ABSTRACT
To find inherited causes of autism-spectrum disorders, we studied families in which parents share ancestors, enhancing the role of inherited factors. We mapped several loci, some containing large, inherited, homozygous deletions that are likely mutations. The largest deletions implicated genes, including PCDH10 (protocadherin 10) and DIA1 (deleted in autism1, or c3orf58), whose level of expression changes in response to neuronal activity, a marker of genes involved in synaptic changes that underlie learning. A subset of genes, including NHE9 (Na+/H+ exchanger 9), showed additional potential mutations in patients with unrelated parents. Our findings highlight the utility of "homozygosity mapping" in heterogeneous disorders like autism but also suggest that defective regulation of gene expression after neural activity may be a mechanism common to seemingly diverse autism mutations.
Subject(s)
Autistic Disorder/genetics , Chromosome Mapping , Mutation , Adaptor Proteins, Signal Transducing/genetics , Animals , Autistic Disorder/physiopathology , Brain/metabolism , Cadherins/genetics , Consanguinity , Female , Formins , Gene Deletion , Gene Dosage , Gene Expression Regulation , Genes, Recessive , Genetic Predisposition to Disease , Homozygote , Humans , Lod Score , Male , Neurons/physiology , Oligonucleotide Array Sequence Analysis , Pedigree , Polymorphism, Single Nucleotide , Protocadherins , Rats , Sodium-Hydrogen Exchangers/genetics , Transcription Factors/genetics , Transcription Factors/metabolismABSTRACT
Reelin is an extracellular matrix-associated protein important in the regulation of neuronal migration during cerebral cortical development. Point mutations in the RELN gene have been shown to cause an autosomal recessive human brain malformation termed lissencephaly with cerebellar hypoplasia (LCH). Recent work has raised the possibility that reelin may also play a pathogenic role in other neuropsychiatric disorders. We sought, therefore, to define more precisely the phenotype of RELN gene disruption. To do this, we performed a clinical, radiological, and molecular study of a family in whom multiple individuals carry a chromosomal inversion that disrupts the RELN locus. A 6-year-old girl homozygous for the pericentric inversion 46,XX,inv7(p11.2q22) demonstrated the same clinical features that have been previously described in association with RELN point mutations. The girl's brain magnetic resonance imaging (MRI) findings, including pachygyria and severe cerebellar hypoplasia, were identical to those seen with RELN point mutations. Fluorescence in situ hybridization confirmed that one of the breakpoints of this inversion mapped to within the RELN gene, and Western blotting revealed an absence of detectable serum reelin protein. Several relatives who were heterozygous for this inversion were neurologically normal and had no signs of psychotic illness. Our findings demonstrate the distinctive phenotype of LCH, which is easily distinguishable from other forms of lissencephaly. Although RELN appears to be critical for normal cerebral and cerebellar development, its role, if any, in the pathogenesis of psychiatric disorders remains unclear.
Subject(s)
Brain/abnormalities , Cell Adhesion Molecules, Neuronal/genetics , Extracellular Matrix Proteins/genetics , Nerve Tissue Proteins/genetics , Serine Endopeptidases/genetics , Cell Adhesion Molecules, Neuronal/blood , Cell Adhesion Molecules, Neuronal/deficiency , Cell Adhesion Molecules, Neuronal/physiology , Central Nervous System Diseases/genetics , Cerebellum/abnormalities , Cerebral Cortex/abnormalities , Child , Chromosome Inversion , Chromosomes, Human, Pair 7/genetics , Cytogenetics , Extracellular Matrix Proteins/blood , Extracellular Matrix Proteins/deficiency , Extracellular Matrix Proteins/physiology , Female , Heterozygote , Homozygote , Humans , In Situ Hybridization, Fluorescence , Magnetic Resonance Imaging , Male , Mental Disorders/genetics , Nerve Tissue Proteins/blood , Nerve Tissue Proteins/deficiency , Nerve Tissue Proteins/physiology , Pedigree , Phenotype , Reelin Protein , Serine Endopeptidases/blood , Serine Endopeptidases/deficiency , Serine Endopeptidases/physiologyABSTRACT
PURPOSE: To explore the concerns of at-risk relatives of colorectal cancer patients about genetic discrimination and their awareness of current legislative protections. METHODS: A questionnaire was sent to unaffected individuals with a family history of colorectal cancer who had enrolled in the Johns Hopkins Hereditary Colorectal Cancer Registry (N = 777). RESULTS: Of the 470 respondents, approximately half rated their level of concern about genetic discrimination as high. The majority of respondents, 79%, learned about genetic discrimination from at least one media source (television, newspapers, magazines, and radio). If they were to pursue genetic testing, respondents with a higher level of concern about genetic discrimination would be significantly more likely to pay out of pocket, use an alias, or ask for test results to be excluded from their medical record. Awareness and understanding of legislation regarding genetic discrimination was found to be minimal. CONCLUSION: Findings from this study demonstrate the negative effect of concerns about genetic discrimination on decisions about utilization of genetic services. Stronger legislative protections against genetic discrimination and increased public education through the scientific community and media sources are needed.
