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Whole‐exome sequencing of T‐B+ severe combined immunodeficiency in Egyptian infants, JAK3 predominance and novel variants


El Hawary, R; Meshaal, S; Mauracher, Andrea A; Opitz, Lennart; Abd Elaziz, D; Lotfy, S; Eldash, A; Boutros, J; Galal, N; Pachlopnik Schmid, J; Elmarsafy, A (2021). Whole‐exome sequencing of T‐B+ severe combined immunodeficiency in Egyptian infants, JAK3 predominance and novel variants. Clinical and Experimental Immunology, 203(3):448-457.

Abstract

Severe combined immunodeficiency (SCID) is fatal if not treated with immune reconstitution. In Egypt, T‐B+ SCID accounts for 38·5% of SCID diagnoses. An accurate genetic diagnosis is essential for choosing appropriate treatment modalities and for offering genetic counseling to the patient’s family. The objectives of this study were to describe the clinical, immunological and molecular characteristics of a cohort of twenty Egyptian patients with T‐B+ SCID. The initial diagnosis (based on clinical features and flow cytometry) was followed by molecular investigation (whole‐exome sequencing). All patients had the classic clinical picture for SCID, including failure to thrive (n = 20), oral candidiasis (n = 17), persistent diarrhea (n = 14), pneumonia (n = 13), napkin dermatitis (n = 10), skin rash (n = 7), otitis media (n = 3) and meningitis (n = 2). The onset of manifestations was at the age of 2·4 ± 1·6 months and diagnosis at the age of 6·7 ± ·5 months, giving a diagnostic delay of 4·3 months. JAK3 gene variants were most frequent (n = 12) with three novel variants identified, followed by IL2Rγ variants (n = 6) with two novel variants. IL7Rα and CD3ε variants were found once, with a novel variant each. T‐B+NK− SCID accounted for approximately 90% of the Egyptian patients with T‐B+SCID. Of these T‐B+NK− SCID cases, 60% were autosomal recessive syndromes caused by JAK3 mutations and 30% were X‐linked syndromes. It might be useful to sequence the JAK3 gene (i.e. targeted Sanger sequencing) in all T‐B+ SCID patients, especially after X‐linked SCID has been ruled out. Hence, no more than 10% of T‐B+ SCID patients might require next‐generation for a molecular diagnosis.

Abstract

Severe combined immunodeficiency (SCID) is fatal if not treated with immune reconstitution. In Egypt, T‐B+ SCID accounts for 38·5% of SCID diagnoses. An accurate genetic diagnosis is essential for choosing appropriate treatment modalities and for offering genetic counseling to the patient’s family. The objectives of this study were to describe the clinical, immunological and molecular characteristics of a cohort of twenty Egyptian patients with T‐B+ SCID. The initial diagnosis (based on clinical features and flow cytometry) was followed by molecular investigation (whole‐exome sequencing). All patients had the classic clinical picture for SCID, including failure to thrive (n = 20), oral candidiasis (n = 17), persistent diarrhea (n = 14), pneumonia (n = 13), napkin dermatitis (n = 10), skin rash (n = 7), otitis media (n = 3) and meningitis (n = 2). The onset of manifestations was at the age of 2·4 ± 1·6 months and diagnosis at the age of 6·7 ± ·5 months, giving a diagnostic delay of 4·3 months. JAK3 gene variants were most frequent (n = 12) with three novel variants identified, followed by IL2Rγ variants (n = 6) with two novel variants. IL7Rα and CD3ε variants were found once, with a novel variant each. T‐B+NK− SCID accounted for approximately 90% of the Egyptian patients with T‐B+SCID. Of these T‐B+NK− SCID cases, 60% were autosomal recessive syndromes caused by JAK3 mutations and 30% were X‐linked syndromes. It might be useful to sequence the JAK3 gene (i.e. targeted Sanger sequencing) in all T‐B+ SCID patients, especially after X‐linked SCID has been ruled out. Hence, no more than 10% of T‐B+ SCID patients might require next‐generation for a molecular diagnosis.

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Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > University Children's Hospital Zurich > Medical Clinic
Dewey Decimal Classification:610 Medicine & health
Scopus Subject Areas:Health Sciences > Immunology and Allergy
Life Sciences > Immunology
Uncontrolled Keywords:Immunology, Immunology and Allergy
Language:English
Date:1 March 2021
Deposited On:18 Jan 2021 06:45
Last Modified:12 Feb 2021 02:11
Publisher:Wiley-Blackwell Publishing, Inc.
ISSN:0009-9104
OA Status:Closed
Free access at:Publisher DOI. An embargo period may apply.
Publisher DOI:https://doi.org/10.1111/cei.13536
PubMed ID:33040328

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