PCR-free whole exome sequencing: Cost-effective and efficient in detecting rare mutations

AbstractThis retrospective study was aiming to determine the cost effectiveness of whole exome sequencing (WES) in the diagnosis of children with developmental delay in a developing country. In this study of 40 patients, the average cost of traditional investigations and indirect costs related to rehabilitation and medications per child were USD847 and 6,585 per year, respectively. With a current cost for WES of approximately USD1,200, we concluded that performing WES could be cost effective, even in countries with limited resources, as it provides the option for genetic counseling in affected families with an ultimate reduction of overall financial burden to both parents and health care system.

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A domestic cat whole exome sequencing resource for trait discovery

10.1101/2020.06.01.128405 ◽

2020 ◽

Author(s):

Alana R. Rodney ◽

Reuben M. Buckley ◽

Robert S. Fulton ◽

Catrina Fronick ◽

Todd Richmond ◽

...

Keyword(s):

Exome Sequencing ◽

Whole Exome Sequencing ◽

Rare Diseases ◽

Sex Chromosome ◽

Cost Effective ◽

Domestic Cat ◽

Whole Genome Sequence ◽

Exome Capture ◽

Variant Discovery ◽

Whole Exome

AbstractOver 94 million domestic cats are considered pets, who, as our companions, are also susceptible to cancers, common and rare diseases. Whole exome sequencing (WES) is a cost-effective strategy to study their putative disease-causing variants. Presented is ~35.8 Mb exome capture design based on the annotated Felis_catus_9.0 genome assembly, covering 201,683 regions of the cat genome. WES was conducted on 41 cats from various breeds with known and unknown diseases and traits, including 10 cats with prior whole genome sequence (WGS) data available, to test WES capture probe performance. A WES and WGS comparison was completed to understand variant discovery capability of each platform. At ~80x exome coverage, the percent of on-target base coverage >20x was 96.4% with an average of 10.4% off-target. For variant discovery, greater than 98% of WGS SNPs were also discovered by WES. Platform specific variants were mainly restricted to a small number of sex chromosome and olfactory receptor genes. Within the 41 cats with ~31 diseases and normal traits, 45 previously known disease or trait causal variants were observed, such as Persian progressive retinal degeneration and hydrocephalus. Novel candidate variants for polycystic kidney disease and atrichia in the Peterbald breed were also identified as well as a new cat patient with a known variant for cystinuria. These results show the discovery potential of deep exome sequencing to validate existing disease gene models and identify novel gene candidate alleles for many common and rare diseases in cats.

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Whole Exome Sequencing in Idiopathic Short Stature: rare mutations affecting growth

10.21203/rs.2.16842/v1 ◽

2019 ◽

Author(s):

Shahab Noorian ◽

Farzaneh Rohani ◽

Shahram Savad ◽

Kourosh Kabir ◽

Nami Mohammadian Khonsari ◽

...

Keyword(s):

Short Stature ◽

Exome Sequencing ◽

Whole Exome Sequencing ◽

Genetic Disorders ◽

Correct Diagnosis ◽

Test Results ◽

Rare Mutations ◽

Whole Exome ◽

Common Causes ◽

Blood Specimens

Abstract Introduction: one of the most common causes of referrals to paediatricians is short stature (ISS), some pathogenic mutations may present exactly similar to non-pathogenic causes, our goal is to identify and treat these patients labelled ISS with these mutations and hopefully treat them correctly. Materials and Methods: We assessed All children under the age of fifteen years labelled as ISS. Fourteen of them were confirmed to be ISS and thus were allowed in our study. Afterwards, we pooled their blood specimens and ordered a whole-exome sequencing (WES) test. Results: five patient had normal WES results. Four patients had rare motions that were not studied in the previous literature but due to the functions of the genes, and our patients’ phenotypes it is highly possible that these mutations caused our patients’ short stature. Four patients had known genetic mutations causing short stature. One patient had a mutation with no effect on height. With the help of WES, some rare mutations were found, with the patients’ phenotype and evaluation we identified their function, we diagnosed some other patients’ rare genetic disorders and assessed the possible effect of their mutation on their height and phenotype we aimed to determine how many children labelled as ISS are correctly diagnosed. By WES most of our patient achieved the correct diagnosis which would be impossible to diagnose without WES; thus the reason for their short stature was identified, with the correct diagnosis now we can aim for the proper treatment.

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Whole Exome Sequencing in Idiopathic Short Stature: Rare Mutations Affecting Growth

10.21203/rs.2.22066/v1 ◽

2020 ◽

Author(s):

Nami Mohammadian Khonsari ◽

Shahab Noorian ◽

Farzaneh Rohani ◽

Sharham Savad ◽

Kourosh Kabir ◽

...

Keyword(s):

Short Stature ◽

Exome Sequencing ◽

Whole Exome Sequencing ◽

Correct Diagnosis ◽

Idiopathic Short Stature ◽

Genetic Mutations ◽

The Past ◽

Rare Mutations ◽

Whole Exome ◽

Directing Attention

Abstract Introduction Evaluation of short stature is a challenge for pediatricians and in the process, idiopathic short stature (ISS) is an often diagnosis of exclusion. Non-pathogenetic mutations affecting height may present with phenotypes similar to the pathogenetic mutations. In this study, we aim to identify the underlying genetic cause of short stature in patients diagnosed with ISS and investigate potential treatments for them. Materials and Methods We identified 14 children in our practice who were under the age of 15 and were initially labelled as ISS. Then, we evaluated their plasma whole-exome sequencing (WES). Results Out of the 14 patients assessed with WES, five had normal results and correctly diagnosed with ISS. However, four of them had rare mutations that have not been extensively studied in the past. Due to the functions of these mutated genes and our patients’ phenotypes, we suspect that these mutations played a role in the short stature. Out of the remaining five patients, four had genetic mutations known to cause short stature and one had a mutation that was known not to affect height. Conclusion In patients who are initially diagnosed with ISS, WES can help to identify rare mutations that may play a role in short stature. Directing attention to these genes, may help with the correct diagnosis and choosing proper treatment for the patients.

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Whole-Exome Sequencing in Idiopathic Short Stature: Rare Mutations Affecting Growth

Journal of Pediatric Genetics ◽

10.1055/s-0040-1716400 ◽

2020 ◽

Author(s):

Shahab Noorian ◽

Nami Mohammadian Khonsari ◽

Shahram Savad ◽

Benyamin Hakak-Zargar ◽

Tessa Voth ◽

...

Keyword(s):

Short Stature ◽

Exome Sequencing ◽

Whole Exome Sequencing ◽

Treatment Options ◽

Idiopathic Short Stature ◽

Genetic Causes ◽

Rare Mutations ◽

Whole Exome ◽

Common Diagnosis

AbstractIdiopathic short stature (ISS) is a common diagnosis of exclusion in patients with short stature (SS). We aimed to identify the genetic causes of SS in patients with ISS and investigate treatment options. Fourteen children with diagnosis of ISS were identified, and whole-exome sequencing (WES) was subsequently conducted on blood-derived DNA. Five patients were correctly diagnosed with ISS and four had rare mutations that have not been previously reported. Four patients had mutations known to cause SS and one had a mutation that was known not to affect height. WES can help identify rare mutations implicated in ISS.

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Whole exome sequencing in unclassified autoinflammatory diseases: more monogenic diseases in the pipeline?

Rheumatology ◽

10.1093/rheumatology/keaa165 ◽

2020 ◽

Author(s):

Can Kosukcu ◽

Ekim Z Taskiran ◽

Ezgi Deniz Batu ◽

Erdal Sag ◽

Yelda Bilginer ◽

...

Keyword(s):

Exome Sequencing ◽

Whole Exome Sequencing ◽

Disease Onset ◽

Cost Effective ◽

Bioinformatic Analysis ◽

Autoinflammatory Diseases ◽

Whole Exome ◽

Monogenic Diseases ◽

Strong Candidate ◽

Generation Sequencing

Abstract Objective Autoinflammatory diseases (AIDs) are characterized by recurrent sterile systemic inflammation attacks. More than half of the patients remain genetically undiagnosed with next-generation sequencing panels for common AIDs. In this study, we aimed to define phenotype-genotype correlations in a cohort of unclassified AID patients via whole exome sequencing (WES). Methods Patients with features of AIDs were included in this study followed in the Department of Pediatric Rheumatology at Hacettepe University. They were first screened for MEFV with Sanger sequencing and then WES performed for the patients with clinically insignificant results. Pre-analysis of WES data was done by considering the 13 most common AID-related genes. Further bioinformatic analysis was performed if the patient remained genetically undiagnosed. Results The median age at disease onset was 1.2 years (range 0.2–16) and at the time of study recruitment was 14 years (range 3.5–17). In our cohort, WES provided a definite or probable disease-causing variant in 4 of 11 patients (36%). Heterozygous mutations for two of these genes were previously associated with neurological defects (ADAM17, TBK1), also homozygous ADAM17 mutations were observed in one family with neonatal inflammatory skin and bowel disease. Besides, two genes (LIG4, RAG1) were associated with immunodeficiency although the patients had presented with inflammatory features. Finally, for one patient, we associated a strong candidate gene (NLRC3) with autoinflammatory features. Conclusion WES strategy is cost-effective and provides substantial results for a selected group of undefined AID patients. Our results will contribute to the spectrum of unclassified AIDs.

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Whole exome sequencing cost saving in primary immunodeficiency

PharmacoEconomics & Outcomes News ◽

10.1007/s40274-020-7152-3 ◽

2020 ◽

Vol 862 (1) ◽

pp. 34-34

Keyword(s):

Cost Saving ◽

Exome Sequencing ◽

Whole Exome Sequencing ◽

Primary Immunodeficiency ◽

Whole Exome ◽

Sequencing Cost

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Diagnostic Yield and Economic Implications of Whole-Exome Sequencing for ASD Diagnosis in Israel

Genes ◽

10.3390/genes13010036 ◽

2021 ◽

Vol 13 (1) ◽

pp. 36

Author(s):

Rotem Tal-Ben Ishay ◽

Apurba Shil ◽

Shirley Solomon ◽

Noa Sadigurschi ◽

Hadeel Abu-Kaf ◽

...

Keyword(s):

Cost Effectiveness ◽

Exome Sequencing ◽

Whole Exome Sequencing ◽

Diagnostic Yield ◽

Cost Effective ◽

Autism Spectrum ◽

Chromosomal Microarray Analysis ◽

Economic Implications ◽

Whole Exome ◽

Jewish Children

Whole-exome sequencing (WES) is an effective approach to identify the susceptibility of genetic variants of autism spectrum disorder (ASD). The Israel Ministry of Health supports WES as an adjunct tool for ASD diagnosis, despite its unclear diagnostic yield and cost effectiveness. To address this knowledge gap, we applied WES to a population-based sample of 182 Bedouin and Jewish children with ASD from southern Israel, and assessed its yield in a gene panel of 205 genes robustly associated with ASD. We then compared the incremental cost-effectiveness ratios (ICERs) for an ASD diagnosis by WES, chromosomal microarray analysis (CMA), and CMA + WES. Overall, 32 ASD candidate variants were detected in 28 children, corresponding to an overall WES diagnostic yield of 15.4%. Interestingly, the diagnostic yield was significantly higher for the Bedouin children than for the Jewish children, i.e., 27.6% vs. 11.1% (p = 0.036). The most cost-effective means for genetic testing was the CMA alone, followed closely by the CMA + WES strategy (ICER = USD 117 and USD 124.8 per child). Yet, WES alone could become more cost effective than the other two approaches if there was to be a 25% increase in its yield or a 50% decrease in its cost. These findings suggest that WES should be recommended to facilitate ASD diagnosis in Israel, especially for highly consanguineous populations, such as the Bedouin.

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