Genome wide gene expression in a patient with 15q13.3 homozygous microdeletion syndrome
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE43583 | GEO | 2013/02/17
SECONDARY ACCESSION(S): PRJNA186785
REPOSITORIES: GEO
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Project description:We identified a novel homozygous 15q13.3 microdeletion in a young boy with a complex neurodevelopmental disorder characterized by severe cerebral visual impairment with additional signs of congenital stationary night blindness (CSNB), congenital hypotonia with areflexia, profound intellectual disability, and refractory epilepsy. The mechanisms by which the genes in the deleted region exert their effect are unclear. In this paper we probed the role of downstream effects of the deletions as a contributing mechanism to the molecular basis of the observed phenotype. We analyzed gene expression of lymphoblastoid cells derived from peripheral blood of the proband and his relatives to ascertain the relative effects of the homozygous and heterozygous deletions. The proband with 15q13.3 homozygous deletion and his parents with 15q13.3 heterozygous deletions described in our previous report 15 were evaluated using Affymetrix aCGH-244K arrays (build hg18). The aCGH data were validated by qPCR using primers specific to CHRNA7 as previously described. 15 The extended family and comparison subjects were also screened using the CHRNA7 primers. Immortalized lymphoblastoid lines were created from the proband, his mother, father, a paternal half sister, a paternal half brother, a paternal grandmother and two paternal great uncles. Three lymphoblastoid lines from age- and sex- matched normally developing comparison subjects with normal chromosomes were obtained from the Coriell cell repository [(AG14724 (8 yo), AG14948 (10 yo), AG14980 (9 yo)] were used for gene expression comparison with the proband. The samples from the father, mother and paternal grandmother with heterozygous 15q13.3 deletions were compared to samples from lymphoblastoid cells from adult male and female subjects respectively (normal copy number for 15q13.3 determined by qPCR).
2013-02-17 | E-GEOD-43583 | biostudies-arrayexpress
Project description:Background: Deletions in the 15q13.3 region are associated with several neuropsychiatric disorders, including autism and schizophrenia. Association studies in humans and functional studies in mice have suggested that several genes within the 15q13.3 microdeletion may play a role in neuronal dysfunction, but the intermediate molecular mechanisms remain unknown. Methods: Induced pluripotent stem cells from 3 patients with the 15q13.3 microdeletion and 3 sex-matched controls were generated and converted into induced neurons. We analyzed the genome-wide effects of the 15q13.3 microdeletion on gene expression, DNA methylation, chromatin accessibility, and sensitivity to cisplatin-induced DNA damage. We also evaluated gene expression changes in induced neurons containing CRISPR knockouts of single 15q13.3 microdeletion genes. Results: In both cell types, gene copy number change within the 15q13.3 microdeletion was accompanied by significantly decreased gene expression and no compensatory changes in DNA methylation or chromatin accessibility, supporting the model that haploinsufficiency of genes within the deleted region drives the disorder. Further, we observed global effects of the microdeletion on the transcriptome and epigenome, with disruptions in several neuropsychiatric disorder-associated pathways, such as Wnt signaling, ribosome biogenesis, DNA binding, and cell adhesion. Conclusions: Our multi-omics analyses of the 15q13.3 microdeletion revealed downstream effects in pathways previously associated with neuropsychiatric disorders. This molecular systems analysis can also be applied to other brain relevant chromosomal aberrations to further our etiological understanding of neuropsychiatric disorders.
2021-03-28 | GSE135131 | GEO
Project description:The 3q-syndrome is a well-known genetic condition caused by interstitial deletion in the long arm of chromosome 3. The phenotype of this syndrome is variable and the great variability in the extent of these deletions lead to a wide spectrum of clinical manifestations. Terminal 12p deletion represents one of the rarest subtelomeric imbalance, patients with distal monosomy 12p present different phenotypes ranging from muscular hypotonia to autism spectrum disorders. Here we report a prenatal diagnosis of a male fetus presenting ultrasounds evidence of corpus callosum dysplasia and ventriculomegaly showing a 3q13q21.2 deletion and a 12p13.33 microdeletion paternally inherited. Among several features previously attributed to the terminal deletion of 3q, corpus callosum dysplasia and ventriculomegaly has rarely been reported together. As the 12p13.33 microdeletion in the father was associated only to muscular hypotonia and joint laxity, involvement of terminal 12p deletions in fetus clinical features was not possible to verify in prenatal period. This report may provide a reference for prenatal diagnosis and genetic counseling in patients who have prenatal diagnosis of 3q13q21.2 deletions and 12p13.33 microdeletion.
2022-11-10 | E-MTAB-12413 | biostudies-arrayexpress
Project description:The study presents three cases of patients with deletions within 16p11.2 regions. Every child had characteristic craniofacial dysmorphic features and hand or feet abnormalities. The first proband had additionally obesity, epilepsy, moderate intellectual disability, aphasia, motor delay, hyperinsulinism and café au lait spots. The second proband suffered from cardiac, pulmonary and hematological problems. The third proband had motor delay, bronchial asthma and umbilical hernia. Although each patient presented characteristic features of the syndrome, children differed in clinical pictures among themselves. The genetic diagnosis of the 16p11.2 deletion syndrome was made in children at different age, based on the multiplex ligation probe-dependent amplification (MLPA) analysis and/or microarrays methods. This study highlights the impact of the size of deleted regions, as they may affect the clinical picture of patients with 16p11.2 microdeletion syndrome. Reported cases indicates the key role of the interdisciplinary approach in 16p11.2 microdeletion syndrome diagnostics, as the care of patients with this deletion is based on regular health assessment and adjustment of the nervous system development therapy
2020-10-07 | GSE159129 | GEO
Project description:Background: The 15q13.3 microdeletion has pleiotropic effects ranging from apparently healthy to severely affected individuals with intellectual disability, epilepsy, and neuropsychiatric disorders. Previous studies have investigated several genes within the deletion as potential drivers, but the pathomechanism and the underlying basis of the variable phenotype remain elusive. Methods: We analyzed the effects of the 15q13.3 microdeletion on genome-wide gene expression using native RNA-seq data from blood of 3 probands with the 15q13.3 microdeletion and 4 sex- and age-matched control subjects. We assessed differentially expressed genes (DEGs), gene ontology (GO) enrichment, protein-protein interaction (PPI) functional modules, as well as gene expression in different brain developmental stages. Results: The haploinsufficiency of genes within the deleted region was not transcriptionally compensated, suggesting that a dosage effect may contribute to the pathomechanism. Although GO and PPI showed that regulation of gene expression is perturbed, we could not identify a singular driving transcription factor. We observed network-wide dysregulatory effects suggesting that the phenotype is not caused by a singular critical gene. A significant proportion of DEGs, which are silenced in the adult brain, have maximum expression during the prenatal stage of brain development. Based on DEGs and their PPI partners we identified altered functional modules related to immune and inflammatory processes, as well as nervous system development. Conclusions: We show that the 15q13.3 microdeletion has a ubiquitous impact on transcriptome pattern, especially dysregulation of genes involved in brain development. The effect on immune and inflammatory responses cannot be fully assessed based on the test material, i.e. blood. Possibly, the high phenotypic variability seen in 15q13.3 microdeletion could stem from an increased vulnerability during brain development, instead of a specific pathomechanism.
2022-08-08 | GSE197903 | GEO
Project description:Copy number variants at chromosome 15q13.3 contribute to liability for multiple intellectual and developmental disabilities (IDDs) including Autism Spectrum Disorder (ASD). Individuals with duplications of this interval, which includes the gene CHRNA7, have IDDs with variable penetrance. However, the basis of such differential affectation remains uncharacterized.Methods: Induced pluripotent stem cell (iPSC) models were generated from two first degree relatives with the same 15q13.3 duplication, a boy with distinct features of autism and emotional dysregulation (the affected proband, AP) and his clinically unaffected mother (the UM). These models were compared to unrelated control subjects lacking this duplication (UC, male and female). iPSC-derived neural progenitors and cortical neuroids consisting of cortical excitatory and inhibitory neurons were used to model potential contributors to neuropsychiatric impairment. Results: The AP-derived model uniquely exhibited disruptions of cellular physiology and neurodevelopment not observed in either the UM or in unrelated male and female controls. These included enhanced neural progenitor proliferation but impaired neuronal differentiation, maturation, and migration, and increased endoplasmic reticulum (ER) stress in neural progenitors. Both the AP’s neuronal migration deficit and elevated ER stress could be selectively rescued by different pharmacologic agents. Neuronal gene expression was also specifically dysregulated in the AP, including altered expression of genes related to behavior, psychological disorders, neuritogenesis, neuronal migration, and WNT signaling. By contrast with these AP-specific phenotypes, both the AP- and UM-derived neurons exhibited shared alterations of neuronal function, including elevated cholinergic activity consistent with increased homomeric CHRNA7 channel activity.Conclusion: Together, these data define both affectation-specific phenotypes seen only in the AP, as well as abnormalities observed in both individuals with CHRNA7 duplication, the AP and UM, but not in UC-derived neurons. This is, to our knowledge, the first study to use a human stem cell-based platform to study the basis of variable affectation in cases of 15q13.3 duplication at the cellular, molecular, and functional levels. This work suggests potential approaches for suppressing abnormal neurodevelopment or physiology that may contribute to severity of affectation in this proband. Some of these AP-specific neurodevelopmental anomalies, or the functional anomalies observed in both 15q13.3 duplication carriers (the AP and UM), could also contribute to the differential phenotypic penetrance seen in other individuals with 15q13.3 duplication.
2021-06-07 | GSE143908 | GEO
Project description:Filamin C (encoded by the FLNC gene) is a large actin-cross-linking protein involved in shaping the actin cytoskeleton in response to signaling events both at the sarcolemma and at myofibrillar Z-discs of cross-striated muscle cells. Multiple mutations in FLNC are associated with myofibrillar myopathies of autosomal dominant inheritance. Here, we describe a boy with congenital onset of generalized muscular hypotonia and muscular weakness, delayed motor development but no cardiac involvement associated with a homozygous FLNC mutation affecting the rod domain of the protein. To demonstrate pathogenicity of this homozygous FLNC-mutation described, ultra-morphological, proteomic and functional investigations were performed in addition to immunological studies of known marker proteins for dominant filaminopathies. Our results showed that the mutant protein is expressed to similar quantities as the wildtype variant in control skeletal muscle fibres, alters the proteomic signature of quadriceps muscle, and results in the presence of ultrastructural perturbations. Moreover, comparable findings for filaminopathy marker proteins were found in both, our homozygous and a dominant case. The mutant protein is less stable and more prone to degradation by proteolytic enzymes than the wildtype variant. These combined findings extend the currently recognized clinical, genetic and biochemical spectrum of filaminopathies. The unusual congenital presentation of the disease indicates that homozygosity for a mutation in filamin C severely aggravates the phenotype.
2020-07-24 | PXD016657 | Pride
Project description:Recurrent deletions on 15q13.3 have been identified as a predisposition to mental retardation, epilepsy and psychiatric disease. We report compound heterozygous deletions on 15q13.3 in one patients with severe encephalopathy and seizures. We analysed two independent patients with severe encephalopathy and seizures and found heterozygous deletions on 15q13.3 in both patients.
2011-03-05 | E-GEOD-20564 | biostudies-arrayexpress
Project description:Genome wide gene expression in a patient with 15q13.3 homozygous microdeletion syndrome
| PRJNA186785 | ENA
Project description:Recurrent deletions on 15q13.3 have been identified as a predisposition to mental retardation, epilepsy and psychiatric disease. We report compound heterozygous deletions on 15q13.3 in one patients with severe encephalopathy and seizures.
2011-03-05 | GSE20564 | GEO