scholarly journals Whole genome analysis of an extended pedigree with Prader–Willi Syndrome, hereditary hemochromatosis, and dysautonomia-like symptoms

2015 ◽  
Author(s):  
Han Fang ◽  
Yiyang Wu ◽  
Margaret Yoon ◽  
Laura T. Jiménez-Barrón ◽  
Jason A. O'Rawe ◽  
...  
Keyword(s):  
De Novo ◽  
Chromosome Region ◽  
Hereditary Hemochromatosis ◽  
Copy Number Variations ◽  
Prader Willi Syndrome ◽  
Whole Genome ◽  
Whole Genome Analysis ◽  
Phenotypic Data ◽  
Human Phenotype ◽  
Congenital Insensitivity

This report includes the discovery and analysis of a pedigree with Prader–Willi Syndrome (PWS), hereditary hemochromatosis (HH), and dysautonomia-like symptoms. Nine members of the family participated in whole genome sequencing (WGS), which enabled a wide scope of variant calling from single-nucleotide polymorphisms to copy number variations. First, a 5.5 Mb de novo deletion is identified in the chromosome region 15q11.2 to 15q13.1 in the boy with PWS. Second, a female invididual with HH is homozygous for the p.C282Y variant in HFE, a mutation known to be associated with HH. Her brother is homozygous for the same variant, although he has yet to be clinically diagnosed with HH. Third, none of the people with dysautonomia-like symptoms carry any reported or novel rare variants in IKBKAP that are implicated in familial dysautonomia (FD - HSAN III). Although two people with dysautonomia-like symptoms carry two heterozygous variants in NTRK1, a gene that has been shown to contribute to HSAN IV (congenital insensitivity to pain with anhidrosis, a disease that closely resembles FD), this variant is not present in the third proband. Fourth, WGS revealed pharmacogenetic variants influencing the metabolism of warfarin and simvastatin, which are being routinely prescribed to the proband. Finally, reports of the phenotypes were standardized with the Human Phenotype Ontology annotation, which may facilitate the search for other families with similar phenotypes. Due to the extreme heterogeneity and insufficient knowledge of human diseases, it is of crucial importance that both phenotypic data and genomic data are standardized and shared.

scholarly journals Prader-Willi Syndrome due to an Unbalanced de novo Translocation t(15;19)(q12;p13.3)

2016 ◽  
Vol 150 (1) ◽  
pp. 29-34 ◽  
Author(s):  
Vy Dang ◽  
Abhilasha Surampalli ◽  
Ann M. Manzardo ◽  
Stephanie Youn ◽  
Merlin G. Butler ◽  
...  
Keyword(s):  
De Novo ◽  
Chromosome Region ◽  
Genetic Disorder ◽  
Type I ◽  
Prader Willi Syndrome ◽  
Stk11 Gene ◽  
Feeding Difficulties ◽  
First Case ◽  
Increased Risk ◽  
Hands And Feet

Prader-Willi syndrome (PWS) is a complex, multisystem genetic disorder characterized by endocrine, neurologic, and behavioral abnormalities. We report the first case of an unbalanced de novo reciprocal translocation of chromosomes 15 and 19, 45,XY,-15,der(19)t(15;19)(q12;p13.3), resulting in monosomy for the PWS critical chromosome region. Our patient had several typical features of PWS including infantile hypotonia, a poor suck and feeding difficulties, tantrums, skin picking, compulsions, small hands and feet, and food seeking, but not hypopigmentation, a micropenis, cryptorchidism or obesity as common findings seen in PWS at the time of examination at 6 years of age. He had seizures noted from 1 to 3 years of age and marked cognitive delay. High-resolution SNP microarray analysis identified an atypical PWS type I deletion in chromosome 15 involving the proximal breakpoint BP1. The deletion extended beyond the GABRB3 gene but was proximal to the usual distal breakpoint (BP3) within the 15q11q13 region, and GABRA5, GABRG3, and OCA2 genes were intact. No deletion of band 19p13.3 was detected; therefore, the patient was not at an increased risk of tumors from the Peutz-Jeghers syndrome associated with a deletion of the STK11 gene.

Nonivasive prenatal DNA-screening the scope and the prospects of whole-genome sequencing

2020 ◽  
pp. 69-70
Author(s):  
Е. Шубина ◽  
И.Ю. Барков ◽  
А.Ю. Гольцов ◽  
И.С. Мукосей ◽  
Т.О. Кочеткова ◽  
...  
Keyword(s):  
High Risk ◽  
Whole Genome Sequencing ◽  
Genome Sequencing ◽  
Pregnancy Outcomes ◽  
Test Performance ◽  
Large Scale ◽  
Copy Number Variations ◽  
Whole Genome ◽  
Trisomy 8 ◽  
Whole Genome Analysis

Неинвазивный пренатальный ДНК-скрининг (НИПС) начал использоваться в клинической практике в 2011г. и в настоящее время широко применяется, как и в мире, так и в России. Проанализирована встречаемость «редких» анеуплоидий при проведении полногеномного НИПС у 2061 пациенток и исходы беременностей при наличии таких результатов. Показано, что при анализе всего генома для полногеномного варианта НИПС можно получить дополнительную информацию, важную как для прогноза течения беременности, так и для прогноза плода. Это позволяет выделить дополнительную небольшую группу беременных, которым может быть рекомендовано более пристальное наблюдение в течение беременности или проведение дополнительных диагностических процедур. Однако для определения чувствительности и специфичности определения «редких» анеуплодий и CNV в настоящий момент недостаточно данных. Noninvasive prenatal DNA screening (NIPS) is getting more widespread in clinical practice in Russia and all around the world. The use of shallow whole-genome sequencing for NIPS allows analysis of all chromosome aneuploidies; hence there are large-scale studies only on test performance on common trisomies. This study aimed to analyze the prevalence of «rare» aneuploidies using whole-genome NIPS and pregnancy outcomes in case of a high risk of «rare» aneuploidy. Noninvasive prenatal DNA screening was performed using in house developed protocol. We have analyzed 2061 samples. In 8 cases (0.4%) high-risk of rare trisomy was detected (3 - trisomy 7, 2 - trisomy 8, 1 - trisomy 10, 2 - trisomy 15). We have identified two cases of a high risk of large copy number variations (CNV). For all of the high-risk cases, we have information about pregnancy outcomes. Thereby whole-genome analysis will enable us to get the additional information and reveal pregnancies in need of further observation or testing. Hence there is not enough data for the estimation of sensitivity and specificity of detection of «rare» aneuploidies.

scholarly journals PlasmidTron: assembling the cause of phenotypes from NGS data

2017 ◽  
Author(s):  
Andrew J. Page ◽  
Alexander Wailan ◽  
Yan Shao ◽  
Kim Judge ◽  
Gordon Dougan ◽  
...  
Keyword(s):  
Virulence Factors ◽  
Bacterial Population ◽  
Population Studies ◽  
De Novo ◽  
Whole Genome ◽  
Accession Number ◽  
Phenotypic Data ◽  
Bacterial Populations ◽  
Short Read ◽  
Link Type

AbstractWhen defining bacterial populations through whole genome sequencing (WGS) the samples often have detailed associated metadata that relate to disease severity, antimicrobial resistance, or even rare biochemical traits. When comparing these bacterial populations, it is apparent that some of these phenotypes do not follow the phylogeny of the host i.e. they are genetically unlinked to the evolutionary history of the host bacterium. One possible explanation for this phenomenon is that the genes are moving independently between hosts and are likely associated with mobile genetic elements (MGE). However, identifying the element that is associated with these traits can be complex if the starting point is short read WGS data. With the increased use of next generation WGS in routine diagnostics, surveillance and epidemiology a vast amount of short read data is available and these types of associations are relatively unexplored. One way to address this would be to perform assembly de novo of the whole genome read data, including its MGEs. However, MGEs are often full of repeats and can lead to fragmented consensus sequences. Deciding which sequence is part of the chromosome, and which is part of a MGE can be ambiguous. We present PlasmidTron, which utilises the phenotypic data normally available in bacterial population studies, such as antibiograms, virulence factors, or geographic information, to identify sequences that are likely to represent MGEs linked to the phenotype. Given a set of reads, categorised into cases (showing the phenotype) and controls (phylogenetically related but phenotypically negative), PlasmidTron can be used to assemble de novo reads from each sample linked by a phenotype. A k-mer based analysis is performed to identify reads associated with a phylogenetically unlinked phenotype. These reads are then assembled de novo to produce contigs. By utilising k-mers and only assembling a fraction of the raw reads, the method is fast and scalable to large datasets. This approach has been tested on plasmids, because of their contribution to important pathogen associated traits, such as AMR, hence the name, but there is no reason why this approach cannot be utilized for any MGE that can move independently through a bacterial population. PlasmidTron is written in Python 3 and available under the open source licence GNU GPL3 from https://github.com/sanger-pathogens/plasmidtron.DATA SUMMARYSource code for PlasmidTron is available from Github under the open source licence GNU GPL 3; (url - https://goo.gl/ot6rT5)Simulated raw reads files have been deposited in Figshare; (url - https://doi.org/10.6084/m9.figshare.5406355.vl)Salmonella enterica serovar Weltevreden strain VNS10259 is available from GenBank; accession number GCA_001409135.Salmonella enterica serovar Typhi strain BL60006 is available from GenBank; accession number GCA_900185485.Accession numbers for all of the Illumina datasets used in this paper are listed in the supplementary tables.I/We confirm all supporting data, code and protocols have been provided within the article or through supplementary data files. ⊠IMPACT STATEMENTPlasmidTron utilises the phenotypic data normally available in bacterial population studies, such as antibiograms, virulence factors, or geographic information, to identify sequences that are likely to represent MGEs linked to the phenotype.

scholarly journals Whole-genome analysis of de novo and polymorphic retrotransposon insertions in Autism Spectrum Disorder

2021 ◽  
Author(s):  
Rebeca Borges-Monroy ◽  
Chong Chu ◽  
Caroline Dias ◽  
Jaejoon Choi ◽  
Soohyun Lee ◽  
...  
Keyword(s):  
Autism Spectrum Disorder ◽  
De Novo ◽  
Copy Number Variants ◽  
Autism Spectrum ◽  
Spectrum Disorder ◽  
Mendelian Disease ◽  
Whole Genome ◽  
Loss Of Function ◽  
Whole Genome Analysis ◽  
Bioinformatic Tools

AbstractRetrotransposons are dynamic forces in evolutionary genomics and have been implicated as causes of Mendelian disease and hereditary cancer, but their role in Autism Spectrum Disorder (ASD) has never been systematically defined. Here, we report 86,154 polymorphic retrotransposon insertions including >60% not previously reported and 158 de novo retrotransposition events identified in whole genome sequencing (WGS) data of 2,288 families with ASD from the Simons Simplex Collection (SSC). As expected, the overall burden of de novo events was similar between ASD individuals and unaffected siblings, with 1 de novo insertion per 29, 104, and 192 births for Alu, L1, and SVA respectively, and 1 de novo insertion per 20 births total, while the location of transposon insertions differed between ASD and unaffected individuals. ASD cases showed more de novo L1 insertions than expected in ASD genes, and we also found de novo intronic retrotransposition events in known syndromic ASD genes in affected individuals but not in controls. Additionally, we observed exonic insertions in genes with a high probability of being loss-of-function intolerant, including a likely causative exonic insertion in CSDE1, only in ASD individuals. Although de novo retrotransposition occurs less frequently than single nucleotide and copy number variants, these findings suggest a modest, but important, impact of intronic and exonic retrotransposition mutations in ASD and highlight the utility of developing specific bioinformatic tools for high-throughput detection of transposable element insertions.

scholarly journals Whole-genome analysis reveals the contribution of non-coding de novo transposon insertions to autism spectrum disorder

Mobile DNA ◽  
2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Rebeca Borges-Monroy ◽  
Chong Chu ◽  
Caroline Dias ◽  
Jaejoon Choi ◽  
Soohyun Lee ◽  
...  
Keyword(s):  
Autism Spectrum Disorder ◽  
De Novo ◽  
Autism Spectrum ◽  
Spectrum Disorder ◽  
Mendelian Disease ◽  
Whole Genome ◽  
Loss Of Function ◽  
Whole Genome Analysis ◽  
Bioinformatic Tools ◽  
High Throughput Detection

Abstract Background Retrotransposons have been implicated as causes of Mendelian disease, but their role in autism spectrum disorder (ASD) has not been systematically defined, because they are only called with adequate sensitivity from whole genome sequencing (WGS) data and a large enough cohort for this analysis has only recently become available. Results We analyzed WGS data from a cohort of 2288 ASD families from the Simons Simplex Collection by establishing a scalable computational pipeline for retrotransposon insertion detection. We report 86,154 polymorphic retrotransposon insertions—including > 60% not previously reported—and 158 de novo retrotransposition events. The overall burden of de novo events was similar between ASD individuals and unaffected siblings, with 1 de novo insertion per 29, 117, and 206 births for Alu, L1, and SVA respectively, and 1 de novo insertion per 21 births total. However, ASD cases showed more de novo L1 insertions than expected in ASD genes. Additionally, we observed exonic insertions in loss-of-function intolerant genes, including a likely pathogenic exonic insertion in CSDE1, only in ASD individuals. Conclusions These findings suggest a modest, but important, impact of intronic and exonic retrotransposon insertions in ASD, show the importance of WGS for their analysis, and highlight the utility of specific bioinformatic tools for high-throughput detection of retrotransposon insertions.

scholarly journals GAAP: A Genome Assembly + Annotation Pipeline

2019 ◽  
Vol 2019 ◽  
pp. 1-12 ◽  
Author(s):  
Jinhwa Kong ◽  
Sun Huh ◽  
Jung-Im Won ◽  
Jeehee Yoon ◽  
Baeksop Kim ◽  
...  
Keyword(s):  
Genome Analysis ◽  
De Novo ◽  
Transcriptome Assembly ◽  
Genomic Analysis ◽  
Whole Genome ◽  
High Throughput Analysis ◽  
Whole Genome Analysis ◽  
A Genome ◽  
Base Sequences ◽  
Wide Range

Genomic analysis begins with de novo assembly of short-read fragments in order to reconstruct full-length base sequences without exploiting a reference genome sequence. Then, in the annotation step, gene locations are identified within the base sequences, and the structures and functions of these genes are determined. Recently, a wide range of powerful tools have been developed and published for whole-genome analysis, enabling even individual researchers in small laboratories to perform whole-genome analyses on their objects of interest. However, these analytical tools are generally complex and use diverse algorithms, parameter setting methods, and input formats; thus, it remains difficult for individual researchers to select, utilize, and combine these tools to obtain their final results. To resolve these issues, we have developed a genome analysis pipeline (GAAP) for semiautomated, iterative, and high-throughput analysis of whole-genome data. This pipeline is designed to perform read correction, de novo genome (transcriptome) assembly, gene prediction, and functional annotation using a range of proven tools and databases. We aim to assist non-IT researchers by describing each stage of analysis in detail and discussing current approaches. We also provide practical advice on how to access and use the bioinformatics tools and databases and how to implement the provided suggestions. Whole-genome analysis of Toxocara canis is used as case study to show intermediate results at each stage, demonstrating the practicality of the proposed method.

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