Loss of NHEJ1 Protein Due to a Novel Splice Site Mutation in a Family Presenting with Combined Immunodeficiency, Microcephaly, and Growth Retardation and Literature Review

Abstract

Patients presenting with CID, microcephaly, and growth retardation should be screened for NHEJ1 gene mutations. We discuss our data in the context of one of our patients who is still alive at the age of 30 years, without transplantation, and who is the longest known survivor of this disease.

An immunocompetent patient with a nonsense mutation in NHEJ1 gene

“…Flow-cytometry in these patients demonstrates low T cell, very low or absent B cell and normal NK cell count. Serum immunoglobulin levels in these patients are generally low for IgG and IgA, and normal or high for IgM [3, 9, 18]. Our Patient had leukopenia with low level of CD19+ cells and very high level of CD56+ cells.…”

“…Given the vital role of repairing DSBs, mutation in any of the NHEJ genes, cause disruption in the immune system development, particularly B cell and T cell maturation, resulting in SCID [6, 8]. SCID presents early during the first few months of life and displays with severe bacterial and opportunistic infections, particularly respiratory infections [9].…”

Case Report: Refractory Cytopenia With a Switch From a Transient Monosomy 7 to a Disease-Ameliorating del(20q) in a NHEJ1-Deficient Long-term Survivor

“…The case presented herein is only the second NHEJ1-deficient patient who reached adulthood without transplantation (29). Despite the early onset of a refractory cytopenia with a transient monosomy 7 and the emergence and subsequent expansion of a del(20q) clone many years later, his disease neither progressed into a bona fide myeloid malignancy nor did it require any specific therapeutic care during the now overall 20 year-long observation period.…”

“…Nevertheless, NHEJ1 deficiencies still affect the respective repair and recombination processes quite profoundly, so that the ensuing clinical consequences usually resemble those of the otherwise more severe LIG4 defects (34). Less than 50 cases with bi-allelic NHEJ1 loss-of-function pathogenic variants have so far been documented in the literature (21,29,31,32,36,37,(42)(43)(44). The heterogeneous phenotypes and variable clinical courses of patients with different but also identical pathogenic variants severely impede any attempts to establish an even only approximate genotype-phenotype relationship, not least also because the effects of the diverse pathogenic variants are also cell type-specific and differentiation stage-dependent (29,42,45).…”

Extreme Phenotypes With Identical Mutations: Two Patients With Same Non-sense NHEJ1 Homozygous Mutation

“…One explanation for the different degree of lymphopenia found in Cernunnos-deficient patients (P1 and P2) might be the existence of alternative DNA repair proteins that only work to repair DSBs generated during lymphocyte development (3). It has been described that RAG complex and Cernunnos functionally overlap in the repair of DNA breaks during antigen receptor assembly ensuring stabilization of DNA ends after DNA cleavage by RAG (15).…”