DNA recombination defects in Kuwait: Clinical, immunologic and genetic profile

Al‐Herz, Waleed; Massaad, Michel J.; Chou, Janet; Notarangelo, Luigi D.; Geha, Raif S.

doi:10.1016/j.clim.2017.10.006

Cited by 8 publications

(8 citation statements)

References 34 publications

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“…We consider delayed diagnosis as the major cause for a poor survival outcome in our cohort. Our data is consistent with countries where newborn screening (NBS) for SCID has not yet been implemented (18). Without NBS, asymptomatic diagnosis for SCID is possible only in a scenario of strong family history.…”

Section: Discussionsupporting

confidence: 88%

“…The frequency of mutations in RAG1/2 (21 %) in the current study is like United States (21%) and the Netherlands (32%), but much less compared to Greece (41%) and Serbia (61%) where a common founder gene defect in RAG1 is likely (18). A patient with microcephaly, flat nasal bridge, short philtrum was suspected of a defect in DNA Ligase IV (1) but was identified with a RAG1 defect.…”

Section: Discussionmentioning

confidence: 48%

“…We observed 36% rate of consanguinity in our cohort which is intermediate to countries like Iran, Kuwait (18) where a very high rate of consanguinity (77%) exists and UK which has 3% rate of consanguineous marriages (23).…”

Section: Discussionmentioning

confidence: 48%

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Clinical, Immunological, and Molecular Findings in 57 Patients With Severe Combined Immunodeficiency (SCID) From India

et al. 2019

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Severe combined immunodeficiency (SCID) represents one of the most severe forms of primary immunodeficiency (PID) disorders characterized by impaired cellular and humoral immune responses. Here, we report the clinical, immunological, and molecular findings in 57 patients diagnosed with SCID from India. Majority of our patients (89%) presented within 6 months of age. The most common clinical manifestations observed were recurrent pneumonia (66%), failure to thrive (60%), chronic diarrhea (35%), gastrointestinal infection (21%), and oral candidiasis (21%). Hematopoietic Stem Cell Transplantation (HSCT) is the only curative therapy available for treating these patients. Four patients underwent HSCT in our cohort but had a poor survival outcome. Lymphopenia (absolute lymphocyte counts/μL <2,500) was noted in 63% of the patients. Based on immunophenotypic pattern, majority of the cases were T−B− SCID (39%) followed by T−B+ SCID (28%). MHC class II deficiency accounted for 10.5% of our patient group. A total of 49 patients were molecularly characterized in this study and 32 novel variants were identified in our cohort. The spectrum of genetic defects in our cohort revealed a wide genetic heterogeneity with the major genetic cause being RAG1/2 gene defect (n = 12) followed by IL2RG (n = 9) and JAK3 defects (n = 9). Rare forms of SCID like Purine nucleoside phosphorylase (PNP) deficiency, reticular dysgenesis, DNA-Protein Kinase (DNA-PKcs) deficiency, six cases of MHC class II deficiency and two ZAP70 deficiency were also identified in our cohort. Fourteen percent of the defects still remained uncharacterized despite the application of next generation sequencing. With the exception of MHC class II deficiency and ZAP70 deficiency, all SCID patients had extremely low T cell receptor excision (TRECs) (<18 copies/μL).

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Section: Discussionsupporting

confidence: 88%

Section: Discussionmentioning

confidence: 48%

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Clinical, Immunological, and Molecular Findings in 57 Patients With Severe Combined Immunodeficiency (SCID) From India

et al. 2019

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“…Several cohort studies with international collaborators are published, and a recent review of literature enumerate the number of published cases with RAG deficiency over 400 (2, 4, 7-9, 13, 14, 23). Among the population with high rate of consanguity, founder variants for RAG genes were proposed among the Amish and in the Middle East (26)(27)(28).…”

Section: Discussionmentioning

confidence: 99%

The Clinical and Genetic Spectrum of 82 Patients With RAG Deficiency Including a c.256_257delAA Founder Variant in Slavic Countries

et al. 2020

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Background: Variants in recombination-activating genes (RAG) are common genetic causes of autosomal recessive forms of combined immunodeficiencies (CID) ranging from severe combined immunodeficiency (SCID), Omenn syndrome (OS), leaky SCID, and CID with granulomas and/or autoimmunity (CID-G/AI), and even milder presentation with antibody deficiency.Objective: We aim to estimate the incidence, clinical presentation, genetic variability, and treatment outcome with geographic distribution of patients with the RAG defects in populations inhabiting South, West, and East Slavic countries.Methods: Demographic, clinical, and laboratory data were collected from RAG-deficient patients of Slavic origin via chart review, retrospectively. Recombinase activity was determined in vitro by flow cytometry-based assay.Results: Based on the clinical and immunologic phenotype, our cohort of 82 patients from 68 families represented a wide spectrum of RAG deficiencies, including SCID (n = 20), OS (n = 37), and LS/CID (n = 25) phenotypes. Sixty-seven (81.7%) patients carried RAG1 and 15 patients (18.3%) carried RAG2 biallelic variants. We estimate that the minimal annual incidence of RAG deficiency in Slavic countries varies between 1 in 180,000 and 1 in 300,000 live births, and it may vary secondary to health care disparities in these regions. In our cohort, 70% (n = 47) of patients with RAG1 variants carried p.K86Vfs * 33 (c.256_257delAA) allele, either in homozygous (n = 18, 27%) or in compound heterozygous (n = 29, 43%) form. The majority (77%) of patients with homozygous RAG1 p.K86Vfs * 33 variant originated from Vistula watershed area in Central and Eastern Poland, and compound heterozygote cases were distributed among all Slavic countries except Bulgaria. Clinical and immunological presentation of homozygous RAG1 p.K86Vfs * 33 cases was highly diverse (SCID, OS, and AS/CID) suggestive of strong influence of additional genetic and/or epigenetic factors in shaping the final phenotype. Conclusion:We propose that RAG1 p.K86Vfs * 33 is a founder variant originating from the Vistula watershed region in Poland, which may explain a high proportion of homozygous cases from Central and Eastern Poland and the presence of the variant in all Slavs. Our studies in this cohort of RAG1 founder variants confirm that clinical and immunological phenotypes only partially depend on the underlying genetic defect. As access to HSCT is improving among RAG-deficient patients in Eastern Europe, we anticipate improvements in survival.

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“…Differently from other studies focused on populations with high rate of consanguinity [34,35], many patients enrolled in this work had non-consanguineous parents (59%), suggesting a highly mutation rate in these genes as well as a large occurrence of heterozygous carriers. Intriguingly, although individuals with RAG heterozygous missense mutations do not seems associated to typical RAG phenotype, we observed three patients presenting as CID and autoimmune cytopenia carrying only a single missense heterozygous mutation in RAG genes (data not shown) suggesting that other factors, not yet fully understood, could influence this genetic background.…”

Section: Discussionmentioning

confidence: 84%

Clinical, Immunological and Molecular Variability of RAG Deficiency: a Retrospective Analysis of 22 RAG Patients

Cifaldi

Rivalta

Amodio

et al. 2021

Preprint

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Purpose RAG deficiency is associated with a variety of clinical phenotypes. We described clinical, immunological and molecular characterization within a cohort of 22 RAG patients focused on the possible correlation between clinical and genetic data. Methods Immunological and genetic features were investigated by Multiparametric Flow Cytometry and by Sanger or Next generation sequencing (NGS) respectively. Results Patients represented a broad spectrum of RAG deficiencies: SCID n=8, OS n=6, LS/AS n=4 and CID n=4. Four novel mutation in RAG1 gene and one in RAG2 were reported. The primary symptom at presentation were infections (81.8%). Infections and autoimmunity occurred together in the majority of cases (63.6%). Fifteen out of 22 (68.2%) patients presented autoimmune/hyperinflammatory manifestations. Four patients experienced severe autoimmune cytopenia refractory to different lines of therapy. Total lymphocytes count was reduced or almost lacking in SCID group. CD4 cells count was higher in OS patients. B lymphocytes were variably detected in AS and CID groups. Eighteen patients underwent HSCT permitting definitive control of autoimmune/hyperinflammatory manifestations in twelve of them (80%). Conclusion RAG deficiency still represents a challenge in the tracing of effective management and follow-up, notably considering the inability to predict the disease course in atypical cases. Immune dysregulation manifestations are common features often refractory to conventional medical management. Severe and early autoimmune refractory cytopenia is frequent and could be the first symptom of onset. Prompt recognition of RAG deficiency in patients with early onset of autoimmune/hyperinflammatory manifestations could contribute to the choice of a timely and specific treatment preventing the onset of other complications.

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DNA recombination defects in Kuwait: Clinical, immunologic and genetic profile

Cited by 8 publications

References 34 publications

Clinical, Immunological, and Molecular Findings in 57 Patients With Severe Combined Immunodeficiency (SCID) From India

Clinical, Immunological, and Molecular Findings in 57 Patients With Severe Combined Immunodeficiency (SCID) From India

The Clinical and Genetic Spectrum of 82 Patients With RAG Deficiency Including a c.256_257delAA Founder Variant in Slavic Countries

Clinical, Immunological and Molecular Variability of RAG Deficiency: a Retrospective Analysis of 22 RAG Patients

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