Genetic diagnosis of inborn errors of immunity using clinical exome sequencing

Kwon, Soon Sung; Cho, Youn Keong; Hahn, Seung Min; Oh, Jiyoung; Won, Dongju; Shin, Saeam; Kang, Joong Koo; Ahn, Jong Gyun; Lee, Seung Tae; Choi, Jong Rak

doi:10.3389/fimmu.2023.1178582

Cited by 3 publications

(2 citation statements)

References 37 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…While for the most frequent IEI category in adults, IEI with predominantly antibody deficiencies, the screening tests seem relatively straightforward (immunoglobulin levels, response to vaccinations), the diagnostic procedures for other categories of IEI are more complex 12 . Also, most genetic studies in PID have a limited diagnostic yield, varying between 15% and 30%, with lower yields in adults 14–16 . Lymphocyte flowcytometry (LFC) of peripheral blood is a readily available diagnostic tool and is becoming increasingly important in diagnosing IEI 17–20 .…”

Section: Introductionmentioning

confidence: 99%

“…12 Also, most genetic studies in PID have a limited diagnostic yield, varying between 15% and 30%, with lower yields in adults. [14][15][16] Lymphocyte flowcytometry (LFC) of peripheral blood is a readily available diagnostic tool and is becoming increasingly important in diagnosing IEI. [17][18][19][20] The results of a recent Egyptian study of more than a thousand pediatric patients support the value of LFC for IEI diagnosis: with a very detailed LFC protocol, including protein expression assays, 73% of patients with an IEI could be diagnosed.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Cluster analysis of flowcytometric immunophenotyping with extended T cell subsets in suspected immunodeficiency

Seitz,

Gaitan,

Berkemeier

et al. 2023

Immunity Inflam & Disease

View full text Add to dashboard Cite

BackgroundPatients with immunodeficiencies commonly experience diagnostic delays resulting in morbidity. There is an unmet need to identify patients earlier, especially those with high risk for complications. Compared to immunoglobulin quantification and flowcytometric B cell subset analysis, expanded T cell subset analysis is rarely performed in the initial evaluation of patients with suspected immunodeficiency. The simultaneous interpretation of multiple immune variables, including lymphocyte subsets, is challenging.ObjectiveTo evaluate the diagnostic value of cluster analyses of immune variables in patients with suspected immunodeficiency.MethodsRetrospective analysis of 38 immune system variables, including seven B cell and sixteen T cell subpopulations, in 107 adult patients (73 with immunodeficiency, 34 without) evaluated at a tertiary outpatient immunology clinic. Correlation analyses of individual variables, k‐means cluster analysis with evaluation of the classification into “no immunodeficiency” versus “immunodeficiency” and visual analyses of hierarchical heatmaps were performed.ResultsBinary classification of patients into groups with and without immunodeficiency was correct in 54% of cases with the full data set and increased to 69% and 75% of cases, respectively, when only 16 variables with moderate (p < .05) or 7 variables with strong evidence (p < .01) for a difference between groups were included. In a cluster heatmap with all patients but only moderately differing variables and a heatmap with only immunodeficient patients restricted to T cell variables alone, segregation of most patients with common variable immunodeficiency and combined immunodeficiency was observed.ConclusionCluster analyses of immune variables, including detailed lymphocyte flowcytometry with T cell subpopulations, may support clinical decision making for suspected immunodeficiency in daily practice.

show abstract

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Cluster analysis of flowcytometric immunophenotyping with extended T cell subsets in suspected immunodeficiency

Seitz,

Gaitan,

Berkemeier

et al. 2023

Immunity Inflam & Disease

View full text Add to dashboard Cite

show abstract

A novel mutation in FNIP1 associated with a syndromic immunodeficiency and cardiomyopathy

Spivak,

Lev,

Simon

et al. 2024

Immunogenetics

View full text Add to dashboard Cite

Genetic variants in Folliculin interacting protein 1 (FNIP1) were recently discovered as monogenic causes for immunodeficiency and cardiomyopathy, with only a few patients diagnosed thus far. In this study, we describe a patient harboring a novel genetic variant in FNIP1 causing immunodeficiency with cardiac involvement. Clinical and immunological workups were performed. Genetic evaluation utilizing whole-exome sequencing (WES) and Sanger sequencing was conducted. The index patient (subject II-4) presented with hypertrophic cardiomyopathy, recurrent infections, and chronic diarrhea during infancy. Immune workup revealed agammaglobulinemia and a lack of B lymphocytes. Genetic evaluation identified a homozygous 13-bp duplication variant in FNIP1 (c.52_64dupGCGCCCGGCCGCG, p. Asp22GlyfsTer21) resulting in a frameshift in exon 1/18. She was treated with supplemental intravenous immunoglobulins (IVIg) with good control of sinopulmonary and gastrointestinal manifestations. Her sibling (subject II-1) had similar clinical features, along with dysmorphic facial features and hypotony, and succumbed to cardiogenic shock at the age of 2 months, prior to genetic evaluation. Diagnosis of novel immunodeficiencies promotes our understanding of the immune system, enabling genetic counseling as herein, and may assist in the development of novel medical therapies in the future. FNIP1 loss-of-function should be considered in patients presenting in infancy with cardiac manifestations along with agammaglobulinemia (and B-cell lymphopenia).

show abstract

Immunogenetic Landscape in Pediatric Common Variable Immunodeficiency

Szczawińska-Popłonyk,

Ciesielska,

Konarczak

et al. 2024

IJMS

View full text Add to dashboard Cite

Common variable immunodeficiency (CVID) is the most common symptomatic antibody deficiency, characterized by heterogeneous genetic, immunological, and clinical phenotypes. It is no longer conceived as a sole disease but as an umbrella diagnosis comprising a spectrum of clinical conditions, with defects in antibody biosynthesis as their common denominator and complex pathways determining B and T cell developmental impairments due to genetic defects of many receptors and ligands, activating and co-stimulatory molecules, and intracellular signaling molecules. Consequently, these genetic variants may affect crucial immunological processes of antigen presentation, antibody class switch recombination, antibody affinity maturation, and somatic hypermutation. While infections are the most common features of pediatric CVID, variants in genes linked to antibody production defects play a role in pathomechanisms of immune dysregulation with autoimmunity, allergy, and lymphoproliferation reflecting the diversity of the immunogenetic underpinnings of CVID. Herein, we have reviewed the aspects of genetics in CVID, including the monogenic, digenic, and polygenic models of inheritance exemplified by a spectrum of genes relevant to CVID pathophysiology. We have also briefly discussed the epigenetic mechanisms associated with micro RNA, DNA methylation, chromatin reorganization, and histone protein modification processes as background for CVID development.

show abstract

Genetic diagnosis of inborn errors of immunity using clinical exome sequencing

Cited by 3 publications

References 37 publications

Cluster analysis of flowcytometric immunophenotyping with extended T cell subsets in suspected immunodeficiency

Cluster analysis of flowcytometric immunophenotyping with extended T cell subsets in suspected immunodeficiency

A novel mutation in FNIP1 associated with a syndromic immunodeficiency and cardiomyopathy

Immunogenetic Landscape in Pediatric Common Variable Immunodeficiency

Contact Info

Product

Resources

About