Targeted high-throughput sequencing technique for the molecular diagnosis of primary immunodeficiency disorders

Zuo, Hua; Wei, Wei; Bu, Ding Fang; Li, Huan Huan; Ding, Fei; Zhu, Ping

doi:10.1097/md.0000000000012695

Cited by 8 publications

(8 citation statements)

References 24 publications

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“…Next‐generation sequencing of different cohorts of subjects with primary immunodeficiency or hemophagocytic lymphohistiocytosis (HLH) reported least eight AP3B1 variants (Table S4) in a heterozygous state with or without a variant in another (synergistic) gene. These findings suggest that heterozygous AP3B1 variants may contribute to an immunologic phenotype (Chi et al, 2018; Gallo et al, 2016; Gao, Zhu, Huang, & Zhou, 2015; Miao et al, 2019; Mukda et al, 2017; Tesi et al, 2015; Xu et al, 2017). These variants have not been reported in HPS subjects but were included in this report because they may cause HPS when occurring in a homozygous or compound heterozygous state.…”

Section: Introductionmentioning

confidence: 99%

“…Individuals with HPS‐2 that present to an immunologist with (severe) immunodeficiency may escape diagnosis due to emphasis on their immunodeficiency, other mild manifestations (e.g., hypopigmentation, ocular findings, and bleeding diathesis) may be overlooked, there may be unfamiliarity with HPS‐2, and costs and lack of availability of AP3B1 genetic testing may provide obstacles to diagnosis. However, the recent significant number of heterozygous AP3B1 variants identified by next‐generation sequencing in cohorts with immunodeficiency disorders (Chi et al, 2018; Gallo et al, 2016; Gao et al, 2015; Miao et al, 2019; Mukda et al, 2017; Tesi et al, 2015; Xu et al, 2017) emphasizes the importance of including AP3B1 in immunodeficiency‐related gene panels and may result in the diagnosis of additional HPS‐2 cases.…”

Section: Introductionmentioning

confidence: 99%

“…Heterozygous HPS1 , HPS4 , and DTNBP1 variants were reported in familial (Stearman et al, 2019) or sporadic (Deng et al, 2018) pulmonary fibrosis cases (Tables 3, 6, and 9). Heterozygous AP3B1 variants have been reported in cases with primary immunodeficiency (Chi et al, 2018; Gallo et al, 2016) or HLH (Gao et al, 2015; Miao et al, 2019; Mukda et al, 2017; Tesi et al, 2015; Xu et al, 2017; Table 4), and heterozygous variants in AP3D1 , HPS3 , and HPS4 were reported in cases with autism spectrum disorder or schizophrenia (Fromer et al, 2014; Iossifov et al, 2014; Takata et al, 2018).…”

Section: Introductionmentioning

confidence: 99%

“…These findings suggest that heterozygous AP3B1 variants may contribute to an immunologic phenotype (Chi et al, 2018;Gallo et al, 2016;Gao, Zhu, Huang, & Zhou, 2015;Miao et al, 2019;Mukda et al, 2017;Tesi et al, 2015;Xu et al, 2017). These variants have not been reported in HPS subjects but were included in this report because they may cause HPS when occurring in a homozygous or compound heterozygous state.…”

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confidence: 95%

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Hermansky–Pudlak syndrome: Mutation update

et al. 2020

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Hermansky-Pudlak syndrome (HPS) is a group of 10 autosomal recessive multisystem disorders, each defined by the deficiency of a specific gene. HPS-associated genes encode components of four ubiquitously expressed protein complexes: Adaptor protein-3 (AP-3) and biogenesis of lysosome-related organelles complex-1 (BLOC-1) through -3. All individuals with HPS exhibit albinism and a bleeding diathesis; additional features occur depending on the defective protein complex. Pulmonary fibrosis is associated with AP-3 and BLOC-3 deficiency, immunodeficiency with AP-3 defects, and gastrointestinal symptoms are more prevalent and severe in BLOC-3 deficiency. Therefore, identification of the HPS subtype is valuable for prognosis, clinical management, and treatment options. The prevalence of HPS is estimated at 1-9 per 1,000,000. Here we summarize 264 reported and novel variants in 10 HPS genes and estimate that~333 Puerto Rican HPS subjects and~385 with other ethnicities are reported to date. We provide pathogenicity predictions for missense and splice site variants and list variants with high minor allele frequencies. Current cellular and clinical aspects of HPS are also summarized. This review can serve as a manifest for molecular diagnostics and genetic counseling aspects of HPS.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

mentioning

confidence: 95%

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Hermansky–Pudlak syndrome: Mutation update

et al. 2020

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“…Several reports have been published listing 10 different mutations in CORO1A, which describe patients suffering from either autosomal recessive SCID [85,[93][94][95] or hemophagocytic lymphohistiocytosis [96,97], whereas copy number duplication has been linked to autism [98]. Patients diagnosed with SCID suffered from recurrent bacterial and viral infections of the respiratory tracts and lungs, as well as skin lesions and chronic warts [85,[93][94][95].…”

Section: Coronin-1a Deficiencymentioning

confidence: 99%

When Actin is Not Actin’ Like It Should: A New Category of Distinct Primary Immunodeficiency Disorders

2020

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An increasing number of primary immunodeficiencies (PIDs) have been identified over the last decade, which are caused by deleterious mutations in genes encoding for proteins involved in actin cytoskeleton regulation. These mutations primarily affect hematopoietic cells and lead to defective function of immune cells, such as impaired motility, signaling, proliferative capacity, and defective antimicrobial host defense. Here, we review several of these immunological “actinopathies” and cover both clinical aspects, as well as cellular mechanisms of these PIDs. We focus in particular on the effect of these mutations on human neutrophil function.

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Evolutionary preservation of CpG dinucleotides in RAG1 may elucidate the relatively high rate of methylation-mediated mutagenesis of RAG1 transposase

Fawzy,

Nazmy,

El-Sheikh

et al. 2024

Immunol Res

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Recombination-activating gene 1 (RAG1) is a vital player in V(D)J recombination, a fundamental process in primary B cell and T cell receptor diversification of the adaptive immune system. Current vertebrate RAG evolved from RAG transposon; however, it has been modified to play a crucial role in the adaptive system instead of being irreversibly silenced by CpG methylation. By interrogating a range of publicly available datasets, the current study investigated whether RAG1 has retained a disproportionate level of its original CpG dinucleotides compared to other genes, thereby rendering it more exposed to methylation-mediated mutation. Here, we show that 57.57% of RAG1 pathogenic mutations and 51.6% of RAG1 disease-causing mutations were associated with CpG methylation, a percentage that was significantly higher than that of its RAG2 cofactor alongside the whole genome. The CpG scores and densities for all RAG ancestors suggested that RAG transposon was CpG denser. The percentage of the ancestral CpG of RAG1 and RAG2 were 6% and 4.2%, respectively, with no preference towards CG containing codons. Furthermore, CpG loci of RAG1 in sperms were significantly higher methylated than that of RAG2. In conclusion, RAG1 has been exposed to CpG mediated methylation mutagenesis more than RAG2 and the whole genome, presumably due to its late entry to the genome later with an initially higher CpG content.

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Targeted high-throughput sequencing technique for the molecular diagnosis of primary immunodeficiency disorders

Abstract: Supplemental Digital Content is available in the text

Cited by 8 publications

References 24 publications

Hermansky–Pudlak syndrome: Mutation update

Hermansky–Pudlak syndrome: Mutation update

When Actin is Not Actin’ Like It Should: A New Category of Distinct Primary Immunodeficiency Disorders

Evolutionary preservation of CpG dinucleotides in RAG1 may elucidate the relatively high rate of methylation-mediated mutagenesis of RAG1 transposase

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