NHEJ1 – Cernunnos-XLF Deficiency

NHEJ1 encodes the XRCC4-like factor (XLF), a core component of the classical nonhomologous end-joining (C-NHEJ) pathway essential for double-strand break repair and V(D)J recombination. Biallelic loss-of-function variants in NHEJ1 result in Cernunnos-XLF deficiency (MONDO:0012650), a radiosensitive autosomal recessive severe combined immunodeficiency (SCID) characterized by microcephaly, growth retardation, and lymphoid defects (NHEJ1; Cernunnos-XLF deficiency).

Clinical reports describe a total of nine unrelated probands (three siblings from one family, five Egyptian patients from three families, and one Iranian infant) presenting with T- B+ NK+ SCID and features including microcephaly, bird-like facies, growth delay, lymphopenia, neutropenia, normocytic anemia, diarrhea, feeding difficulties, restlessness, and failure to thrive (9 probands) (PMID:28741180; PMID:37703920; PMID:35656589). The autosomal recessive inheritance is confirmed by homozygosity in consanguineous pedigrees and complete segregation in three families.

The variant spectrum includes canonical splice-site changes (c.178-1G>A; c.390+1G>T), nonsense alleles (c.532C>T (p.Arg178Ter)), and frameshift insertions (c.233dup (p.Asn78LysfsTer14)) all predicted to abolish XLF function. A recurrent founder nonsense variant, c.532C>T (p.Arg178Ter), has been observed across independent pedigrees.

Segregation analysis in three consanguineous families demonstrated co-segregation of homozygous variants with disease in multiple affected siblings, including two additional relatives beyond each index case ([PMID:28741180]; [PMID:37703920]).

Functional studies in murine models and human cells reveal that XLF operates redundantly with ATM-dependent factors (H2AX, 53BP1) to facilitate C-NHEJ and V(D)J recombination. Combined XLF/53BP1 or XLF/H2AX deficiency in mice leads to severe blocks in lymphocyte development and genomic instability ([PMID:22308489]). Human NHEJ1-deficient induced pluripotent stem cells exhibit impaired nonhomologous end-joining, heightened apoptosis of primitive hematopoietic progenitors, and failure to form teratomas, recapitulating the SCID phenotype ([PMID:23818183]).

Mechanistically, loss of XLF causes defective end-joining, reduced recent thymic emigrants, skewed memory T-cell profiles, and hypogammaglobulinemia, consistent with haploinsufficiency of a nonredundant NHEJ factor. Rescue experiments in XLF-null somatic cells confirm that wild-type XLF cDNA restores DNA repair and V(D)J recombination capacity.

Gene-level evidence meets a Strong ClinGen category (9 probands; multi-family segregation; concordant cellular and animal models). Genetic evidence is Strong (biallelic pathogenic variants in nine probands; autosomal recessive inheritance), and functional evidence is Moderate (robust mechanistic studies in mice and human iPSCs).

Key Take-home: NHEJ1 variant screening is indicated in patients with T- B+ NK+ SCID, microcephaly, growth failure, and sensitivity to ionizing radiation.

References

• Molecular genetics & genomic medicine • 2022 • Cernunnos defect in an Iranian patient with T- B+ NK+ severe combined immunodeficiency: A case report and review of the literature. PMID:35656589
• European journal of medical genetics • 2023 • Cernunnos deficiency: Further delineation in 5 Egyptian patients. PMID:37703920
• Journal of clinical immunology • 2017 • 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. PMID:28741180
• Proceedings of the National Academy of Sciences of the United States of America • 2012 • Functional redundancy between repair factor XLF and damage response mediator 53BP1 in V(D)J recombination and DNA repair. PMID:22308489
• Stem cells (Dayton, Ohio) • 2013 • Brief report: a human induced pluripotent stem cell model of cernunnos deficiency reveals an important role for XLF in the survival of the primitive hematopoietic progenitors. PMID:23818183

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