Inheritance

Autosomal recessive

Prevalence

 <1 / 1 000 000

Source:Orphanet

Rapid or full curation?

ClinGen / GenCC / BabySeq / HGMD

ClinGen SCID-CID GCEP accessed 06.14.2023

Clinical Validity Scoring Notes and points

ClinGen SCID-CID expert panel, accessed 06.14.2023

NHEJ1 was first reported in relation to autosomal recessive Cernunnos-XLF deficiency in 2003 (Dai et al., PMID: 12604777). Cernunnos-XLF deficiency is a severe combined immunodeficiency (NHEJ1-SCID) characterized by profound T- and B-lymphocytopenia, microcephaly, growth retardation, and sensitivity to ionizing radiation. At least 9 unique variants (missense, nonsense, frameshift, small insertions, and gross deletions) have been reported in humans. Evidence supporting this gene-disease relationship includes case-level and experimental data.

Summary of Case Level Data: 12.70 points.

Variants in this gene have been reported in at least 13 probands in 6 publications (PMID: 16439204, PMID:12604777, PMID: 24511403, PMID: 20597108, PMID: 30666249, PMID: 28741180). More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached.

Summary of Experimental Evidence: 4.50 points.

This gene-disease association is supported by animal models, rescue in patient cells, and protein interaction studies (PMID: 17360556, PMID: 16439205, PMID: 16439204). Using yeast two-hybrid screening and coimmunoprecipitation techniques, Ahnesorg P, et al. (2006), demonstrated that XLF directly interacts with the XRCC4-Ligase IV complex in vitro and in vivo and that siRNA-mediated downregulation of XLF in human cell lines leads to radiosensitivity and impaired NHEJ. Zha S, et al. (2007) used gene-targeted mutation to delete exons 4 and 5 from both copies of the Cernunnos-XLF gene in mouse ES cells. Analyses of these ES cells showed they produce no readily detectable Cernunnos-XLF protein, are highly sensitive to ionizing radiation, and have intrinsic DNA DSB repair defects. Additionally, the Cernunnos-XLF mutations led to increased spontaneous genomic instability, including translocations.

In summary, there is definitive evidence to support the relationship between NHEJ1 and autosomal recessive Cernunnos-XLF deficiency. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time.

This classification was approved by the ClinGen SCID-CID GCEP on the meeting date May 20, 2021 (SOP Version 8).

Gene Clinical Validity Standard Operating Procedures (SOP) - SOP8

Clinical Validity Points Total

16.5

Source: ClinGen SCID-CID GCEP accessed 06.14.2023

Clinical Validity Classification

Definitive

Source: ClinGen SCID-CID GCEP accessed 06.14.2023

Molecular Mechanism

Loss of function

From ClinGen SCID-ID curation:

c.11dup (p.Glu5fs) NMD+, exon 2

c.532C>T (p.Arg178Ter), NMD+,  exon 5 

c.169C>T (p.Arg57Ter) - NMD+ exon 3

Source: ClinGen SCID-CID expert panel, accessed 06.14.2023

Penetrance

(list source/PMID)

Complete

Source:

Age of Onset

(list source/PMID)

Childhood (PMID: 16439204

Severity

Severe

Clinical Features

severe combined immunodeficiency (NHEJ1-SCID) characterized by profound T- and B-lymphocytopenia, microcephaly, facial gestalt, growth retardation, and sensitivity to ionizing radiation

Sources: from ClinGen curation

Gene SOPs & Notes

n/a

Curation Summary:

The NHEJ1 is associated with autosomal recessive Cernunnos-XLF deficiency, which is characterized by profound T- and B-lymphocytopenia, microcephaly, facial gestalt, growth retardation, and sensitivity to ionizing radiation. 

Case ID, Curator name, Date, Jira ticket link

Andrea Oza, 06/14/2023