DCLRE1C – Omenn Syndrome

Omenn syndrome (OS) is an autosomal recessive form of severe combined immunodeficiency characterized by erythrodermia, hepatosplenomegaly, lymphadenopathy, alopecia and a restricted T-cell receptor repertoire. It arises from hypomorphic or null mutations in ARTEMIS, the nuclease encoded by DCLRE1C, which is essential for hairpin opening during V(D)J recombination and DNA double-strand break repair (PMID:16763459).

Initial genetic evidence came from a compound heterozygous patient harboring c.2T>C (p.Met1Thr) and c.103C>G (p.His35Asp) mutations in DCLRE1C, presenting with OS features and radiosensitivity in fibroblasts (PMID:15731174). A consanguineous family study identified a homozygous c.1636C>T (p.Gln546Ter) variant in three siblings with antibody deficiency and Omenn-like immunophenotype, alongside nine additional patients with DCLRE1C mutations from the same region (12 probands total) (PMID:26476407). Moreover, a Saudi cohort screened seven OS patients and found gross deletions of exons 1–3 or 1–4 in DCLRE1C in 7 unrelated cases (PMID:19912631). Collectively, ~20 probands across multiple families support a definitive gene–disease relationship.

Segregation analysis demonstrated concordant autosomal recessive inheritance with three affected siblings in one pedigree, compound heterozygotes in another, and unrelated familial cases showing biallelic transmission of loss-of-function alleles (PMID:15731174; PMID:26476407).

The variant spectrum includes start-loss and missense mutations (c.2T>C (p.Met1Thr), c.103C>G (p.His35Asp)), nonsense alleles (c.1636C>T (p.Gln546Ter)), splice-site defects (c.464+1G>A), frameshifts and recurrent gross deletions of exons 1–3/1–4 via homologous recombination (59% of alleles) (PMID:19953608). Hypomorphic alleles yield residual V(D)J recombination and milder ‘leaky’ SCID or antibody-deficiency phenotypes.

Functional assays corroborate pathogenicity: primary fibroblasts from cases show impaired hairpin opening and enhanced radiosensitivity, V(D)J recombination assays reveal reduced coding-joint formation and increased microhomology at junctions (PMID:18034425), and a mouse Artemis‐P70 model recapitulates B- and T-cell lymphopenia and genomic instability (PMID:19349461). Splice-site mutations were corrected in vitro by antisense oligonucleotides restoring wild-type transcript and NHEJ activity (PMID:21390052).

Although most OS patients harbor DCLRE1C or RAG1/2 defects, a subset lacks identifiable mutations, indicating genetic heterogeneity and the need for expanded gene panels (PMID:15964782).

Integration of genetic segregation, a broad allelic series, and concordant functional data establishes a definitive association between DCLRE1C mutations and Omenn syndrome. Clinical testing for ARTEMIS variants is critical for early diagnosis, family counseling, and timely hematopoietic stem cell transplantation.

Key Take-home: Biallelic DCLRE1C mutations cause Omenn syndrome via defective V(D)J recombination and DNA repair; ARTEMIS sequencing should be integral to SCID diagnostic algorithms.

References

• Blood • 2005 • Omenn syndrome due to ARTEMIS mutations. PMID:15731174
• Human molecular genetics • 2015 • DCLRE1C (ARTEMIS) mutations causing phenotypes ranging from atypical severe combined immunodeficiency to mere antibody deficiency. PMID:26476407
• Clinical immunology (Orlando, Fla.) • 2005 • Omenn's syndrome occurring in patients without mutations in recombination activating genes. PMID:15964782
• BMC medical genetics • 2009 • Molecular analysis of T-B-NK+ severe combined immunodeficiency and Omenn syndrome cases in Saudi Arabia. PMID:19912631
• Human mutation • 2010 • The most frequent DCLRE1C (ARTEMIS) mutations are based on homologous recombination events. PMID:19953608
• European journal of immunology • 2007 • Defective Artemis nuclease is characterized by coding joints with microhomology in long palindromic-nucleotide stretches. PMID:18034425
• The Journal of experimental medicine • 2009 • Impact of a hypomorphic Artemis disease allele on lymphocyte development, DNA end processing, and genome stability. PMID:19349461
• Genes and immunity • 2011 • Artemis splice defects cause atypical SCID and can be restored in vitro by an antisense oligonucleotide. PMID:21390052
• Current opinion in rheumatology • 2006 • Omenn syndrome: a lack of tolerance on the background of deficient lymphocyte development and maturation. PMID:16763459

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