Genetic Testing in Egyptian Patients with Inborn Errors of Immunity: a Single-Center Experience

Hawary, Rabab El; Meshaal, Safa; Elaziz, Dalia Abd; Alkady, Radwa; Lotfy, Sohilla; Eldash, Alia; Erfan, Aya; Saad, Mai; Darwish, Rania K.; Boutros, Jeannette; Galal, Nermeen; Elmarsafy, Aisha

doi:10.1007/s10875-022-01272-y

Cited by 17 publications

(8 citation statements)

References 25 publications

(29 reference statements)

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“…Protein expression assays increased the spectrum of the diagnoses achieved and helped reach definitive diagnosis in several disorders like, DOCK8 deficiency, LRBA deficiency, XLA, CGD, Perforin deficiency, ADA deficiency, IL7RA deficiency, LADI and MHC-II deficiency [ 12 , 21 , 22 , 27 ]. Also, sending out for genetic testing has been cut down based on optimizing the molecular diagnosis strategy adapted in our center guided by the FCM [ 28 ]. Based on the FCM results, 744 patients (73%) were categorized and diagnosed with one of IEI disorders.…”

Section: Discussionmentioning

confidence: 99%

Flow cytometry optimizing the diagnostic approach in inborn errors of immunity: experience from Egypt

Meshaal

Hawary

Eldash

et al. 2022

Allergy Asthma Clin Immunol

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Background Human inborn errors of immunity (IEI) are a group of inherited genetic disorders of the immune system. IEI Patients suffer from severe repeated infections, autoimmunity, lymphadenopathy and/or increased susceptibility to malignancies. IEI are due to absence, disproportion, or loss of function of immune cells; mostly inherited in autosomal recessive manner, hence are more common in countries with high rate of consanguinity. Definite diagnosis of IEI is achieved by genetic analysis, however it is not always available. Aim: to report on different IEI categories and impact of expanding the use of flow cytometry (FCM) in diagnosis, categorization and follow up of IEI patients in a highly consanguineous population. Methods Retrospective chart review on different IEI categories diagnosed at the primary immunodeficiency center in Cairo University Specialized Pediatric hospital from 2011 to 2021 based on expanding the use of FCM. Results 1510 IEI patients were diagnosed; 480 were diagnosed genetically with FMF, 11 with cystic fibrosis and 1019 patients were diagnosed with other IEI disorders. Phagocytic defects were the commonest (30%) followed by severe combined immunodeficiency (22%) and combined immunodeficiency (18.3%). FCM testing properly diagnosed and categorized 73% of the cases. Conclusion Using multi-color FCM to evaluate immune cells populations, subpopulations, functions, and intracellular proteins expression is proved a useful cost-effective method for screening, categorization and follow up of IEI patients. FCM can improve the diagnosis of IEI significantly when tests are properly targeted and well designed. This study presents a 10-year experience in diagnosis of IEI using FCM at a tertiary referral center in a setting of limited resources and yet high prevalence of IEI.

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Section: Discussionmentioning

confidence: 99%

Flow cytometry optimizing the diagnostic approach in inborn errors of immunity: experience from Egypt

Meshaal

Hawary

Eldash

et al. 2022

Allergy Asthma Clin Immunol

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“…The MENA cohort's higher rate of reported consanguinity, broader clinical spectrum and more systematic application of WES likely contributed to their overall higher diagnostic yield. However, our approach produced at least comparable yields to TGP-focused or mixed sequencing approaches applied to IEI-specific diagnostics in other resource-constrained settings [13,[141][142]. Some studies reported a smaller incremental gain in diagnostic yield from the addition of WES to TGPs [4,141], but ours was significantly higher.…”

Section: Many Of Our Index Patients Did Not Present With the Most 'Ca...mentioning

confidence: 68%

A Next Generation Sequencing (NGS)-based approach to diagnosing Algerian patients with suspected Inborn Errors of Immunity (IEIs)

Peng

Al-Ddafari²,

Caballero-Oteyza³

et al. 2023

Preprint

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The advent of next-generation sequencing (NGS) technologies has greatly expanded our understanding of both the clinical spectra and genetic landscape of inborn errors of immunity (IEIs). As history has shown and recent large-scale studies of monogenic risk for severe COVID have confirmed, endogamous populations may be enriched for unique, ancestry-specific disease-causing variants as a consequence of geography and/or culture. From a diagnostic perspective, this consideration may significantly impact molecular testing and analysis strategies. Herein, we report on the diagnostic yield of a 2-step NGS-based testing approach beginning with targeted gene panels (TGPs) and reflexing to whole exome sequencing (WES) if negative for Northwest Algerian patients with suspected IEIs. A total of fourteen families were screened using TGPs tailored to their IEI subtypes of common variable immunodeficiency (CVID), inflammatory bowel disease (IBD) or chronic mucocutaneous candidiasis (CMC)-hyperIgE syndrome (HIES), resulting in a total of four definitive or highly likely molecular diagnoses (29% yield). Subsequent application of WES to eight of the ten remaining unsolved cases yielded an additional four diagnoses, giving a 57% overall yield. At least two additional individuals were found to harbor suggestive candidate variants on exome warranting further investigation, while others carried candidate variants or known risk alleles likely contributing to their clinical findings. Only in one patient’s case did we fail to identify any viable potential candidates. By achieving diagnostic yields comparable to those currently quoted for application of short-read NGS to IEI detection, our study demonstrates the viability of a 2-step NGS-based testing strategy in a selected endogamous population. Data from our localized cohort also showed some similarities and differences from NGS studies performed on larger regional IEI cohorts. Finally, our results also highlight many short-comings currently inherent to the application of genomics for clinical IEI diagnostics. Not only does the global community need to address ongoing inequities in representation, access, and infrastructure, but the ability to obtain precise and detailed clinical data remains paramount for achieving diagnostic certainty in the face of complex genotype-phenotype relationships.

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“…Patient had severe lymphopenia, hypogammaglobulinemia (low IgG and IgA), reduced CD3, CD4, CD8, CD19, CD56 and CD45RA, in addition to reduced all B cell subsets. This patient was diagnosed at a later stage by molecular genetic testing; Next generation sequencing (NGS) revealed homozygous mutation in NHEJ1 gene, con rming Cernunnos-XLF de ciency, a rare form of combined immunode ciency with typical presenting features [15].…”

Section: Laboratory Analysismentioning

confidence: 93%

Immune status of patients with inherited bone marrow failure syndromes: A Single-center analysis

Lotfy,

Ghattas,

Elhady

et al. 2024

Preprint

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Inherited bone marrow failure syndromes (IBMFS) comprise a heterogeneous group of rare cancer prone genetic disorders with hematologic and physical abnormalities. The immune status of patients with an IBMFS is not entirely clear; however there are some suggestions that a few patients exhibit various degrees of qualitative immune dysfunction. Recently, there are novel and rare PID syndromes that have been associated with cytopenia secondary to bone marrow failure, but they are not always taken into consideration, phenotypic overlap may impair the correct diagnosis. This study included twenty-one patients diagnosed with IBMFS; 17 Fanconi anemia patients and 4 Diamond-Blackfan anemia patients. Evaluation of immune status was done by assessing complete blood count with differential leucocytic count, immunophenotyping of lymphocytes by Flow cytometry (CD3, CD4, CD8, CD19, CD56, B cell maturation, and naïve/memory T cells), as well as immunoglobulins assay (IgG, IgM, IgA levels). Results: Neutropenia was detected in 74% of (N= 15/21) with severity ranging from mild (24%) to severe neutropenia (36%), and all were FA patients. Lymphopenia was detected in 57% of the patients (N=12/21). Low immunoglobulin levels for age were detected in 28.6% of the patients (N=6/21). Most of FA patients had low counts of CD19 B cells, CD27+IgD+ non class switched B cells, CD27+IgD- switched memory B cells, CD27-IgD+ naïve B cells, as well as, low CD4 T Helper cells, CD45 RA naïve T cells, CD56 NK cells, CD45RO memory T cells. In DBA, limited by small sample size, no abnormalities were detected in T cell population, low NK cell counts were reported in two patients. Low CD27-IgD+, CD27+Ig D+ and CD27+IgD were detected in 2/4 of the patients while CD45RA naïve T cells were reduced in only one patient. A positive correlation between the frequency of hospitalization due to infections and degree of bone marrow hypocellularity was found. The degree of lymphopenia, low CD3, CD4, CD8, CD19 and defective T cell maturation subsets were statistically significant variables associated with occurrence of significant infections. Conclusion: IBMFS patients have altered immune status, possibility of the presence of some degree of overlap between IBMFS and certain PIDs associated with cytopenias and special somatic features might be found. Immunological assessment for patients with IBMFS should be considered as a part of routine work up of such patients.

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Genetic Testing in Egyptian Patients with Inborn Errors of Immunity: a Single-Center Experience

Cited by 17 publications

References 25 publications

Flow cytometry optimizing the diagnostic approach in inborn errors of immunity: experience from Egypt

Flow cytometry optimizing the diagnostic approach in inborn errors of immunity: experience from Egypt

A Next Generation Sequencing (NGS)-based approach to diagnosing Algerian patients with suspected Inborn Errors of Immunity (IEIs)

Immune status of patients with inherited bone marrow failure syndromes: A Single-center analysis

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