Rapid Low-Cost Microarray-Based Genotyping for Genetic Screening in Primary Immunodeficiency

Suratannon, Narissara; Wijck, Rogier T. A. van; Broer, Linda; Xue, Laixi; Meurs, Joyce B. J. van; Barendregt, Barbara H.; Burg, Mirjam van der; Dik, Willem A.; Chatchatee, Pantipa; Langerak, Anton W.; Swagemakers, Sigrid; Goos, Jacqueline A.C.; Mathijssen, Irene M J; Dalm, Virgil A. S. H.; Suphapeetiporn, Kanya; Heezen, Kim C.; Drabwell, Jose; Uitterlinden, André G.; Spek, Peter J. van der; Hagen, P. Martin van

doi:10.3389/fimmu.2020.00614

Cited by 23 publications

(20 citation statements)

References 17 publications

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“…To the best of our knowledge, this is the first comprehensive analytical validation of the GSA for clinical genotyping. Our findings support and extend recently reported research studies assessing the utility of the GSA for genetic screening in primary immunodeficiency (45), for population-based genomic screening for rare and medically relevant variation (46), and for detecting rare and clinically relevant markers in multiethnic Indian populations (47).…”

Section: Discussionsupporting

confidence: 90%

“…Some of the pros and cons of using the GSA are summarized in Table 10 below. The test characteristics of the GSA compared to WGS clearly show that the GSA is not a diagnostic genomic test for individuals with rare disorders because, as shown by our MAP59 results and recent research studies (45,46), it lacks robustness for genotyping rare variants as well as probes for detection of private familial disease variants. On the other hand, we show that the GSA has the analytical robustness to serve as a clinical screen for genotypes for which one can establish robust cluster files for the AA, AB, and BB genotypes.…”

Section: Discussionmentioning

confidence: 85%

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Establishing Analytical Validity of BeadChip Array Genotype Data by Comparison to Whole-Genome Sequence and Standard Benchmark Datasets

Cherukuri

Soe

Condon

et al. 2021

Preprint

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Background Clinical use of genotype data requires high positive predictive value (PPV) and thorough understanding of the genotyping platform characteristics. BeadChip arrays, such as the Global Screening Array (GSA), potentially offer a high-throughput, low-cost clinical screen for known variants. We hypothesize that quality assessment and comparison to whole-genome sequence and benchmark data establish the analytical validity of GSA genotyping.Methods To test this hypothesis, we selected 263 samples from Coriell, generated GSA genotypes in triplicate, generated whole genome sequence (rWGS) genotypes, assessed the quality of each set of genotypes, and compared each set of genotypes to each other and to the 1000 Genomes Phase 3 (1KG) genotypes, a performance benchmark. For 59 genes (MAP59), we also performed theoretical and empirical evaluation of variants deemed medically actionable predispositions.Results Quality analyses detected sample contamination and increased assay failure along the chip margins. Comparison to benchmark data demonstrated that > 82% of the GSA assays had a PPV of 1. GSA assays targeting transitions, genomic regions of high complexity, and common variants performed better than those targeting transversions, regions of low complexity, and rare variants. Comparison of GSA data to rWGS and 1KG data showed >99.3% concordance across all measured parameters. GSA detection of variation within the MAP59 genes was 3/261 consistent with predictions from prior studies.Conclusion We establish the analytical validity of GSA assays using quality analytics and comparison to benchmark and rWGS data. GSA assays meet the standards of a clinical screen although assays interrogating rare variants, transversions, and variants within low-complexity regions require careful evaluation.

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Section: Discussionsupporting

confidence: 90%

Section: Discussionmentioning

confidence: 85%

Establishing Analytical Validity of BeadChip Array Genotype Data by Comparison to Whole-Genome Sequence and Standard Benchmark Datasets

Cherukuri

Soe

Condon

et al. 2021

Preprint

View full text Add to dashboard Cite

show abstract

“…Recently, the cost of SNP arrays has decreased appreciably, driven by the very large sample sizes needed to perform genome-wide association studies. SNP arrays also allow allelotyping, generally small deletions/duplications need confirmation by an alternate method or are not detectable [ 44 ]. The drawback of SNP array includes inability to provide the exact breakpoint, hence, whether the deletion in the presenting report is in-frame or not needs further validating techniques.…”

Section: Discussionmentioning

confidence: 99%

Compound heterozygous variants including a novel copy number variation in a child with atypical ataxia-telangiectasia: a case report

et al. 2021

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Background Ataxia-telangiectasia is a rare autosomal recessive, neurodegenerative disorder caused by alterations in the ATM gene. The majority of ATM pathogenic variants are frameshift or nonsense variants which are predicted to truncate the whole ATM protein. Herein, we report on an ataxia telangiectasia child with atypical phenotype who was identified as compound heterozygous for two ATM variants involving a previously described pathogenic single nucleotide variation (SNV) and a novel copy number variation (CNV). Case presentation A 6-year-old boy presented with delayed development and oculomotor apraxia. Brain magnetic resonance imaging showed interval development of mild atrophy in the cerebellum. Serum alpha fetoprotein level was in normal range. Next-generation sequencing and single-nucleotide polymorphism array tests were performed. Next-generation sequencing revealed a heterozygous nonsense pathogenic variant in ATM, c.742C > T (p.Arg248Ter) inherited from the father. Single-nucleotide polymorphism array revealed a compound heterozygous CNV, arr[GRCh37] 11q22.3(10851766–108183226) × 1, 31460 bp (exons 24–40 deletion of ATM) inherited from the mother, which was validated by reverse transcription-polymerase chain reaction analysis (RT-PCR). We demonstrated that this variant (NM_000051.4:c.3403_6006del) generated a product of in-frame deletion of exon 24–40 of ATM (p.Ser1135_Gln2002del). Conclusions The compound heterozygosity for ATM variants involving a previously described pathogenic SNV and a novel CNV may be associated with the atypical clinical manifestations. This clinical report extends the genetic and phenotypic spectrum of ATM pathogenic variants in atypical ataxia-telangiectasia, thus making implementation of advanced analysis beyond the routine next-generation sequencing an important consideration in diagnosis and rehabilitation services for children with ataxia-telangiectasia.

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“…Commercial availability of NGS services and the rapid decline in cost have allowed genetic diagnosis for rare diseases to be more accessible and affordable (16). Genotyping microarrays targeting known pathogenic variants in PID can be a low-cost strategy to facilitate genetic screening in areas with no access to traditional methods of genetic diagnosis (17). Alternatively, international PID molecular diagnostic and research networks led by quaternary centers in very-high-HDI countries/regions like the Asian Primary Immunodeficiency Network (APID Network) established by the University of Hong Kong have been offering free sequencing and e-consultation to patients in countries/regions where advanced immunologic testing or clinical genetics services are deficient (18,19).…”

Section: Discussionmentioning

confidence: 99%

Current Perspectives and Unmet Needs of Primary Immunodeficiency Care in Asia Pacific

et al. 2020

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correlated with average testing level (r = 0.742, p = 0.002). Cases from medium-HDI countries/regions focused on learning how to investigate a patient for PIDs in cases of severe or atypical infections, whereas those from very-high-HDI countries/regions, from which most faculty members originated, listed hematopoietic stem cell transplantation and gene therapy, newborn screening, and research as learning issues more frequently. Conclusion: There are unique HDI-related PID resource and training needs in each country/region. APSID proposes HDI group-specific strategies to improve PID care and education in her member countries/regions. Further quantitative analysis of needs in PID care in Asia Pacific is needed for lobbying governments to increase their support for PID care and research.

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Rapid Low-Cost Microarray-Based Genotyping for Genetic Screening in Primary Immunodeficiency

Cited by 23 publications

References 17 publications

Establishing Analytical Validity of BeadChip Array Genotype Data by Comparison to Whole-Genome Sequence and Standard Benchmark Datasets

Establishing Analytical Validity of BeadChip Array Genotype Data by Comparison to Whole-Genome Sequence and Standard Benchmark Datasets

Compound heterozygous variants including a novel copy number variation in a child with atypical ataxia-telangiectasia: a case report

Current Perspectives and Unmet Needs of Primary Immunodeficiency Care in Asia Pacific

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