NOVEL NON-CODING VARIANT IN DCLRE1C SEGREGATES WITH DISTINCT SEVERE COMBINED IMMUNODEFICIENCY PHENOTYPES AND HODGKIN LYMPHOMA IN CONSANGUINEOUS SIBLINGS

Abstract

Severe combined immunodeficiency (SCID) results from a defect in the differentiation of hematopoietic stem cells into mature T lymphocytes, affecting both T and B cells and potentially involving NK cells. Aim: To report three siblings with a new likely pathogenic DCLRE1C biallelic variant with an autosomal recessive pattern of inheritance. We describe the clinical manifestations, diagnostic journey, and the importance of genetic diagnosis. Results: The ascertained family comprises healthy third-degree cousin parents and three children who exhibited diverse symptoms: the 11-year-old female proband presented with disseminated varicella, hemophagocytic lymphohistiocytosis, and Epstein–Barr virus (EBV)-positive Hodgkin lymphoma (HL); the 24 years-old brother had severe peripheral warts and blindness due to ocular toxoplasmosis; the 8 years-old sister had facial perforating lichen planus and mild extremity warts. All siblings had profound B and T lymphopenia and variable hypogammaglobulinemia. KREC and TREC levels were null for the three siblings, while they were within normal ranges among parents. Augmented whole exome sequencing ruled out GATA2 haplodeficiency and revealed a homozygous likely pathogenic variant in the DCLRE1C gene (NM_001033855.3.246+1G>A), which affected the metallo-beta-lactamase domain, leading to exon skipping and a truncated ARTEMIS protein. Both parents presented the same heterozygous variant. Our data further suggested a lack of the canonical isoform of the ARTEMIS protein. Analysis of the TCR Vβ repertoire in the mother and siblings revealed at least one allele with a discrepant frequency fold change (FC) compared to healthy controls (log2 FC > —2—). The mother, 8-year-old sister, and brother each presented one discrepant allele. The 11-year-old sister, however, presented four discrepant alleles. In silico molecular modeling further pointed to the presence of other ARTEMIS isoforms with residual function, which could account for the leaky-SCID rather than a typical SCID phenotype in these siblings. Discussion: SCID is characterized by life-threatening infections, failure to thrive, and early childhood onset. Variants in DCLRE1C can lead to a spectrum of phenotypes from SCID to mild antibody deficiency. The most adopted treatment for SCID is hematopoietic stem cell transplantation (HSCT). However, there is no clear indication of it in the leaky phenotype scenario. The histological type and age of HL of the proband are consistent with the literature on SCID patients, where EBV-related lymphomas are a common neoplasm, with the main age of onset around 10 years old. This family illustrates the genetic heterogeneity and variable clinical presentation of SCID, emphasizing the role of genetic testing in diagnosis and management. The variant identified is novel and contributes to the understanding of DCLRE1C -related immunodeficiency. The leaky phenotype precludes early clinical diagnosis, which could have been achieved with newborn genetic screening. Conclusion: This work reinforces the recognition of HL as part of the constellation of leaky-SCID possible phenotypes and highlights the importance of comprehensive genetic testing for diagnosing inborn errors of immunity. We suggest that this new DLRE1C variant could be reclassified as pathogenic upon functional confirmation.