrial enzyme assays that showed a pronounced mitochondrial hyperproliferation and a partial respiratory chain block most parsimoniously placed at the level of complex III, suggesting candidate gene loci for autism within the critical region may affect pathways influencing mitochondrial function.

No evidence for linkage of liability to autism to HOXA1 in a sample from the CPEA network.

A recent study by Ingram et al. [2000b: Teratology 62:393-405] suggests a (His)73(Arg) polymorphism (A:G) in HOXA1 contributes substantially to a liability for autism. Using 68 individuals diagnosed with Autism Spectrum Disorders, they found a significant dearth of G homozygotes and biased transmission of G alleles from parents to affected offspring, especially from mothers.

Presence of large deletions in kindreds with autism.

Autism is caused, in part, by inheritance of multiple interacting susceptibility alleles. To identify these inherited factors, linkage analysis of multiplex families is being performed on a sample of 105 families with two or more affected sibs. Segregation patterns of short tandem repeat polymorphic markers from four chromosomes revealed null alleles at four marker sites in 12 families that were the result of deletions ranging in size from 5 to >260 kb.