Cernunnos-XLF deficiency

Summary

Cernunnos-XLF deficiency (MONDO:0012650) is a disease caused by NHEJ1 (GenCC Strong), with 1 cohort gene.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: NHEJ1 (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 205
• Phenotypes (HPO): 16

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		5	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

16 HPO clinical features (Orphanet curated; top 16 by frequency):

HPO ID	Term	Frequency
HP:0000252	Microcephaly	Very frequent (80-99%)
HP:0000320	Bird-like facies	Very frequent (80-99%)
HP:0000340	Sloping forehead	Very frequent (80-99%)
HP:0000414	Bulbous nose	Very frequent (80-99%)
HP:0000444	Convex nasal ridge	Very frequent (80-99%)
HP:0001510	Growth delay	Very frequent (80-99%)
HP:0001888	Lymphopenia	Very frequent (80-99%)
HP:0004313	Decreased circulating antibody level	Very frequent (80-99%)
HP:0005403	Decreased total T cell count	Very frequent (80-99%)
HP:0010976	Decreased total B cell count	Very frequent (80-99%)
HP:0001873	Thrombocytopenia	Frequent (30-79%)
HP:0001903	Anemia	Frequent (30-79%)
HP:0002718	Recurrent bacterial infections	Occasional (5-29%)
HP:0002721	Immunodeficiency	Occasional (5-29%)
HP:0002960	Autoimmunity	Occasional (5-29%)
HP:0004429	Recurrent viral infections	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	Cernunnos-XLF deficiency
Mondo ID	MONDO:0012650
MeSH	C566970
OMIM	611291
Orphanet	169079
DOID	DOID:0061090
SNOMED CT	720853005
UMLS	C1969799
MedGen	369590
GARD	0017045
Is cancer (heuristic)	no

Also known as: Cernunnos deficiency · Cernunnos XLFD · Cernunnos-XLF deficiency · combined immunodeficiency-microcephaly-growth retardation-sensitivity to ionising radiation syndrome · combined immunodeficiency-microcephaly-growth retardation-sensitivity to ionizing radiation syndrome · NHEJ1 deficiency · SCID, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive, and sensitivity to ionising radiation due to Nhej1 deficiency · SCID, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive, with microcephaly, Growth retardation, and sensitivity to ionising radiation · severe combined immunodeficiency with microcephaly, growth retardation, and sensitivity to ionising radiation · severe combined immunodeficiency with sensitivity to ionising radiation due to Nhej1 deficiency

Data availability: 205 ClinVar variants · 3 GenCC gene-disease records · 6 cell lines.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › immunodeficiency disease › combined immunodeficiency › severe combined immunodeficiency › T-B- severe combined immunodeficiency › Cernunnos-XLF deficiency

Related subtypes (15): severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-negative, due to adenosine deaminase deficiency, short-limb skeletal dysplasia with severe combined immunodeficiency, combined immunodeficiency with skin granulomas, reticular dysgenesis, severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive, severe combined immunodeficiency due to DCLRE1C deficiency, Omenn syndrome, DNA ligase IV deficiency, neutrophil immunodeficiency syndrome, combined immunodeficiency due to partial RAG1 deficiency, severe combined immunodeficiency due to LCK deficiency, severe combined immunodeficiency due to DNA-PKcs deficiency, immunodeficiency 73b with defective neutrophil chemotaxis and lymphopenia, immunodeficiency 73c with defective neutrophil chemotaxis and hypogammaglobulinemia, reticular dysgenesis-like severe combined immunodeficiency

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

205 retrieved; paginated sample, class counts are floors:

84 likely benign, 76 uncertain significance, 22 pathogenic, 10 likely pathogenic, 5 benign, 5 benign/likely benign, 3 conflicting classifications of pathogenicity

ClinVar	Variant (HGVS)	Gene	Classification	Review
1453461	NM_024782.3(NHEJ1):c.670_671del (p.Gln224fs)	NHEJ1	Pathogenic	criteria provided, single submitter
1458287	NM_024782.3(NHEJ1):c.569_570insTTTTTTTTTTTTTTTTTTTTNNNNNNNNNNCTGTCCTCGTGATACGCCCGCCTCGGCCTCCCAAAGTGCTGGGATTACAGGCGTGAGCCACCGCGCCCGGCCGAAAATTCCTTCTT (p.Leu190fs)	NHEJ1	Pathogenic	criteria provided, single submitter
1705616	NM_024782.3(NHEJ1):c.134G>A (p.Trp45Ter)	NHEJ1	Pathogenic	criteria provided, multiple submitters, no conflicts
2030418	NM_024782.3(NHEJ1):c.94C>T (p.Gln32Ter)	NHEJ1	Pathogenic	criteria provided, single submitter
2122980	NM_024782.3(NHEJ1):c.75_78dup (p.Val27fs)	NHEJ1	Pathogenic	criteria provided, single submitter
2734397	NM_024782.3(NHEJ1):c.526C>T (p.Arg176Ter)	NHEJ1	Pathogenic	criteria provided, multiple submitters, no conflicts
2968501	NM_024782.3(NHEJ1):c.546del (p.Glu182fs)	NHEJ1	Pathogenic	criteria provided, single submitter
3021248	NM_024782.3(NHEJ1):c.75del (p.Lys26fs)	NHEJ1	Pathogenic	criteria provided, single submitter
3247343	NC_000002.11:g.(?220011382)(220011480_?)del	NHEJ1	Pathogenic	criteria provided, single submitter
3336660	NM_024782.3(NHEJ1):c.169C>T (p.Arg57Ter)	NHEJ1	Pathogenic	no assertion criteria provided
3336661	NM_024782.3(NHEJ1):c.236T>C (p.Leu79Pro)	NHEJ1	Pathogenic	no assertion criteria provided
3336662	NM_024782.3(NHEJ1):c.233dup (p.Asn78fs)	NHEJ1	Pathogenic	no assertion criteria provided
3720410	NM_024782.3(NHEJ1):c.501C>A (p.Tyr167Ter)	NHEJ1	Pathogenic	criteria provided, single submitter
419273	NM_024782.3(NHEJ1):c.530-2A>T	NHEJ1	Pathogenic	criteria provided, multiple submitters, no conflicts
4735399	NM_024782.3(NHEJ1):c.31C>T (p.Gln11Ter)	NHEJ1	Pathogenic	criteria provided, single submitter
4766092	NM_024782.3(NHEJ1):c.489_490del (p.Glu163fs)	NHEJ1	Pathogenic	criteria provided, single submitter
536739	NM_024782.3(NHEJ1):c.643C>T (p.Gln215Ter)	NHEJ1	Pathogenic	criteria provided, single submitter
845632	NM_024782.3(NHEJ1):c.369C>A (p.Cys123Ter)	NHEJ1	Pathogenic	criteria provided, single submitter
982	NM_024782.3(NHEJ1):c.367T>C (p.Cys123Arg)	NHEJ1	Pathogenic	no assertion criteria provided
983	NM_024782.3(NHEJ1):c.532C>T (p.Arg178Ter)	NHEJ1	Pathogenic	criteria provided, multiple submitters, no conflicts
984	NM_024782.3(NHEJ1):c.177+1_177+3delinsTT	NHEJ1	Pathogenic	no assertion criteria provided
985	NM_024782.3(NHEJ1):c.11dup (p.Glu5fs)	NHEJ1	Pathogenic	criteria provided, multiple submitters, no conflicts
1466691	NM_024782.3(NHEJ1):c.530-1G>A	NHEJ1	Likely pathogenic	criteria provided, single submitter
1484040	NM_024782.3(NHEJ1):c.529+1G>A	NHEJ1	Likely pathogenic	criteria provided, single submitter
2030417	NM_024782.3(NHEJ1):c.390+1G>A	NHEJ1	Likely pathogenic	criteria provided, single submitter
2053597	NM_024782.3(NHEJ1):c.177+1G>A	NHEJ1	Likely pathogenic	criteria provided, single submitter
3585675	NM_024782.3(NHEJ1):c.348dup (p.Phe117fs)	NHEJ1	Likely pathogenic	criteria provided, single submitter
3585676	NM_024782.3(NHEJ1):c.16C>T (p.Gln6Ter)	NHEJ1	Likely pathogenic	criteria provided, single submitter
3585677	NM_024782.3(NHEJ1):c.1A>G (p.Met1Val)	NHEJ1	Likely pathogenic	criteria provided, single submitter
4277774	NM_024782.3(NHEJ1):c.76A>G (p.Lys26Glu)	NHEJ1	Likely pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 3 · Orphanet: 1 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

GenCC gene–disease validity (cohort genes)

the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.

Gene	Classification	Inheritance	Disease	Records
NHEJ1	Strong	Autosomal recessive	Cernunnos-XLF deficiency	3

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
NHEJ1	Orphanet:169079	Cernunnos-XLF deficiency

Cohort genes → proteins

1 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	1

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
NHEJ1	HGNC:25737	ENSG00000187736	Q9H9Q4	Non-homologous end-joining factor 1	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
NHEJ1	Non-homologous end-joining factor 1	DNA repair protein involved in DNA non-homologous end joining (NHEJ); it is required for double-strand break (DSB) repair and V(D)J recombination and is also involved in telomere maintenance.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 1 · Druggable fraction: 0.0

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Other/Unknown	1	1.8×	0.558

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
NHEJ1	Other/Unknown	no		XLF-like_N, XRCC4-like_N_sf, NHEJ_factor

Expression context

Cohort genes with no expression data: 0.

1 cohort gene are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	1
unknown	0

Top tissues across cohort

Tissue	Cohort genes
mucosa of transverse colon	1
primordial germ cell in gonad	1
rectum	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
NHEJ1	189	ubiquitous	marker	rectum, primordial germ cell in gonad, mucosa of transverse colon

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
NHEJ1	1,312

Structural data

PDB: 1 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
NHEJ1	Q9H9Q4	26

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 1. Enrichment computed across 1 evidence-associated genes (1 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Nonhomologous End-Joining (NHEJ)	1	167.9×	0.006	NHEJ1

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
positive regulation of ligase activity	1	5617.3×	0.001	NHEJ1
immunoglobulin V(D)J recombination	1	2808.7×	0.001	NHEJ1
double-strand break repair via nonhomologous end joining	1	421.3×	0.004	NHEJ1
response to ionizing radiation	1	411.0×	0.004	NHEJ1
T cell differentiation	1	383.0×	0.004	NHEJ1
telomere maintenance	1	267.5×	0.005	NHEJ1
B cell differentiation	1	218.9×	0.005	NHEJ1
central nervous system development	1	115.4×	0.009	NHEJ1

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 1

Druggability breadth: 0 of 1 evidence-associated genes (0%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
NHEJ1	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Pharmacogenomics

Cohort genes with a PharmGKB record: 1; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

0 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	NHEJ1

Undrugged target profiles

1 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
NHEJ1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.