Unbiased targeted next-generation sequencing molecular approach for primary immunodeficiency diseases

Al‐Mousa, Hamoud; Abouelhoda, Mohamed; Monies, Dorota; Tassan, Nada Al; Al-Ghonaium, Abdulaziz; Al‐Saud, Bandar; Al-Dhekri, Hasan; Arnaout, Rand; Al‐Muhsen, Saleh; Ades, N.; Elshorbagi, Sahar; Gazlan, Sulaiman Al; Sheikh, Farrukh; Dasouki, Majed; El-Baik, Lina; Elamin, Tanzeil; Jaber, Amal; Kheir, Omnia; El‐Kalioby, Mohamed; Subhani, Shazia; Idrissi, Eman Al; AlZahrani, Mofareh; Al-Helale, Maryam; Alnader, Noukha; AlOtaibi, Afaf; Kattan, Rana F.; Abdelrahman, Khalid Al; Breacan, Muna M. Al; Humaid, Faisal S. Bin; Wakil, Salma M.; Alzayer, Fadi; Al-Dusery, Haya; Faquih, Tariq; Alhissi, Safa; Meyer, Brian F.; Hawwari, Abbas

doi:10.1016/j.jaci.2015.12.1310

Cited by 102 publications

(98 citation statements)

References 24 publications

(35 reference statements)

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“…Some of these families may also have polygenic PIDD, which remains an active area of investigation. A stepwise approach for PIDD diagnostics with targeted next generation sequencing (NGS), 20 followed as needed by WES and/or whole-genome sequencing (WGS) has been previously proposed. 19 Our findings support such an approach, although use of WES and/or WGS may ultimately become preferred to targeted multi-gene panel testing as technologies advance to provide results in a comparable timeframe.…”

Section: Discussionmentioning

confidence: 99%

“…Targeted capture of a limited number of PIDD genes can often deliver molecular diagnostic results within weeks or days, at a lower cost, while gene hunting with inadequate coverage of regions of interest may highlight pitfalls associated with currently available WES and WGS. 18-20, 83-86 WES, however, allows for detection of variants in potentially novel gene candidates. It can uncover mutations in other genes, such as CFTR , that mimic PIDD.…”

Section: Discussionmentioning

confidence: 99%

“…While the utility of targeted capture of a panel of known PIDD genes has been demonstrated, this method has limitations, for example the inability to detect new disease genes. 18-20 Whole-exome sequencing (WES) has the potential to provide rapid molecular diagnoses and improve diagnostic yield, 21, 22 which is particularly useful in clinically and genetically heterogeneous disorders such as PIDD.…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Primary immunodeficiency diseases: Genomic approaches delineate heterogeneous Mendelian disorders

Stray-Pedersen

Sorte

Samarakoon

et al. 2017

Journal of Allergy and Clinical Immunology

237

203

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Background Primary immunodeficiency diseases (PIDDs) are clinically and genetically heterogeneous disorders thus far associated with mutations in more than 300 genes. The clinical phenotypes derived from distinct genotypes may overlap. Genetic etiology can be a prognostic indicator of disease severity and can influence treatment decisions. Objective To investigate the ability of whole-exome screening methods to detect disease-causing variants in individuals with PIDDs. Methods Individuals with PIDDs from 278 families from 22 countries were investigated using whole-exome sequencing (WES). Computational CNV prediction pipelines and an exome-tiling chromosomal microarray were also applied to identify intragenic copy number variants (CNVs). Analytic approaches initially focused on 475 known or candidate PIDD genes, but were non-exclusive and were further tailored based upon clinical data, family history and immunophenotyping. Results A likely molecular diagnosis was achieved in 110 (40%) unrelated probands. Clinical diagnosis was revised in about half (60/110) and management was directly altered in nearly a quarter (26/110) of families based on the molecular findings. Twelve PIDD-causing CNVs were detected, including seven smaller than 30 Kb that would not have been detected with conventional diagnostic CNV arrays. Conclusion This high-throughput genomic approach enabled detection of disease-related variants in unexpected genes, permitted detection of low-grade constitutional, somatic and revertant mosaicism, and provided evidence of a mutational burden in mixed PIDD immunophenotypes.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Primary immunodeficiency diseases: Genomic approaches delineate heterogeneous Mendelian disorders

Stray-Pedersen

Sorte

Samarakoon

et al. 2017

Journal of Allergy and Clinical Immunology

237

203

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“…These genetic defects would not have been discovered by targeted NGS since these genes were previously not described in PID patients. It is likely many CVID cases will not have a genetic diagnosis following targeted NGS [22]. We have not offered routine diagnostic testing for CVID partly due to its locus heterogeneity and variable clinical phenotypes due to unknown environmental and genetic factors.…”

Section: Discussionmentioning

confidence: 99%

“…Targeted NGS or gene panels are less complicated and laborious than WES or WGS. The diagnostic rate for unsolved cases using gene panels have been reported in the range of 15–25% [22, 25–27]. Most of these cases were atypical clinical presentations of known PIDs.…”

Section: Discussionmentioning

confidence: 99%

Comprehensive genetic testing for primary immunodeficiency disorders in a tertiary hospital: 10-year experience in Auckland, New Zealand

Woon

Ameratunga

2016

Allergy Asthma Clin Immunol

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Background and purposeNew Zealand is a developed geographically isolated country in the South Pacific with a population of 4.4 million. Genetic diagnosis is the standard of care for most patients with primary immunodeficiency disorders (PIDs).MethodsSince 2005, we have offered a comprehensive genetic testing service for PIDs and other immune-related disorders with a published sequence. Here we present results for this program, over the first decade, between 2005 and 2014.ResultsWe undertook testing in 228 index cases and 32 carriers during this time. The three most common test requests were for X-linked lymphoproliferative (XLP), tumour necrosis factor receptor associated periodic syndrome (TRAPS) and haemophagocytic lymphohistiocytosis (HLH). Of the 32 suspected XLP cases, positive diagnoses were established in only 2 patients. In contrast, genetic defects in 8 of 11 patients with suspected X-linked agammaglobulinemia (XLA) were confirmed. Most XLA patients were initially identified from absence of B cells. Overall, positive diagnoses were made in about 23% of all tests requested. The diagnostic rate was lowest for several conditions with locus heterogeneity.ConclusionsThorough clinical characterisation of patients can assist in prioritising which genes should be tested. The clinician-driven customised comprehensive genetic service has worked effectively for New Zealand. Next generation sequencing will play an increasing role in disorders with locus heterogeneity.

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Screening for primary immunodeficiency diseases by next‐generation sequencing in early life

Sun

Yang

et al. 2020

Clin & Trans Imm

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Objective. We aimed to use next-generation sequencing (NGS) for the early diagnosis of primary immunodeficiency diseases (PIDs) and define its effects on medical management for an infant cohort in early life. Methods. A single-centre study was conducted from November 2015 to April 2018. Infants less than 3 months old with infections or abnormal white blood cell counts were enrolled in the study. Gene variants were analysed by NGS, and once a mutation was found in a PID-associated gene, the immune functions associated with this mutation were detected. The diagnosis rate of PIDs in the cohort was the main outcome. The patients received corresponding management and follow-up treatments. Results. Among 2392 patients who were genetically tested with NGS, 51 infants were diagnosed with PIDs. Seven types of PIDs were detected, and the most common (25/51, 49%) were combined immunodeficiencies with associated or syndromic features. Thirty-five patients (68.6%) were cured or had improved outcomes after being diagnosed with PID. The NGS cost was US $280 per case. Conclusions. This study not only highlighted the potential of NGS to rapidly deliver molecular diagnoses of PIDs but also indicated that the prevalence of PIDs is underestimated. With broader use, this approach has the potential to alter clinical strategies.

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Unbiased targeted next-generation sequencing molecular approach for primary immunodeficiency diseases

Cited by 102 publications

References 24 publications

Primary immunodeficiency diseases: Genomic approaches delineate heterogeneous Mendelian disorders

Primary immunodeficiency diseases: Genomic approaches delineate heterogeneous Mendelian disorders

Comprehensive genetic testing for primary immunodeficiency disorders in a tertiary hospital: 10-year experience in Auckland, New Zealand

Screening for primary immunodeficiency diseases by next‐generation sequencing in early life

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