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1
المؤلفون: Moyra Smith, Thomas H. Wassink, Rebecca S. Frantz, Joseph Piven, Deb Childress, Laura Jenkins, Christopher W. Bartlett, Val C. Sheffield, M. Anne Spence, Veronica J. Vieland, Rhinda Goedken
المصدر: American Journal of Medical Genetics Part B: Neuropsychiatric Genetics. :36-44
مصطلحات موضوعية: Male, Proband, Candidate gene, Linkage disequilibrium, Genotype, Genetic Linkage, DNA Mutational Analysis, Biology, Cellular and Molecular Neuroscience, Gene mapping, Genetic linkage, medicine, Humans, Genetic Predisposition to Disease, Heritability of autism, Amino Acid Sequence, Autistic Disorder, Genetics (clinical), Family Health, Genetics, Polymorphism, Genetic, Sequence Homology, Amino Acid, ADP-Ribosylation Factors, GTPase-Activating Proteins, Telomere, medicine.disease, Developmental disorder, Psychiatry and Mental health, Chromosomes, Human, Pair 2, Mutation, Autism, Female, Chromosome Deletion, Lod Score, Microsatellite Repeats
الوصف: 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. We then genotyped polymorphic markers downstream from the breakpoint region in a sample of autism affected sibling pair families. Both the chromosomal breakpoints and linkage analyses focused our attention on the gene centaurin gamma-2 (CENTG2), an attractive candidate gene based also on its function and pattern of expression. We therefore assessed CENTG2 for its involvement in autism by (1) screening its exons for variants in 199 autistic and 160 non-autistic individuals, and (2) genotyping and assessing intra-genic polymorphisms for linkage and linkage disequilibrium (LD). The exon screen revealed a Ser --> Gly substitution in one proband, an Arg --> Gly substitution in another, and a number of additional variants unique to the autism families. No unique variants were found in the control subjects. The genotyping produced strong evidence for linkage from two intronic polymorphisms, with a maximum two-point HLOD value of 3.96 and a posterior probability of linkage (PPL) of 51%. These results were contradicted, however, by substantially weaker evidence for linkage from multi-point analyses and by no evidence of LD. We conclude, therefore, that 2q37.3 continues to be a region of interest for autism susceptibility, and that CENTG2 is an intriguing candidate gene that merits further scrutiny for its role in autism.
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المؤلفون: Veronica J. Vieland, Rhinda Goedken, Rebecca S. Frantz, Val C. Sheffield, Molly Losh, Thomas H. Wassink, Joseph Piven
المصدر: Human Genetics. 117:200-206
مصطلحات موضوعية: Genetic Markers, Male, Genetics, Chromosome, Disease, Uniparental Disomy, Biology, medicine.disease, Human genetics, Uniparental disomy, Pedigree, Developmental disorder, Chromosomes, Human, Pair 1, Child, Preschool, Mutation, medicine, Humans, Autism, Female, Autistic Disorder, Imprinting (psychology), Abnormality, Genetics (clinical)
الوصف: We report a male child with autism found to have maternal uniparental disomy (UPD) of chromosome 1. The child met diagnostic criteria for the three symptom domains of autism: language impairment, deficient social communication and excessively rigid and repetitive behaviours. He also had a variety of features often associated with autism, including mild mental retardation, small head circumference, hyperactivity, poor fine motor skills, slightly dysmorphic facial features and a heightened interest in olfactory stimulation. His brother, who did not have chromosome 1 UPD, was also autistic. The mother, but not the father, had a history of psychiatric illness and a number of personality and social traits similar to the core features of autism. The discovery of the cytogenetic abnormality was made during the course of a genome-wide linkage screen, wherein genotypes at 6 out of 17 chromosome 1 markers were non-Mendelian and all transmissions were consistent with UPD. Further genotyping (a total of 54 markers) revealed alternating regions of heterodisomy and isodisomy. Whereas chromosome 1 UPD has not been shown to cause disease by effects on imprinting, numerous reports exist of the abnormality unmasking recessive disease-causing mutations. In agreement with this, one of the regions of isodisomy overlaps an emerging chromosome 1 region of interest in autism located at 150-160 Mb.
