Genetic screening in a Brazilian cohort with inborn errors of immunity.
Genetic screening
Inborn errors of immunity
Single nucleotide variants
Whole exome sequencing
Journal
BMC genomic data
ISSN: 2730-6844
Titre abrégé: BMC Genom Data
Pays: England
ID NLM: 101775394
Informations de publication
Date de publication:
17 08 2023
17 08 2023
Historique:
received:
25
11
2022
accepted:
07
08
2023
medline:
21
8
2023
pubmed:
18
8
2023
entrez:
17
8
2023
Statut:
epublish
Résumé
Inherited genetic defects in immune system-related genes can result in Inborn Errors of Immunity (IEI), also known as Primary Immunodeficiencies (PID). Diagnosis of IEI disorders is challenging due to overlapping clinical manifestations. Accurate identification of disease-causing germline variants is crucial for appropriate treatment, prognosis, and genetic counseling. However, genetic sequencing is challenging in low-income countries like Brazil. This study aimed to perform genetic screening on patients treated within Brazil's public Unified Health System to identify candidate genetic variants associated with the patient's phenotype. Thirteen singleton unrelated patients from three hospitals in Rio de Janeiro were enrolled in this study. Genomic DNA was extracted from the peripheral blood lymphocytes of each patient, and whole exome sequencing (WES) analyses were conducted using Illumina NextSeq. Germline genetic variants in IEI-related genes were prioritized using a computational framework considering their molecular consequence in coding regions; minor allele frequency ≤ 0.01; pathogenicity classification based on American College of Medical Genetics and Genomics and the Association for Molecular Pathology (ACMG/AMP) guidelines gathered from the VarSome clinical database; and IEI-related phenotype using the Franklin tool. The genes classification into IEI categories follows internationally recognized guidelines informed by the International Union of Immunological Societies Expert Committee. Additional methods for confirmation of the variant included Sanger sequencing, phasing analysis, and splice site prediction. A total of 16 disease-causing variants in nine genes, encompassing six different IEI categories, were identified. X-Linked Agammaglobulinemia, caused by BTK variations, emerged as the most prevalent IEI disorder in the cohort. However, pathogenic and likely pathogenic variants were also reported in other known IEI-related genes, namely CD40LG, CARD11, WAS, CYBB, C6, and LRBA. Interestingly, two patients with suspected IEI exhibited pathogenic variants in non-IEI-related genes, ABCA12 and SLC25A13, potentially explaining their phenotypes. Genetic screening through WES enabled the detection of potentially harmful variants associated with IEI disorders. These findings contribute to a better understanding of patients' clinical manifestations by elucidating the genetic basis underlying their phenotypes.
Sections du résumé
BACKGROUND
Inherited genetic defects in immune system-related genes can result in Inborn Errors of Immunity (IEI), also known as Primary Immunodeficiencies (PID). Diagnosis of IEI disorders is challenging due to overlapping clinical manifestations. Accurate identification of disease-causing germline variants is crucial for appropriate treatment, prognosis, and genetic counseling. However, genetic sequencing is challenging in low-income countries like Brazil. This study aimed to perform genetic screening on patients treated within Brazil's public Unified Health System to identify candidate genetic variants associated with the patient's phenotype.
METHODS
Thirteen singleton unrelated patients from three hospitals in Rio de Janeiro were enrolled in this study. Genomic DNA was extracted from the peripheral blood lymphocytes of each patient, and whole exome sequencing (WES) analyses were conducted using Illumina NextSeq. Germline genetic variants in IEI-related genes were prioritized using a computational framework considering their molecular consequence in coding regions; minor allele frequency ≤ 0.01; pathogenicity classification based on American College of Medical Genetics and Genomics and the Association for Molecular Pathology (ACMG/AMP) guidelines gathered from the VarSome clinical database; and IEI-related phenotype using the Franklin tool. The genes classification into IEI categories follows internationally recognized guidelines informed by the International Union of Immunological Societies Expert Committee. Additional methods for confirmation of the variant included Sanger sequencing, phasing analysis, and splice site prediction.
RESULTS
A total of 16 disease-causing variants in nine genes, encompassing six different IEI categories, were identified. X-Linked Agammaglobulinemia, caused by BTK variations, emerged as the most prevalent IEI disorder in the cohort. However, pathogenic and likely pathogenic variants were also reported in other known IEI-related genes, namely CD40LG, CARD11, WAS, CYBB, C6, and LRBA. Interestingly, two patients with suspected IEI exhibited pathogenic variants in non-IEI-related genes, ABCA12 and SLC25A13, potentially explaining their phenotypes.
CONCLUSIONS
Genetic screening through WES enabled the detection of potentially harmful variants associated with IEI disorders. These findings contribute to a better understanding of patients' clinical manifestations by elucidating the genetic basis underlying their phenotypes.
Identifiants
pubmed: 37592284
doi: 10.1186/s12863-023-01148-z
pii: 10.1186/s12863-023-01148-z
pmc: PMC10433585
doi:
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
47Informations de copyright
© 2023. BioMed Central Ltd., part of Springer Nature.
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