Ethical conundrums in pediatric genomics

Abstract Recent genomic discoveries have improved our understanding of many hematologic diseases and led to novel therapeutic options for many patients. The rapid decrease in the cost of genomic testing has enabled widespread use of clinical genomic testing. However, these advances are accompanied by concomitant challenging ethical concerns. In pediatrics, issues of informed consent for genomic testing, assent, and permission vary significantly by patient age and comprehension. Broader testing strategies, such as whole-exome or whole-genome sequencing, are more likely to yield incidental findings unrelated to the reason for the initial test, and plans to deal with these results when they occur are increasingly important. The lines of clinical care and research are becoming more blurry in the era of precision medicine in which approaches to individual genetic mutations (as opposed to disease phenotypes) occur with increased frequency. Finally, because justice is a fundamental ethical consideration, access to genomic testing and a rigorous approach to utility are critical to individual patients and the field of hematology. In this review, we use 3 cases of genomic testing in pediatric hematology to illustrate core ethical concerns and explore potential solutions.

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A microcosting and cost–consequence analysis of clinical genomic testing strategies in autism spectrum disorder

Genetics in Medicine ◽

10.1038/gim.2017.47 ◽

2017 ◽

Vol 19 (11) ◽

pp. 1268-1275 ◽

Cited By ~ 26

Author(s):

Kate Tsiplova ◽

Richard M Zur ◽

Christian R Marshall ◽

Dimitri J Stavropoulos ◽

Sergio L Pereira ◽

...

Keyword(s):

Autism Spectrum Disorder ◽

Autism Spectrum ◽

Spectrum Disorder ◽

Genomic Testing ◽

Consequence Analysis ◽

Testing Strategies ◽

Cost Consequence ◽

Clinical Genomic

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Review of "A microcosting and cost-consequence analysis of clinical genomic testing strategies in autism spectrum disorder"

10.14322/publons.r913100 ◽

2017 ◽

Author(s):

James Buchanan

Keyword(s):

Autism Spectrum Disorder ◽

Autism Spectrum ◽

Spectrum Disorder ◽

Genomic Testing ◽

Consequence Analysis ◽

Testing Strategies ◽

Cost Consequence ◽

Clinical Genomic

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Confirming putative variants at ≤ 5% allele frequency using allele enrichment and Sanger sequencing

Scientific Reports ◽

10.1038/s41598-021-91142-1 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Yan Helen Yan ◽

Sherry X. Chen ◽

Lauren Y. Cheng ◽

Alyssa Y. Rodriguez ◽

Rui Tang ◽

...

Keyword(s):

Sanger Sequencing ◽

Limit Of Detection ◽

High Sensitivity ◽

Sequencing Errors ◽

Whole Exome ◽

Formalin Fixed Paraffin ◽

Formalin Fixed Paraffin Embedded ◽

Fresh Frozen ◽

The Cost ◽

Allelic Fraction

AbstractWhole exome sequencing (WES) is used to identify mutations in a patient’s tumor DNA that are predictive of tumor behavior, including the likelihood of response or resistance to cancer therapy. WES has a mutation limit of detection (LoD) at variant allele frequencies (VAF) of 5%. Putative mutations called at ≤ 5% VAF are frequently due to sequencing errors, therefore reporting these subclonal mutations incurs risk of significant false positives. Here we performed ~ 1000 × WES on fresh-frozen and formalin-fixed paraffin-embedded (FFPE) tissue biopsy samples from a non-small cell lung cancer patient, and identified 226 putative mutations at between 0.5 and 5% VAF. Each variant was then tested using NuProbe NGSure, to confirm the original WES calls. NGSure utilizes Blocker Displacement Amplification to first enrich the allelic fraction of the mutation and then uses Sanger sequencing to determine mutation identity. Results showed that 52% of the 226 (117) putative variants were disconfirmed, among which 2% (5) putative variants were found to be misidentified in WES. In the 66 cancer-related variants, the disconfirmed rate was 82% (54/66). This data demonstrates Blocker Displacement Amplification allelic enrichment coupled with Sanger sequencing can be used to confirm putative mutations ≤ 5% VAF. By implementing this method, next-generation sequencing can reliably report low-level variants at a high sensitivity, without the cost of high sequencing depth.

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Challenges and Controversies in the Genetic Diagnosis of Hereditary Spastic Paraplegia

Current Neurology and Neuroscience Reports ◽

10.1007/s11910-021-01099-x ◽

2021 ◽

Vol 21 (4) ◽

Author(s):

Lydia Saputra ◽

Kishore Raj Kumar

Keyword(s):

Genetic Diagnosis ◽

Spastic Paraplegia ◽

Limb Weakness ◽

Hereditary Spastic Paraplegias ◽

Gene Testing ◽

Testing Strategies ◽

Whole Exome ◽

The Right ◽

Gene Panels ◽

High Degree

Abstract Purpose of Review The hereditary spastic paraplegias (HSPs) are a group of disorders characterised by progressive lower limb weakness and spasticity. We address the challenges and controversies involved in the genetic diagnosis of HSP. Recent Findings There is a large and rapidly expanding list of genes implicated in HSP, making it difficult to keep gene testing panels updated. There is also a high degree of phenotypic overlap between HSP and other disorders, leading to problems in choosing the right panel to analyse. We discuss genetic testing strategies for overcoming these diagnostic hurdles, including the use of targeted sequencing gene panels, whole-exome sequencing and whole-genome sequencing. Personalised treatments for HSP are on the horizon, and a genetic diagnosis may hold the key to access these treatments. Summary Developing strategies to overcome the challenges and controversies in HSP may hold the key to a rapid and accurate genetic diagnosis.

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Potential HIV gene therapy strategies

10.31219/osf.io/e5hm2 ◽

2021 ◽

Author(s):

Moataz Dowaidar

Keyword(s):

Gene Therapy ◽

Cord Blood ◽

Gene Editing ◽

Mortality Risks ◽

Recent Advances ◽

Whole Exome ◽

Localization Signal ◽

Cord Blood Cells ◽

The Cost ◽

Therapy Strategies

The CCR5 null genotype generation has been a main focus in the HIV gene therapy industry. The presence of the X4 tropic virus, mobilization of HSPCs, the quality of the cells for manipulation, and gene editing efficiency appear to be the main obstacles in translating this technique. Unintended off-target cleavage is a key problem in CRISPR/Cas9 editing. With the development of small molecule expansion methods for cord blood HSPC, it would be advantageous to modify CCR5 in cord blood cells and expand them for transplantation. The generation of engraftable HSPCS from iPSCs would be an ideal technique for HSCC gene therapy.The haplotype-characterized iPSC would be the donor for many patients, and it could be a commercially available product. The 32 C CR5 homozygous people had no elevated mortality risks according to whole-exome sequencing and whole-genome genotyping, according to CCR 5 positive people, and had no higher mortality risks compared to those who were HIV positive. Recent advances in gene editing, such as non-viral delivery of Cas9 ribonucleoproteins, incorporation of a 3X-nuclear localization signal into spCas9, and use of HiFi Cas9 with chemically modified sgRNAs, can be combined with recent advances in transplantation. Infusing modest doses of gene modified primitive HSPC fractions indicated by CD34 + CD90 + CD45RA-, which can engraft better, is another option for lowering the cost of gene therapy.

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The cost-effectiveness of diagnostic testing strategies for Helicobacter pylori

The American Journal of Gastroenterology ◽

10.1111/j.1572-0241.2000.02193.x ◽

2000 ◽

Vol 95 (7) ◽

pp. 1691-1698 ◽

Cited By ~ 8

Author(s):

Nimish Vakil ◽

David Rhew ◽

Andrew Soll ◽

Joshua J. Ofman

Keyword(s):

Helicobacter Pylori ◽

Cost Effectiveness ◽

Diagnostic Testing ◽

Testing Strategies ◽

The Cost

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Cost Effectiveness of Whole Exome Sequencing for Children with Developmental Delay in a Developing Country: A Study from Jordan

Journal of Pediatric Neurology ◽

10.1055/s-0040-1722265 ◽

2021 ◽

Author(s):

Amira Masri ◽

Hanan Hamamy

Keyword(s):

Cost Effectiveness ◽

Exome Sequencing ◽

Developmental Delay ◽

Developing Country ◽

Whole Exome Sequencing ◽

Financial Burden ◽

Indirect Costs ◽

Cost Effective ◽

Whole Exome ◽

The Cost

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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Phenotype Analysis and Genetic Study of Chinese Patients With Treacher Collins Syndrome

The Cleft Palate-Craniofacial Journal ◽

10.1177/10556656211037509 ◽

2021 ◽

pp. 105566562110375

Author(s):

Meng Lu ◽

Bin Yang ◽

Zixiang Chen ◽

Haiyue Jiang ◽

Bo Pan

Keyword(s):

Rare Variants ◽

Clinical Care ◽

Treacher Collins Syndrome ◽

Chinese Patients ◽

Pathogenic Variants ◽

Premature Termination Codons ◽

Whole Exome ◽

Exome Aggregation Consortium ◽

Phenotype Analysis ◽

Sporadic Cases

Objective The aim of this study was to confirm the pathogenic variants, explore the genotype–phenotype correlation and characteristics of Chinese patients with Treacher Collins syndrome (TCS). Design Clinical details of 3 TCS family cases and 2 sporadic cases were collected and analyzed. Whole-exome sequencing and Sanger sequencing were conducted to detect causative variants. Setting Tertiary clinical care. Patients This study included 8 patients clinically diagnosed with TCS who were from 3 familial cases and 2 sporadic cases. Main Outcome Measures When filtering the database, variants were saved as rare variants if their frequency were less than 0.005 in the 1000 Genomes Project Database, the Exome Aggregation Consortium (ExAC) browser, and the Novogene database, or they would be removed as common ones. The pathogenic variants identified were verified by polymerase chain reaction. The sequencing results were analyzed by Chromas 2.1 software. Results Two novel pathogenic variants (NM_000356.3: c.537del and NM_000356.3: c.1965_1966dupGG) and 2 known pathogenic variants (NM_000356.3: c.1535del, NM_000356.3: c.4131_4135del) were identified within TCOF1 which are predicted to lead to premature termination codons resulting in a truncated protein. There was a known missense SNP (NM_015972.3: c.139G>A) within POLR1D. No phenotype–genotype correlation was observed. Instead, these 8 patients demonstrated the high genotypic and phenotypic heterogeneity of TCS. Conclusions This study expands on the pathogenic gene pool of Chinese patients with TCS. Besides the great variation among patients which is similar to international reports, Chinese patients have their own characteristics in clinical phenotype and pathogenesis mutations.

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