ABSTRACT
Genes disrupted in schizophrenia may be revealed by de novo mutations in affected persons from otherwise healthy families. Furthermore, during normal brain development, genes are expressed in patterns specific to developmental stage and neuroanatomical structure. We identified de novo mutations in persons with schizophrenia and then mapped the responsible genes onto transcriptome profiles of normal human brain tissues from age 13 weeks gestation to adulthood. In the dorsolateral and ventrolateral prefrontal cortex during fetal development, genes harboring damaging de novo mutations in schizophrenia formed a network significantly enriched for transcriptional coexpression and protein interaction. The 50 genes in the network function in neuronal migration, synaptic transmission, signaling, transcriptional regulation, and transport. These results suggest that disruptions of fetal prefrontal cortical neurogenesis are critical to the pathophysiology of schizophrenia. These results also support the feasibility of integrating genomic and transcriptome analyses to map critical neurodevelopmental processes in time and space in the brain.
Subject(s)
Gene Regulatory Networks , Mutation , Prefrontal Cortex/embryology , Protein Interaction Maps , Schizophrenia/genetics , Schizophrenia/metabolism , Brain/embryology , Brain/growth & development , Brain/metabolism , DNA Mutational Analysis , Databases, Genetic , Female , Humans , Male , Neurogenesis , Prefrontal Cortex/growth & development , Prefrontal Cortex/metabolism , Schizophrenia/physiopathology , Transcription, Genetic , TranscriptomeABSTRACT
Genetic studies of autism spectrum disorder (ASD) have established that de novo duplications and deletions contribute to risk. However, ascertainment of structural variants (SVs) has been restricted by the coarse resolution of current approaches. By applying a custom pipeline for SV discovery, genotyping, and de novo assembly to genome sequencing of 235 subjects (71 affected individuals, 26 healthy siblings, and their parents), we compiled an atlas of 29,719 SV loci (5,213/genome), comprising 11 different classes. We found a high diversity of de novo mutations, the majority of which were undetectable by previous methods. In addition, we observed complex mutation clusters where combinations of de novo SVs, nucleotide substitutions, and indels occurred as a single event. We estimate a high rate of structural mutation in humans (20%) and propose that genetic risk for ASD is attributable to an elevated frequency of gene-disrupting de novo SVs, but not an elevated rate of genome rearrangement.
Subject(s)
Autism Spectrum Disorder/genetics , Gene Deletion , Gene Duplication , Alleles , Amino Acid Sequence , Base Sequence , Case-Control Studies , Child , DNA Copy Number Variations , Female , Gene Frequency , Gene Rearrangement , Genetic Loci , Genome, Human , Genotyping Techniques , Humans , INDEL Mutation , Male , Microarray Analysis , Molecular Sequence Data , Pedigree , Reproducibility of Results , Sensitivity and SpecificityABSTRACT
Accurate and timely diagnosis of inherited bone marrow failure and inherited myelodysplastic syndromes is essential to guide clinical management. Distinguishing inherited from acquired bone marrow failure/myelodysplastic syndrome poses a significant clinical challenge. At present, diagnostic genetic testing for inherited bone marrow failure/myelodysplastic syndrome is performed gene-by-gene, guided by clinical and laboratory evaluation. We hypothesized that standard clinically-directed genetic testing misses patients with cryptic or atypical presentations of inherited bone marrow failure/myelodysplastic syndrome. In order to screen simultaneously for mutations of all classes in bone marrow failure/myelodysplastic syndrome genes, we developed and validated a panel of 85 genes for targeted capture and multiplexed massively parallel sequencing. In patients with clinical diagnoses of Fanconi anemia, genomic analysis resolved subtype assignment, including those of patients with inconclusive complementation test results. Eight out of 71 patients with idiopathic bone marrow failure or myelodysplastic syndrome were found to harbor damaging germline mutations in GATA2, RUNX1, DKC1, or LIG4. All 8 of these patients lacked classical clinical stigmata or laboratory findings of these syndromes and only 4 had a family history suggestive of inherited disease. These results reflect the extensive genetic heterogeneity and phenotypic complexity of bone marrow failure/myelodysplastic syndrome phenotypes. This study supports the integration of broad unbiased genetic screening into the diagnostic workup of children and young adults with bone marrow failure and myelodysplastic syndromes.
Subject(s)
Biomarkers, Tumor/genetics , Bone Marrow Neoplasms/diagnosis , Bone Marrow Neoplasms/genetics , Genomics/methods , Mutation/genetics , Myelodysplastic Syndromes/diagnosis , Myelodysplastic Syndromes/genetics , Adolescent , Adult , Aged , Bone Marrow Neoplasms/classification , Child , Child, Preschool , Female , Humans , Infant , Male , Middle Aged , Myelodysplastic Syndromes/classification , Phenotype , Prognosis , Young AdultABSTRACT
Previous research on the treatment of problem behavior has shown differential reinforcement of other behavior (DRO) to be an effective behavior-reduction procedure. However, the extent to which presession descriptions of the DRO contingency enhance intervention effects has not been examined. In the current study, we compared a condition in which a presession rule that described the DRO contingency was given to a condition in which no rule was given for 4 participants. The target behavior was toy play, which served as an analogue to problem behavior maintained by automatic reinforcement. Results showed that DRO was more efficient for 1 participant and more effective for 2 participants when a rule was given.