Project description:The Tousled-like kinases 1 and 2 (TLK1/TLK2) regulate DNA replication, repair and chromatin maintenance. TLK2 variants are associated with ‘Intellectual Disability, Autosomal Dominant 57’ (MRD57), a neurodevelopmental disorder (NDD) characterized by intellectual disability (ID), autism spectrum disorder (ASD) and microcephaly. Several TLK1 variants have been reported in NDDs but their functional significance is unknown. A male patient presenting with ID, seizures, global developmental delay, hypothyroidism, and primary immunodeficiency was determined to have a novel, heterozygous variant in TLK1 (c.1435C>G, p.Q479E) by genome sequencing (GS). Transcriptome sequencing in patient-derived cells confirmed expression of TLK1 transcripts carrying the p.Q479E variant and revealed alterations in genes involved in class switch recombination and cytokine signaling.
Project description:Primary objectives: The primary objective is to investigate circulating tumor DNA (ctDNA) via deep sequencing for mutation detection and by whole genome sequencing for copy number analyses before start (baseline) with regorafenib and at defined time points during administration of regorafenib for treatment efficacy in colorectal cancer patients in terms of overall survival (OS).
Primary endpoints: circulating tumor DNA (ctDNA) via deep sequencing for mutation detection and by whole genome sequencing for copy number analyses before start (baseline) with regorafenib and at defined time points during administration of regorafenib for treatment efficacy in colorectal cancer patients in terms of overall survival (OS).
Project description:A female patient with neurodevelopmental disorder, craniofacial dysmorphisms carrying a novel heterozygous FOXP1 variant, c.1030C>T, p.(Gln344Ter). This variant was not found in the parents, which was consistent with de novo inheritance.
Project description:Autism spectrum disorder (ASD) and mental retardation (MR) represent clinically distinct neurodevelopmental disorders with a complex genetic etiology. Using microarrays we identified de novo copy number variations in the SHANK2 synaptic scaffolding gene in two unrelated ASD and MR patients; DNA sequencing of SHANK2 revealed additional variants including a de novo nonsense mutation and 7 rare inherited changes. Our findings further link common genes between ASD and intellectual disability.
Project description:Rett syndrome (RTT) is an X-linked neurodevelopmental disorder caused by mutations in the gene encoding methyl CpG binding protein 2 (MeCP2) that occur sporadically in 1:10,000 female births. RTT is characterized by a period of largely normal development followed by regression in language and motor skills at 6-18 months of age. To investigate alterations in DNA methylation in RTT, we performed whole genome bisulfite sequencing on brodmann area 9 of human cortex from RTT and matched controls.
Project description:Genome-wide MeDIP-Sequencing of 23 monozygotic twin pairs (n=46) from Australia discordant for major depressive disorder (MDD). MeDIP-seq of 23 monozygotic twin pairs discordant for major depressive disorder. MZ twin pairs were compared to identify significantly differently methylated sites associated with MDD.
Project description:Genome wide DNA methylation profiling of control and neurodevelopmental disorder lymphoblastoid cell lines (LCL). The Illumina Infinium 27k Human DNA methylation Beadchip v1.2 was used to obtain DNA methylation profiles across approximately 27,000 CpGs in LCLs. Samples included 19 control, 18 Rett syndrome, 17 autism and 6 generalized epilepsy LCL samples. Six technical replicates were also included in the analysis. Bisulphite converted DNA from the 60 samples and 5 technical replicates were hybridised to the Illumina Infinium 27k Human Methylation Beadchip v1.2
Project description:Rett syndrome (RTT, OMIM 312750) is a severe X-linked neurodevelopmental disorder linked to heterozygous de novo mutations in the MECP2 gene. MECP2 encodes methyl-CpG-binding protein 2 (MeCP2), which represses gene transcription by binding to 5-methylcytosine residues in symmetrically positioned CpG dinucleotides. The disorder is almost exclusively diagnosed in females, because males affected by the disease usually die perinatally due to severe encephalopathy. Direct MeCP2 target genes underlying the neuropathogenesis of RTT remain largely unknown.
Project description:NEDAMSS (neurodevelopmental disorder with regression, abnormal movements, loss of speech, and seizures, MIM: 618088) is a recently discovered neurological disorder. We developed iPS cells from peripheral blood mononuclear cells of two NEDAMSS patients and performed microarray.
Project description:We examined whether a human neuronal culture system could be used to assess the transcriptional program involved in human neural differentiation and in modeling some of the molecular features of a neurodevelopmental disorder such as autism. Primary normal human neuronal progenitors differentiation for 0, 2, 4, or 8 weeks.