scholarly journals Whole genome sequencing of a sporadic primary immunodeficiency cohort

2018 ◽  
Author(s):  
James E. D. Thaventhiran ◽  
Hana Lango Allen ◽  
Oliver S. Burren ◽  
William Rae ◽  
Daniel Greene ◽  
...  
Keyword(s):  
Whole Genome Sequencing ◽  
Genome Sequencing ◽  
Primary Immunodeficiency ◽  
Genome Wide Association Study ◽  
Diagnostic Yield ◽  
Genetic Diagnosis ◽  
Whole Genome ◽  
Common Variants ◽  
Phenotypic Complexity ◽  
A Genome

AbstractPrimary immunodeficiency (PID) is characterised by recurrent and often life-threatening infections, autoimmunity and cancer, and it presents major diagnostic and therapeutic challenges. Although the most severe forms present in early childhood, the majority of patients present in adulthood, typically with no apparent family history and a variable clinical phenotype of widespread immune dysregulation: about 25% of patients have autoimmune disease, allergy is prevalent, and up to 10% develop lymphoid malignancies1–3. Consequently, in sporadic PID genetic diagnosis is difficult and the role of genetics is not well defined. We addressed these challenges by performing whole genome sequencing (WGS) of a large PID cohort of 1,318 participants. Analysis of coding regions of 886 index cases found disease-causing mutations in known monogenic PID genes in 10.3%, while a Bayesian approach (BeviMed4) identified multiple potential new candidate genes, including IVNS1ABP. Exploration of the non-coding genome revealed deletions in regulatory regions which contribute to disease causation. Finally, a genome-wide association study (GWAS) identified PID-associated loci and uncovered evidence for co-localisation of, and interplay between, novel high penetrance monogenic variants and common variants (at the PTPN2 and SOCS1 loci). This begins to explain the contribution of common variants to variable penetrance and phenotypic complexity in PID. Thus, a cohort-based WGS approach to PID diagnosis can increase diagnostic yield while deepening our understanding of the key pathways influencing human immune responsiveness.

scholarly journals Genome-wide association study and whole-genome sequencing identify a deletion in LRIT3 associated with canine congenital stationary night blindness

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Rueben G. Das ◽  
Doreen Becker ◽  
Vidhya Jagannathan ◽  
Orly Goldstein ◽  
Evelyn Santana ◽  
...  
Keyword(s):  
Association Study ◽  
Whole Genome Sequencing ◽  
Genome Sequencing ◽  
Night Blindness ◽  
Genome Wide Association Study ◽  
Genome Wide Association ◽  
Whole Genome ◽  
Congenital Stationary Night Blindness ◽  
Genome Wide ◽  
A Genome

Abstract Congenital stationary night blindness (CSNB), in the complete form, is caused by dysfunctions in ON-bipolar cells (ON-BCs) which are secondary neurons of the retina. We describe the first disease causative variant associated with CSNB in the dog. A genome-wide association study using 12 cases and 11 controls from a research colony determined a 4.6 Mb locus on canine chromosome 32. Subsequent whole-genome sequencing identified a 1 bp deletion in LRIT3 segregating with CSNB. The canine mutant LRIT3 gives rise to a truncated protein with unaltered subcellular expression in vitro. Genetic variants in LRIT3 have been associated with CSNB in patients although there is limited evidence regarding its apparently critical function in the mGluR6 pathway in ON-BCs. We determine that in the canine CSNB retina, the mutant LRIT3 is correctly localized to the region correlating with the ON-BC dendritic tips, albeit with reduced immunolabelling. The LRIT3-CSNB canine model has direct translational potential enabling studies to help understand the CSNB pathogenesis as well as to develop new therapies targeting the secondary neurons of the retina.

scholarly journals Whole genome sequencing identified a 16 kilobase deletion on ECA13 associated with distichiasis in Friesian horses

BMC Genomics ◽  
2020 ◽  
Vol 21 (1) ◽  
Author(s):  
E. A. Hisey ◽  
H. Hermans ◽  
Z. T. Lounsberry ◽  
F. Avila ◽  
R. A. Grahn ◽  
...  
Keyword(s):  
Whole Genome Sequencing ◽  
Genome Sequencing ◽  
Genome Wide Association Study ◽  
Secondary Infection ◽  
Whole Genome Sequencing Data ◽  
Incomplete Penetrance ◽  
Whole Genome ◽  
Genome Wide ◽  
A Genome

Abstract Background Distichiasis, an ocular disorder in which aberrant cilia (eyelashes) grow from the opening of the Meibomian glands of the eyelid, has been reported in Friesian horses. These misplaced cilia can cause discomfort, chronic keratitis, and corneal ulceration, potentially impacting vision due to corneal fibrosis, or, if secondary infection occurs, may lead to loss of the eye. Friesian horses represent the vast majority of reported cases of equine distichiasis, and as the breed is known to be affected with inherited monogenic disorders, this condition was hypothesized to be a simply inherited Mendelian trait. Results A genome wide association study (GWAS) was performed using the Axiom 670 k Equine Genotyping array (MNEc670k) utilizing 14 cases and 38 controls phenotyped for distichiasis. An additive single locus mixed linear model (EMMAX) approach identified a 1.83 Mb locus on ECA5 and a 1.34 Mb locus on ECA13 that reached genome-wide significance (pcorrected = 0.016 and 0.032, respectively). Only the locus on ECA13 withstood replication testing (p = 1.6 × 10− 5, cases: n = 5 and controls: n = 37). A 371 kb run of homozygosity (ROH) on ECA13 was found in 13 of the 14 cases, providing evidence for a recessive mode of inheritance. Haplotype analysis (hapQTL) narrowed the region of association on ECA13 to 163 kb. Whole-genome sequencing data from 3 cases and 2 controls identified a 16 kb deletion within the ECA13 associated haplotype (ECA13:g.178714_195130del). Functional annotation data supports a tissue-specific regulatory role of this locus. This deletion was associated with distichiasis, as 18 of the 19 cases were homozygous (p = 4.8 × 10− 13). Genotyping the deletion in 955 horses from 54 different breeds identified the deletion in only 11 non-Friesians, all of which were carriers, suggesting that this could be causal for this Friesian disorder. Conclusions This study identified a 16 kb deletion on ECA13 in an intergenic region that was associated with distichiasis in Friesian horses. Further functional analysis in relevant tissues from cases and controls will help to clarify the precise role of this deletion in normal and abnormal eyelash development and investigate the hypothesis of incomplete penetrance.

scholarly journals A Missense Mutation in the KLF7 Gene Is a Potential Candidate Variant for Congenital Deafness in Australian Stumpy Tail Cattle Dogs

Genes ◽  
2021 ◽  
Vol 12 (4) ◽  
pp. 467
Author(s):  
Fangzheng Xu ◽  
Shuwen Shan ◽  
Susan Sommerlad ◽  
Jennifer M. Seddon ◽  
Bertram Brenig
Keyword(s):  
Candidate Gene ◽  
Whole Genome Sequencing ◽  
Genome Sequencing ◽  
Heart Development ◽  
Genome Wide Association Study ◽  
Whole Genome ◽  
Potential Candidate ◽  
Congenital Deafness ◽  
Cardiovascular Development ◽  
A Genome

Congenital deafness is prevalent among modern dog breeds, including Australian Stumpy Tail Cattle Dogs (ASCD). However, in ASCD, no causative gene has been identified so far. Therefore, we performed a genome-wide association study (GWAS) and whole genome sequencing (WGS) of affected and normal individuals. For GWAS, 3 bilateral deaf ASCDs, 43 herding dogs, and one unaffected ASCD were used, resulting in 13 significantly associated loci on 6 chromosomes, i.e., CFA3, 8, 17, 23, 28, and 37. CFA37 harbored a region with the most significant association (−log10(9.54 × 10−21) = 20.02) as well as 7 of the 13 associated loci. For whole genome sequencing, the same three affected ASCDs and one unaffected ASCD were used. The WGS data were compared with 722 canine controls and filtered for protein coding and non-synonymous variants, resulting in four missense variants present only in the affected dogs. Using effect prediction tools, two variants remained with predicted deleterious effects within the Heart development protein with EGF like domains 1 (HEG1) gene (NC_006615.3: g.28028412G>C; XP_022269716.1: p.His531Asp) and Kruppel-like factor 7 (KLF7) gene (NC_006619.3: g.15562684G>A; XP_022270984.1: p.Leu173Phe). Due to its function as a regulator in heart and vessel formation and cardiovascular development, HEG1 was excluded as a candidate gene. On the other hand, KLF7 plays a crucial role in the nervous system, is expressed in the otic placode, and is reported to be involved in inner ear development. 55 additional ASCD samples (28 deaf and 27 normal hearing dogs) were genotyped for the KLF7 variant, and the variant remained significantly associated with deafness in ASCD (p = 0.014). Furthermore, 24 dogs with heterozygous or homozygous mutations were detected, including 18 deaf dogs. The penetrance was calculated to be 0.75, which is in agreement with previous reports. In conclusion, KLF7 is a promising candidate gene causative for ASCD deafness.

scholarly journals Whole genome sequencing in the Middle Eastern Qatari population identifies genetic associations with 45 clinically relevant traits

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Gaurav Thareja ◽  
◽  
Yasser Al-Sarraj ◽  
Aziz Belkadi ◽  
Maryam Almotawa ◽  
...  
Keyword(s):  
Whole Genome Sequencing ◽  
Genome Sequencing ◽  
Genome Wide Association Study ◽  
Clinical Laboratory ◽  
Medical Decision ◽  
Future Application ◽  
Whole Genome ◽  
Genome Wide ◽  
A Genome ◽  
Polygenic Scores

AbstractClinical laboratory tests play a pivotal role in medical decision making, but little is known about their genetic variability between populations. We report a genome-wide association study with 45 clinically relevant traits from the population of Qatar using a whole genome sequencing approach in a discovery set of 6218 individuals and replication in 7768 subjects. Trait heritability is more similar between Qatari and European populations (r = 0.81) than with Africans (r = 0.44). We identify 281 distinct variant-trait-associations at genome wide significance that replicate known associations. Allele frequencies for replicated loci show higher correlations with European (r = 0.94) than with African (r = 0.85) or Japanese (r = 0.80) populations. We find differences in linkage disequilibrium patterns and in effect sizes of the replicated loci compared to previous reports. We also report 17 novel and Qatari-predominate signals providing insights into the biological pathways regulating these traits. We observe that European-derived polygenic scores (PGS) have reduced predictive performance in the Qatari population which could have implications for the translation of PGS between populations and their future application in precision medicine.

scholarly journals Improved diagnostic yield compared with targeted gene sequencing panels suggests a role for whole-genome sequencing as a first-tier genetic test

2017 ◽  
Vol 20 (4) ◽  
pp. 435-443 ◽  
Author(s):  
Anath C Lionel ◽  
Gregory Costain ◽  
Nasim Monfared ◽  
Susan Walker ◽  
Miriam S Reuter ◽  
...  
Keyword(s):  
Whole Genome Sequencing ◽  
Genome Sequencing ◽  
Genetic Test ◽  
Diagnostic Yield ◽  
Gene Sequencing ◽  
Whole Genome ◽  
Targeted Gene Sequencing

scholarly journals Fine Mapping Using Whole-Genome Sequencing Confirms Anti-Müllerian Hormone as a Major Gene for Sex Determination in Farmed Nile Tilapia (Oreochromis niloticus L.)

2019 ◽  
Vol 9 (10) ◽  
pp. 3213-3223 ◽  
Author(s):  
Giovanna Cáceres ◽  
María E. López ◽  
María I. Cádiz ◽  
Grazyella M. Yoshida ◽  
Ana Jedlicki ◽  
...  
Keyword(s):  
Sex Determination ◽  
Whole Genome Sequencing ◽  
Genome Sequencing ◽  
Oreochromis Niloticus ◽  
Nile Tilapia ◽  
Major Gene ◽  
Whole Genome ◽  
Important Species ◽  
Genome Wide ◽  
A Genome

Nile tilapia (Oreochromis niloticus) is one of the most cultivated and economically important species in world aquaculture. Intensive production promotes the use of monosex animals, due to an important dimorphism that favors male growth. Currently, the main mechanism to obtain all-male populations is the use of hormones in feeding during larval and fry phases. Identifying genomic regions associated with sex determination in Nile tilapia is a research topic of great interest. The objective of this study was to identify genomic variants associated with sex determination in three commercial populations of Nile tilapia. Whole-genome sequencing of 326 individuals was performed, and a total of 2.4 million high-quality bi-allelic single nucleotide polymorphisms (SNPs) were identified after quality control. A genome-wide association study (GWAS) was conducted to identify markers associated with the binary sex trait (males = 1; females = 0). A mixed logistic regression GWAS model was fitted and a genome-wide significant signal comprising 36 SNPs, spanning a genomic region of 536 kb in chromosome 23 was identified. Ten out of these 36 genetic variants intercept the anti-Müllerian (Amh) hormone gene. Other significant SNPs were located in the neighboring Amh gene region. This gene has been strongly associated with sex determination in several vertebrate species, playing an essential role in the differentiation of male and female reproductive tissue in early stages of development. This finding provides useful information to better understand the genetic mechanisms underlying sex determination in Nile tilapia.

scholarly journals A combined RNA-seq and whole genome sequencing approach for identification of non-coding pathogenic variants in single families

2020 ◽  
Vol 29 (6) ◽  
pp. 967-979 ◽  
Author(s):  
Revital Bronstein ◽  
Elizabeth E Capowski ◽  
Sudeep Mehrotra ◽  
Alex D Jansen ◽  
Daniel Navarro-Gomez ◽  
...  
Keyword(s):  
Whole Genome Sequencing ◽  
Genome Sequencing ◽  
Genetic Diagnosis ◽  
Genetic Diagnostics ◽  
Whole Genome ◽  
Unique Challenge ◽  
Coding Regions ◽  
Pathogenic Variants ◽  
Number Of Patients ◽  
Coding Variants

Abstract Inherited retinal degenerations (IRDs) are at the focus of current genetic therapeutic advancements. For a genetic treatment such as gene therapy to be successful, an accurate genetic diagnostic is required. Genetic diagnostics relies on the assessment of the probability that a given DNA variant is pathogenic. Non-coding variants present a unique challenge for such assessments as compared to coding variants. For one, non-coding variants are present at much higher number in the genome than coding variants. In addition, our understanding of the rules that govern the non-coding regions of the genome is less complete than our understanding of the coding regions. Methods that allow for both the identification of candidate non-coding pathogenic variants and their functional validation may help overcome these caveats allowing for a greater number of patients to benefit from advancements in genetic therapeutics. We present here an unbiased approach combining whole genome sequencing (WGS) with patient-induced pluripotent stem cell (iPSC)-derived retinal organoids (ROs) transcriptome analysis. With this approach, we identified and functionally validated a novel pathogenic non-coding variant in a small family with a previously unresolved genetic diagnosis.

scholarly journals Local Ancestry Prediction with PyLAE

2020 ◽  
Author(s):  
Alexander Smetanin ◽  
Nikita Moshkov ◽  
Tatiana V. Tatarinova
Keyword(s):  
Whole Genome Sequencing ◽  
Genome Sequencing ◽  
Computational Efficiency ◽  
Source Code ◽  
High Density ◽  
Whole Genome Sequencing Data ◽  
Whole Genome ◽  
Sequencing Data ◽  
Local Ancestry ◽  
A Genome

AbstractSummaryWe developed PyLAE - a new tool for determining local ancestry along a genome using whole-genome sequencing data or high-density genotyping experiments. PyLAE can process an arbitrarily large number of ancestral populations (with or without an informative prior). Since PyLAE does not involve estimation of many parameters, it can process thousands of genomes within a day. Computational efficiency, straightforward presentation of results, and an ease of installation makes PyLAE a useful tool to study admixed populations.Availability and implementationThe source code and installation manual are available at https://github.com/smetam/pylae.

scholarly journals Whole genome sequencing elucidates the species-wide diversity and evolution of fungicide resistance in the early blight pathogen Alternaria solani

2021 ◽  
Author(s):  
Severin Einspanier ◽  
Tamara Susanto ◽  
Nicole Metz ◽  
Pieter J. Wolters ◽  
Vivianne G.A.A. Vleeshouwers ◽  
...  
Keyword(s):  
Genetic Diversity ◽  
Whole Genome Sequencing ◽  
Genome Sequencing ◽  
Fungicide Resistance ◽  
Early Blight ◽  
Management Strategies ◽  
Resistance Management ◽  
Alternaria Solani ◽  
Whole Genome ◽  
A Genome

Early blight of potato is caused by the fungal pathogen Alternaria solani and is an increasing problem worldwide. The primary strategy to control the disease is applying fungicides such as succinate dehydrogenase inhibitors (SDHI). SDHI-resistant strains, showing reduced sensitivity to treatments, appeared in Germany in 2013, five years after introduction of SDHIs. Two primary mutations in the Sdh complex (SdhB-H278Y and SdhC-H134R) have been frequently found throughout Europe. How these resistances arose and spread, and whether they are linked to other genomic features, remains unknown. We performed whole-genome sequencing for A. solani isolates from potato fields across Europe (Germany, Sweden, Belgium, and Serbia) to better understand the pathogen's genetic diversity in general and understand the development and spread of the genetic mutations that lead to SDHI resistance. We used ancestry analysis and phylogenetics to determine the genetic background of 48 isolates. The isolates can be grouped into 7 genotypes. These genotypes do not show a geographical pattern but appear spread throughout Europe. The Sdh mutations appear in different genetic backgrounds, suggesting they arose independently, and the observed admixtures might indicate a higher adaptive potential in the fungus than previously thought. Our research gives insights into the genetic diversity of A. solani on a genome level. The mixed occurrence of different genotypes and apparent admixture in the populations indicate higher genomic complexity than anticipated. The conclusion that SDHI tolerance arose multiple times independently has important implications for future fungicide resistance management strategies. These should not solely focus on preventing the spread of isolates between locations but also on limiting population size and the selective pressure posed by fungicides in a given field to avoid the rise of new mutations in other genetic backgrounds.

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