Dataset Information

Cernunnos defect in an Iranian patient with T^- B⁺ NK⁺ severe combined immunodeficiency: A case report and review of the literature.

ABSTRACT:

Background

Defective Cernunnos gene in nonhomologous end-joining (NHEJ) pathway of the DNA repair is responsible for radiosensitive severe combined immunodeficiency (SCID). Herein, presented a new patient with Cernunnos deficiency and summarized the clinical, immunological, and molecular features of reported patients in the literature.

Case

The patient was a 6-month-old female born to consanguineous parents. She presented with long-lasting fever, diarrhea, poor feeding, and restlessness. She had suffered from recurrent fever of unknown origin and multiple episodes of oral candidiasis. In the physical examination, microcephaly, failure to thrive, oral candidiasis, pustular rash on fingers, and perianal ulcers, but no dysmorphic feature were observed. The immunologic workup revealed lymphopenia, neutropenia, normocytic anemia, low T- but normal B- and natural killer (NK)- cells, low immunoglobulin (Ig)G, and normal IgA, IgM, and IgE. The T-cell receptor excision circle (TREC) was low and the lymphocyte transformation test (LTT) was abnormal to mitogens and antigens. She was diagnosed with T^- B⁺ NK⁺ SCID and improved by intravenous immunoglobulin along with antimicrobials. A homozygous splice site variant, c.390 + 1G > T, at the intron 3 of the NHEJ1, was identified and the diagnosis of Cernunnos deficiency was established. However, while a candidate for hematopoietic stem cell transplantation, she developed sepsis and died at 11 months of age.

Conclusions

Cernunnos deficiency should be considered as a differential diagnosis in patients with microcephaly, growth retardation, recurrent infections, T-cell defects, and hypogammaglobulinemia. The normal B-cell level in the index patient is an unexpected finding in Cernunnos deficiency which requires further evaluation.

SUBMITTER: Jamee M

PROVIDER: S-EPMC9356558 | biostudies-literature | 2022 Aug

REPOSITORIES: biostudies-literature

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Publications

Cernunnos defect in an Iranian patient with T<sup>-</sup> B<sup>+</sup> NK<sup>+</sup> severe combined immunodeficiency: A case report and review of the literature.

Jamee Mahnaz M Khakbazan Fard Nasrin N Fallah Shahrzad S Golchehre Zahra Z Fallahi Mazdak M Shamsian Bibi Shahin BS Sharafian Samin S Chavoshzadeh Zahra Z

Molecular genetics & genomic medicine 20220602 8

<h4>Background</h4>Defective Cernunnos gene in nonhomologous end-joining (NHEJ) pathway of the DNA repair is responsible for radiosensitive severe combined immunodeficiency (SCID). Herein, presented a new patient with Cernunnos deficiency and summarized the clinical, immunological, and molecular features of reported patients in the literature.<h4>Case</h4>The patient was a 6-month-old female born to consanguineous parents. She presented with long-lasting fever, diarrhea, poor feeding, and restle ...[more]

PMID: 35656589

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Project description:Background: Severe combined immunodeficiency (SCID) is characterized by arrested T lymphocyte production and B lymphocyte dysfunction, resulting in life-threatening infections. Early diagnosis of SCID through population-based newborn screening (NBS) optimizes clinical management and outcomes, and also permits identification of previously unknown factors essential for human lymphocyte development. Methods: SCID was detected, prior to onset of infections, by NBS of T cell receptor excision circles, a biomarker for thymic output. Upon confirmation, the affected baby was treated by allogeneic hematopoietic cell transplantation (HCT). The genetic cause was sought by exome sequencing of the patient and parents, followed by functional analysis of a prioritized candidate gene using human hematopoietic stem cells (HSC) and zebrafish embryos. Results: An infant with leaky SCID, craniofacial and dermal abnormalities, and absent corpus callosum had his immune deficit fully corrected by HCT. Exome sequencing revealed a heterozygous, de novo, missense mutation pN441K in BCL11B. The mutant Bcl11b protein had dominant negative activity, abrogating the ability of wild type Bcl11b to bind DNA, arresting T cell lineage development and disrupting HSC migration, revealing a novel function of Bcl11b. The patientâs defects, recapitulated in Bcl11b-deficient zebrafish, were reversed by ectopic expression of intact, but not mutant, human BCL11B. Conclusions: Newborn screening facilitated treatment and identification of a novel etiology for human SCID. Coupling exome sequencing with candidate gene evaluation in human HSC and in zebrafish revealed that a constitutional BCL11B mutation causes human multisystem anomalies with SCID, while also revealing a novel, pre-thymic role for Bcl11b in hematopoietic progenitors. 3 samples were analyzed in duplicate, Sample 1 was human HSC transduced with GFP only lentivirus which served as controls, Sample 2 was human HSC transduced with lentivirus expressing FLAG-tagged WT BCL11B and GFP, Sample 3 was human HSC transduced with lentivirus expressing FLAG-tagged mutant BCL11B and GFP

Project description:BACKGROUND: Children with Severe Combined Immunodeficiency (SCID) lack autologous T lymphocytes and present with multiple infections early in infancy. Omenn syndrome is characterized by the sole emergence of oligoclonal auto-reactive T lymphocytes, resulting in erythroderma and enteropathy. Omenn syndrome (OS) shares the genetic aetiology of T-B-NK+ SCID, with mutations in RAG1, RAG2, or DCLRE1C. METHODS: Patients diagnosed with T-B-NK+ SCID or phenotypes suggestive of Omenn syndrome were investigated by molecular genetic studies using gene tightly linked microsatellite markers followed by direct sequencing of the coding regions and splice sites of the respective candidate genes. RESULTS: We report the molecular genetic basis of T-B-NK+ SCID in 22 patients and of OS in seven patients all of Arab descent from Saudi Arabia. Among the SCID patients, six (from four families) displayed four homozygous missense mutations in RAG1 including V433M, R624H, R394W, and R559S. Another four patients (from three familes) showed 3 novel homozygous RAG2 mutations including K127X, S18X, and Q4X; all of which predict unique premature truncations of RAG2 protein. Among Omenn patients, four (from two families) have S401P and R396H mutations in RAG1, and a fifth patient has a novel I444M mutation in RAG2. Seven other patients (six SCID and one OS) showed a gross deletion in exons 1-3 in DCLRE1C. Altogether, mutations in RAG1/2 and DCLRE1C account for around 50% and 25%, respectively, in our study cohort, a proportion much higher than in previous reported series. Seven (24%) patients lack a known genetic aetiology, strongly suggesting that they carry mutations in novel genes associated with SCID and Omenn disorders that are yet to be discovered in the Saudi population. CONCLUSION: Mutation-free patients who lack a known genetic aetiology are likely to carry mutations in the regulatory elements in the SCID-causing genes or in novel genes that are yet to be discovered. Our efforts are underway to investigate this possibility by applying the whole genome scans on these cases via the use of Affymetrix high density DNA SNP chips in addition to homozygosity mapping.

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Dataset Information

Cernunnos defect in an Iranian patient with T^- B⁺ NK⁺ severe combined immunodeficiency: A case report and review of the literature.

Background

Case

Conclusions

Publications

Cernunnos defect in an Iranian patient with T<sup>-</sup> B<sup>+</sup> NK<sup>+</sup> severe combined immunodeficiency: A case report and review of the literature.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Dataset Information

Cernunnos defect in an Iranian patient with T- B+ NK+ severe combined immunodeficiency: A case report and review of the literature.

Background

Case

Conclusions

Publications

Cernunnos defect in an Iranian patient with T<sup>-</sup> B<sup>+</sup> NK<sup>+</sup> severe combined immunodeficiency: A case report and review of the literature.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Cernunnos defect in an Iranian patient with T^- B⁺ NK⁺ severe combined immunodeficiency: A case report and review of the literature.