DCLRE1C(ARTEMIS) mutations causing phenotypes ranging from atypical severe combined immunodeficiency to mere antibody deficiency

Abstract

Null mutations in genes involved in V(D)J recombination cause a block in B- and T-cell development, clinically presenting as severe combined immunodeficiency (SCID). Hypomorphic mutations in the non-homologous end-joining gene DCLRE1C (encoding ARTEMIS) have been described to cause atypical SCID, Omenn syndrome, Hyper IgM syndrome and inflammatory bowel disease-all with severely impaired T-cell immunity. By whole-exome sequencing, we investigated the molecular defect in a consanguineous family with three children clinically diagnosed with antibody deficiency. We identified perfectly segregating homozygous variants in DCLRE1C in three index patients with recurrent respiratory tract infections, very low B-cell numbers and serum IgA levels. In patients, decreased colony survival after irradiation, impaired proliferative response and reduced counts of naïve T cells were observed in addition to a restricted T-cell receptor repertoire, increased palindromic nucleotides in the complementarity determining regions 3 and long stretches of microhomology at switch junctions. Defective V(D)J recombination was complemented by wild-type ARTEMIS protein in vitro. Subsequently, homozygous or compound heterozygous DCLRE1C mutations were identified in nine patients from the same geographic region. We demonstrate that DCLRE1C mutations can cause a phenotype presenting as only antibody deficiency. This novel association broadens the clinical spectrum associated with ARTEMIS mutations. Clinicians should consider the possibility that an immunodeficiency with a clinically mild initial presentation could be a combined immunodeficiency, so as to provide appropriate care for affected patients.

Congenital neutropenia with variable clinical presentation in novel mutation of the SRP54 gene

“…Our findings further highlight the phenomenon of variable expressivity in primary immunodeficiencies in general and in congenital neutropenia specifically. Previous studies, in genes associated with SCID, including RAG1/2 , ADA , and DCLRE1C 20‐25 and genes associated with CN, including ELANE 26,27 and SBDS , 28 revealed a variable clinical phenotypes in individuals with the same genetic mutation, even in the same family. Moreover, subanalysis of the cohort published by http://Bellanné‐Chantelot et al 5 reveals intrafamilial and interfamilial immunological and clinical variability within patients harboring the same mutation.…”

What Are the Characteristics of the Upper Airway in Patients With Craniofacial Microsomia?

“…Interestingly, we recently identified a similar pattern of sequential production of MBC expressing distinct immunoglobulin subclasses during a lifetime. 24 These findings, together with recent observations using genome-wide sequencing approaches, suggest that consecutive switching along the IGHC locus might deteriorate in patients with PADs, possibly because of combined hypomorphic/deleterious variants, [52][53][54] haploinsufficient genes, [55][56][57][58] and epigenetic modifications 59 involving B-cell response pathways rather than a single genetic defect. Progressive deterioration of sequential classswitching along the IGHC locus, along with reduced MBCs and lack of PCs, leads to a progressively more restricted repertoire and decreased functional capacity of MBCs expressing downstream IgG subclasses.…”

Ligase-4 Deficiency Causes Distinctive Immune Abnormalities in Asymptomatic Individuals

“…Moreover, P2 suffered from panhypogammaglobulinemia, whereas IgG serum levels were modestly reduced in P3 and normal in P1. Yet, severe B cell lymphopenia was observed in all three siblings, and is a typical finding also in patients with other hypomorphic NHEJ defects [40]. DNA rearrangements in the B cell lineage are not restricted to V(D)J recombination, but also include class switch recombination (CSR).…”