scholarly journals Diagnosing Cornelia de Lange syndrome and related neurodevelopmental disorders using RNA-sequencing

2019 ◽  
Author(s):  
Stefan Rentas ◽  
Komal S. Rathi ◽  
Maninder Kaur ◽  
Pichai Raman ◽  
Ian D. Krantz ◽  
...  
Keyword(s):  
Rna Sequencing ◽  
Neurodevelopmental Disorders ◽  
Diagnostic Testing ◽  
Tissue Expression ◽  
Cornelia De Lange Syndrome ◽  
Rna Seq ◽  
Genetic Syndromes ◽  
Gene Testing ◽  
Mendelian Gene ◽  
Cornelia De Lange

ABSTRACTPurposeNeurodevelopmental phenotypes represent major indications for children undergoing clinical exome sequencing. However, 50% of cases remain undiagnosed even upon exome reanalysis. Here we show RNA sequencing (RNA-seq) on human B lymphoblastoid cell lines (LCL) is highly suitable for neurodevelopmental Mendelian gene testing and demonstrate the utility of this approach in suspected cases of Cornelia de Lange syndrome (CdLS).MethodsGenotype-Tissue Expression project transcriptome data for LCL, blood, and brain was assessed for neurodevelopmental Mendelian gene expression. Detection of abnormal splicing and pathogenic variants in these genes was performed with a novel RNA-seq diagnostic pipeline and using a validation CdLS-LCL cohort (n=10) and test cohort of patients who carry a clinical diagnosis of CdLS but negative genetic testing (n=5).ResultsLCLs share isoform diversity of brain tissue for a large subset of neurodevelopmental genes and express 1.8-fold more of these genes compared to blood (LCL, n=1706; whole blood, n=917). This enables testing of over 1000 genetic syndromes. The RNA-seq pipeline had 90% sensitivity for detecting pathogenic events and revealed novel diagnoses such as abnormal splice products in NIPBL and pathogenic coding variants in BRD4 and ANKRD11.ConclusionThe LCL transcriptome enables robust frontline and/or reflexive diagnostic testing for neurodevelopmental disorders.

scholarly journals Diagnosing Cornelia de Lange syndrome and related neurodevelopmental disorders using RNA sequencing

2020 ◽  
Vol 22 (5) ◽  
pp. 927-936 ◽  
Author(s):  
Stefan Rentas ◽  
Komal S. Rathi ◽  
Maninder Kaur ◽  
Pichai Raman ◽  
Ian D. Krantz ◽  
...  
Keyword(s):  
Rna Sequencing ◽  
Neurodevelopmental Disorders ◽  
Cornelia De Lange Syndrome ◽  
Cornelia De Lange

scholarly journals Comprehensive analysis of RNA-sequencing to find the source of 1 trillion reads across diverse adult human tissues

2016 ◽  
Author(s):  
Serghei Mangul ◽  
Harry Taegyun Yang ◽  
Nicolas Strauli ◽  
Franziska Gruhl ◽  
Hagit T. Porath ◽  
...  
Keyword(s):  
B Cell ◽  
Rna Sequencing ◽  
Single Cells ◽  
Cell Receptor ◽  
Tissue Expression ◽  
Read Length ◽  
Rna Seq ◽  
Disease Etiology ◽  
Rna Molecules ◽  
Sequencing Technologies

AbstractHigh throughput RNA sequencing technologies have provided invaluable research opportunities across distinct scientific domains by producing quantitative readouts of the transcriptional activity of both entire cellular populations and single cells. The majority of RNA-Seq analyses begin by mapping each experimentally produced sequence (i.e., read) to a set of annotated reference sequences for the organism of interest. For both biological and technical reasons, a significant fraction of reads remains unmapped. In this work, we develop Read Origin Protocol (ROP) to discover the source of all reads originating from complex RNA molecules, recombinant T and B cell receptors, and microbial communities. We applied ROP to 8,641 samples across 630 individuals from 54 tissues. A fraction of RNA-Seq data (n=86) was obtained in-house; the remaining data was obtained from the Genotype-Tissue Expression (GTEx v6) project. To generalize the reported number of accounted reads, we also performed ROP analysis on thousands of different, randomly selected, and publicly available RNA-Seq samples in the Sequence Read Archive (SRA). Our approach can account for 99.9% of 1 trillion reads of various read length across the merged dataset (n=10641). Using in-house RNA-Seq data, we show that immune profiles of asthmatic individuals are significantly different from the profiles of control individuals, with decreased average per sample T and B cell receptor diversity. We also show that immune diversity is inversely correlated with microbial load. Our results demonstrate the potential of ROP to exploit unmapped reads in order to better understand the functional mechanisms underlying connections between the immune system, microbiome, human gene expression, and disease etiology. ROP is freely available athttps://github.com/smangul1/ropand currently supports human and mouse RNA-Seq reads.

scholarly journals RsQTL: correlation of expressed SNVs with splicing using RNA-sequencing data

2019 ◽  
Author(s):  
Justin Sein ◽  
Liam F. Spurr ◽  
Pavlos Bousounis ◽  
N M Prashant ◽  
Hongyu Liu ◽  
...  
Keyword(s):  
Rna Sequencing ◽  
Tissue Expression ◽  
Supplementary Information ◽  
Rna Seq ◽  
Sequencing Data ◽  
Dynamic Nature ◽  
Dynamic Variation ◽  
Exon Junctions ◽  
Variant Allele Fraction ◽  
Allele Fraction

SummaryRsQTL is a tool for identification of splicing quantitative trait loci (sQTLs) from RNA-sequencing (RNA-seq) data by correlating the variant allele fraction at expressed SNV loci in the transcriptome (VAFRNA) with the proportion of molecules spanning local exon-exon junctions at loci with differential intron excision (percent spliced in, PSI). We exemplify the method on sets of RNA-seq data from human tissues obtained though the Genotype-Tissue Expression Project (GTEx). RsQTL does not require matched DNA and can identify a subset of expressed sQTL loci. Due to the dynamic nature of VAFRNA, RsQTL is applicable for the assessment of conditional and dynamic variation-splicing relationships.Availability and implementationhttps://github.com/HorvathLab/[email protected] or [email protected] InformationRsQTL_Supplementary_Data.zip

Delineating the Profile of Autism Spectrum Disorder Characteristics in Cornelia de Lange and Fragile X Syndromes

2013 ◽  
Vol 118 (1) ◽  
pp. 55-73 ◽  
Author(s):  
Joanna Moss ◽  
Chris Oliver ◽  
Lisa Nelson ◽  
Caroline Richards ◽  
Scott Hall
Keyword(s):  
Autism Spectrum Disorder ◽  
Fragile X Syndrome ◽  
Fragile X ◽  
Autism Spectrum ◽  
Spectrum Disorder ◽  
Cornelia De Lange Syndrome ◽  
Genetic Syndromes ◽  
The Social ◽  
Cornelia De Lange ◽  
Atypical Autism

Abstract An atypical presentation of autism spectrum disorder is noted in Cornelia de Lange and Fragile X syndromes, but there are few detailed empirical descriptions. Participants in this study were individuals with Cornelia de Lange syndrome (n  =  130, M age  =  17.19), Fragile X syndrome (n  =  182, M age  =  16.94), and autism spectrum disorder (n  =  142, M age  =  15.19), who were comparable on chronological age. Using the Social Communication Questionnaire, the proportion meeting cutoff for autism spectrum disorder and autism was 78.6%, and 45.6%, respectively, in Cornelia de Lange syndrome and 83.6% and 48.6% in Fragile X syndrome. Domain and item analyses indicate differing, atypical autism spectrum disorder profiles in Fragile X and Cornelia de Lange syndromes. A limited association between adaptive behavior and autism spectrum disorder was identified in all groups. The findings have implications for intervention in genetic syndromes and conceptualization of autism spectrum disorder in the wider population.

scholarly journals Phenotype-tissue expression and exploration (PTEE) resource facilitates the choice of tissue for RNA-seq-based clinical genetics studies

BMC Genomics ◽  
2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Akhil Velluva ◽  
Maximillian Radtke ◽  
Susanne Horn ◽  
Bernt Popp ◽  
Konrad Platzer ◽  
...  
Keyword(s):  
Gene Expression ◽  
Skeletal Muscle ◽  
Circadian Rhythm ◽  
Neurodevelopmental Disorders ◽  
Tissue Expression ◽  
Clinical Genetics ◽  
Rna Seq ◽  
Valuable Method ◽  
Good Proxy ◽  
Blind Spots

Abstract Background RNA-seq emerges as a valuable method for clinical genetics. The transcriptome is “dynamic” and tissue-specific, but typically the probed tissues to analyze (TA) are different from the tissue of interest (TI) based on pathophysiology. Results We developed Phenotype-Tissue Expression and Exploration (PTEE), a tool to facilitate the decision about the most suitable TA for RNA-seq. We integrated phenotype-annotated genes, used 54 tissues from GTEx to perform correlation analyses and identify expressed genes and transcripts between TAs and TIs. We identified skeletal muscle as the most appropriate TA to inquire for cardiac arrhythmia genes and skin as a good proxy to study neurodevelopmental disorders. We also explored RNA-seq limitations and show that on-off switching of gene expression during ontogenesis or circadian rhythm can cause blind spots for RNA-seq-based analyses. Conclusions PTEE aids the identification of tissues suitable for RNA-seq for a given pathology to increase the success rate of diagnosis and gene discovery. PTEE is freely available at https://bioinf.eva.mpg.de/PTEE/

scholarly journals Rigorous Benchmarking of HLA Callers for RNA Sequencing Data

2021 ◽  
Author(s):  
Ram Ayyala ◽  
Junghyun Jung ◽  
Sergey Knyazev ◽  
SERGHEI MANGUL
Keyword(s):  
Rna Sequencing ◽  
Gold Standard ◽  
Large Scale ◽  
Human Leukocyte ◽  
Tissue Expression ◽  
Hla Typing ◽  
Read Length ◽  
Evaluation Metrics ◽  
Rna Seq ◽  
Sequencing Data

Although precise identification of the human leukocyte antigen (HLA) allele is crucial for various clinical and research applications, HLA typing remains challenging due to high polymorphism of the HLA loci. However, with Next-Generation Sequencing (NGS) data becoming widely accessible, many computational tools have been developed to predict HLA types from RNA sequencing (RNA-seq) data. However, there is a lack of comprehensive and systematic benchmarking of RNA-seq HLA callers using large-scale and realist gold standards. In order to address this limitation, we rigorously compared the performance of 12 HLA callers over 50,000 HLA tasks including searching 30 pairwise combinations of HLA callers and reference in over 1,500 samples. In each case, we produced evaluation metrics of accuracy that is the percentage of correctly predicted alleles (two and four-digit resolution) based on six gold standard datasets spanning 650 RNA-seq samples. To determine the influence of the relationship of the read length over the HLA region on prediction quality using each tool, we explored the read length effect by considering read length in the range 37-126 bp, which was available in our gold standard datasets. Moreover, using the Genotype-Tissue Expression (GTEx) v8 data, we carried out evaluation metrics by calculating the concordance of the same HLA type across different tissues from the same individual to evaluate how well the HLA callers can maintain consistent results across various tissues of the same individual. This study offers crucial information for researchers regarding appropriate choices of methods for an HLA analysis.

scholarly journals Profiling immunoglobulin repertoires across multiple human tissues by RNA Sequencing

2016 ◽  
Author(s):  
Serghei Mangul ◽  
Igor Mandric ◽  
Harry Taegyun Yang ◽  
Nicolas Strauli ◽  
Dennis Montoya ◽  
...  
Keyword(s):  
Rna Sequencing ◽  
Adaptive Immune System ◽  
Tissue Expression ◽  
Computational Method ◽  
Rna Seq ◽  
Variable Regions ◽  
Link Type ◽  
Novel Method ◽  
Immunoglobulin Repertoire ◽  
Secondary Lymphoid Organs

AbstractAssay-based approaches provide a detailed view of the adaptive immune system by profiling immunoglobulin (Ig) receptor repertoires. However, these methods carry a high cost and lack the scale of standard RNA sequencing (RNA-Seq). Here we report the development of ImReP, a novel computational method for rapid and accurate profiling of the immunoglobulin repertoire from regular RNA-Seq data. ImReP can also accurately assemble the complementary determining regions 3 (CDR3s), the most variable regions of Ig receptors. We applied our novel method to 8,555 samples across 53 tissues from 544 individuals in the Genotype-Tissue Expression (GTEx v6) project. ImReP is able to efficiently extract Ig-derived reads from RNA-Seq data. Using ImReP, we have created a systematic atlas of 3.6 million Ig sequences across a broad range of tissue types, most of which have not been studied for Ig receptor repertoires. We also compared the GTEx tissues to track the flow of Ig clonotypes across immune-related tissues, including secondary lymphoid organs and organs encompassing mucosal, exocrine, and endocrine sites, and we examined the compositional similarities of clonal populations between these tissues. The Atlas of Immunoglobulin Repertoires (The AIR), is freely available at https://github.com/smangul1/TheAIR/wiki, is one of the largest collection of CDR3 sequences and tissue types. We anticipate this recourse will enhance future immunology studies and advance the development of therapies for human diseases. ImReP is freely available at https://github.com/mandricigor/imrep/wiki

scholarly journals Cornelia de Lange Syndrome as Paradigm of Chromatinopathies

2021 ◽  
Vol 15 ◽  
Author(s):  
Ilaria Parenti ◽  
Frank J. Kaiser
Keyword(s):  
Transcriptional Regulation ◽  
Chromatin Remodeling ◽  
Neurodevelopmental Disorders ◽  
Molecular Mechanisms ◽  
Cornelia De Lange Syndrome ◽  
Facial Dysmorphism ◽  
Behavioral Disturbances ◽  
Chromatid Cohesion ◽  
Topologically Associated Domains ◽  
Cornelia De Lange

Chromatinopathies can be defined as a class of neurodevelopmental disorders caused by mutations affecting proteins responsible for chromatin remodeling and transcriptional regulation. The resulting dysregulation of gene expression favors the onset of a series of clinical features such as developmental delay, intellectual disability, facial dysmorphism, and behavioral disturbances. Cornelia de Lange syndrome (CdLS) is a prime example of a chromatinopathy. It is caused by mutations affecting subunits or regulators of the cohesin complex, a multisubunit protein complex involved in various molecular mechanisms such as sister chromatid cohesion, transcriptional regulation and formation of topologically associated domains. However, disease-causing variants in non-cohesin genes with overlapping functions have also been described in association with CdLS. Notably, the majority of these genes had been previously found responsible for distinct neurodevelopmental disorders that also fall within the category of chromatinopathies and are frequently considered as differential diagnosis for CdLS. In this review, we provide a systematic overview of the current literature to summarize all mutations in non-cohesin genes identified in association with CdLS phenotypes and discuss about the interconnection of proteins belonging to the chromatinopathies network.

Dermatological manifestations of the Cornelia de Lange syndrome

1966 ◽  
Vol 94 (1) ◽  
pp. 38-43 ◽  
Author(s):  
F. N. Salazar
Keyword(s):  
Cornelia De Lange Syndrome ◽  
Cornelia De Lange
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