Dataset Information

Comprehensive genomic analysis of patients with disorders of cerebral cortical development.

ABSTRACT: Malformations of cortical development (MCDs) manifest with structural brain anomalies that lead to neurologic sequelae, including epilepsy, cerebral palsy, developmental delay, and intellectual disability. To investigate the underlying genetic architecture of patients with disorders of cerebral cortical development, a cohort of 54 patients demonstrating neuroradiologic signs of MCDs was investigated. Individual genomes were interrogated for single-nucleotide variants (SNV) and copy number variants (CNV) with whole-exome sequencing and chromosomal microarray studies. Variation affecting known MCDs-associated genes was found in 16/54 cases, including 11 patients with SNV, 2 patients with CNV, and 3 patients with both CNV and SNV, at distinct loci. Diagnostic pathogenic SNV and potentially damaging variants of unknown significance (VUS) were identified in two groups of seven individuals each. We demonstrated that de novo variants are important among patients with MCDs as they were identified in 10/16 individuals with a molecular diagnosis. Three patients showed changes in known MCDs genes and a clinical phenotype beyond the usual characteristics observed, i.e., phenotypic expansion, for a particular known disease gene clinical entity. We also discovered 2 likely candidate genes, CDH4, and ASTN1, with human and animal studies supporting their roles in brain development, and 5 potential candidate genes. Our findings emphasize genetic heterogeneity of MCDs disorders and postulate potential novel candidate genes involved in cerebral cortical development.

SUBMITTER: Wiszniewski W

PROVIDER: S-EPMC6057976 | biostudies-literature | 2018 Aug

REPOSITORIES: biostudies-literature

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Comprehensive genomic analysis of patients with disorders of cerebral cortical development.

Wiszniewski Wojciech W Gawlinski Pawel P Gambin Tomasz T Bekiesinska-Figatowska Monika M Obersztyn Ewa E Antczak-Marach Dorota D Akdemir Zeynep Hande Coban ZHC Harel Tamar T Karaca Ender E Jurek Marta M Sobecka Katarzyna K Nowakowska Beata B Kruk Malgorzata M Terczynska Iwona I Goszczanska-Ciuchta Alicja A Rudzka-Dybala Mariola M Jamroz Ewa E Pyrkosz Antoni A Jakubiuk-Tomaszuk Anna A Iwanowski Piotr P Gieruszczak-Bialek Dorota D Piotrowicz Malgorzata M Sasiadek Maria M Kochanowska Iwona I Gurda Barbara B Steinborn Barbara B Dawidziuk Mateusz M Castaneda Jennifer J Wlasienko Pawel P Bezniakow Natalia N Jhangiani Shalini N SN Hoffman-Zacharska Dorota D Bal Jerzy J Szczepanik Elzbieta E Boerwinkle Eric E Gibbs Richard A RA Lupski James R JR

European journal of human genetics : EJHG 20180430 8

Malformations of cortical development (MCDs) manifest with structural brain anomalies that lead to neurologic sequelae, including epilepsy, cerebral palsy, developmental delay, and intellectual disability. To investigate the underlying genetic architecture of patients with disorders of cerebral cortical development, a cohort of 54 patients demonstrating neuroradiologic signs of MCDs was investigated. Individual genomes were interrogated for single-nucleotide variants (SNV) and copy number varian ...[more]

PMID: 29706646

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Project description:Infiltrating T-lymphocytes from the peripheral blood into the central nervous system (CNS) play a dynamic role in the development of a neurological immune-mediated diseases. HAM/TSP is a chronic progressive inflammatory neurological disorder associated with human T-cell lymphotropic virus type I (HTLV-I) infection. In this chronic myelopathy, virus-infected circulating T-cells infiltrate the CNS and an immune response is initiated against the components of CNS. As the HTLV-I proviral load (PVL) has been used as the best clinical marker for patient diagnostic with HAM/TSP, we hypothesized there might be a signature on T-cell receptor (TCR) clonal repertoire in these patients, which could distinguish HAM/TSP patients from the healthy population, as well as from patients with a more heterogeneous CNS-reactive inflammatory disease as multiple sclerosis (MS). With this in mind, we applied an innovative unbiased molecular technique – unique molecular identifier (UMI) library-strategy to investigate with high accuracy the TCR clonal repertoire by high throughput sequencing (HTS) technology. cDNA-TCR β-chain libraries were sequenced from 2 million peripheral mononuclear cells (PBMCs) in 14 HAM/TSP patients, 34 MS patients and 20 healthy controls (HC). To address whether the clonal expansion correlates with the patient’s PVL level, analysis of longitudinal TCR repertoire was performed in 2 HAM/TSP patients. Over 5.6 million TCR sequences were generated per sample on HiSeq 2500 Illumina system and analyzed through the molecular identifier groups-based error correction pipeline (MiGEC). Bioinformatic analysis showed that clones with more than 8 reads had a lower coefficient of variation (CV) and then could be used with confidence to evaluate the TCR clonal expansion. While HAM/TSP patients showed the higher clonal T-cell expansion compared to MS and HC, increase of the TCR clonal expansion was inversely correlated with the diversity of TCR repertoire in all subject’s group. In addition, correlation of the PVL with TCR clonal expansion was observed in HAM/TSP patients at longitudinal time-points. Surprisingly, MS patients showed a higher diversity of TCR repertoire along with a very slight clonal T-cell expansion in comparison to either HAM/TSP patients or HC. Despite of the higher TCR clonal expansion in HAM/TSP patients, a non-shared or “private” TCR repertoire was observed in these patients. No clones that shared the same CDR3 amino acid sequences were seen in HC and MS patients. However, a cluster of related CDR3 amino acid sequences were observed for 18 out of 34 MS patients when evaluated by phylogenetic tree analysis. It suggestes that a TCR-repertoire signature might characterize patients with MS. Our findings suggest that even though a unique TCR-b repertoire shapes the immune response in patients with neurological immune-mediated disease, a relatedness on clonal T-cell repertoire exist in MS.

Dataset Information

Comprehensive genomic analysis of patients with disorders of cerebral cortical development.

Publications

Comprehensive genomic analysis of patients with disorders of cerebral cortical development.

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