severe combined immunodeficiency due to DCLRE1C deficiency

Summary

severe combined immunodeficiency due to DCLRE1C deficiency (MONDO:0011225) is a disease caused by DCLRE1C (GenCC Definitive), with 4 cohort genes and 1 clinical trial.

At a glance

• Prevalence: Unknown (Worldwide) [Orphanet-validated]
• Causal gene: DCLRE1C (GenCC Definitive)
• Cohort genes: 4
• ClinVar variants: 1,088
• Phenotypes (HPO): 28
• Clinical trials: 1

Clinical features

Signs & symptoms

Clinical features (HPO)

28 HPO clinical features (Orphanet curated; top 28 by frequency):

HPO ID	Term	Frequency
HP:0005403	Decreased total T cell count	Very frequent (80-99%)
HP:0010976	Decreased total B cell count	Very frequent (80-99%)
HP:0001890	Autoimmune hemolytic anemia	Frequent (30-79%)
HP:0002110	Bronchiectasis	Frequent (30-79%)
HP:0002718	Recurrent bacterial infections	Frequent (30-79%)
HP:0002720	Decreased circulating IgA level	Frequent (30-79%)
HP:0004315	Decreased circulating IgG level	Frequent (30-79%)
HP:0005390	Recurrent opportunistic infections	Frequent (30-79%)
HP:0031292	Cutaneous abscess	Frequent (30-79%)
HP:0200043	Verrucae	Frequent (30-79%)
HP:0200117	Recurrent upper and lower respiratory tract infections	Frequent (30-79%)
HP:6000070	Cutaneous granuloma	Frequent (30-79%)
HP:0000388	Otitis media	Occasional (5-29%)
HP:0000988	Skin rash	Occasional (5-29%)
HP:0001045	Vitiligo	Occasional (5-29%)
HP:0001508	Failure to thrive	Occasional (5-29%)
HP:0001973	Autoimmune thrombocytopenia	Occasional (5-29%)
HP:0002041	Intractable diarrhea	Occasional (5-29%)
HP:0002664	Neoplasm	Occasional (5-29%)
HP:0002960	Autoimmunity	Occasional (5-29%)
HP:0004429	Recurrent viral infections	Occasional (5-29%)
HP:0005681	Juvenile rheumatoid arthritis	Occasional (5-29%)
HP:0009098	Chronic oral candidiasis	Occasional (5-29%)
HP:0011107	Recurrent aphthous stomatitis	Occasional (5-29%)
HP:0011274	Recurrent mycobacterial infections	Occasional (5-29%)
HP:0031123	Recurrent gastroenteritis	Occasional (5-29%)
HP:0045080	Decreased proportion of CD3-positive T cells	Occasional (5-29%)
HP:0000872	Hashimoto thyroiditis	Very rare (<1-4%)

Identifiers

Disease identifiers

Field	Value
Canonical name	severe combined immunodeficiency due to DCLRE1C deficiency
Mondo ID	MONDO:0011225
OMIM	602450
Orphanet	275
DOID	DOID:0060006, DOID:0090012
SNOMED CT	715982006
UMLS	C1865370
MedGen	355454
GARD	0009987
Is cancer (heuristic)	no

Also known as: DCLRE1C severe combined immunodeficiency (disease) · SCID due to ARTEMIS deficiency · SCID due to artemis deficiency · SCID due to DCLRE1C deficiency · SCID, Athabascan type · SCID, Athabaskan type · SCID, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive, with sensitivity to ionising radiation · severe combined immunodeficiency (disease) caused by mutation in DCLRE1C · severe combined immunodeficiency due to ARTEMIS deficiency · severe combined immunodeficiency due to artemis deficiency · severe combined immunodeficiency due to DCLRE1C deficiency · severe combined immunodeficiency with sensitivity to ionising radiation

Data availability: 1,088 ClinVar variants · 94 ClinGen variant curations · 4 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 › severe combined immunodeficiency due to DCLRE1C 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, Omenn syndrome, DNA ligase IV deficiency, neutrophil immunodeficiency syndrome, combined immunodeficiency due to partial RAG1 deficiency, Cernunnos-XLF 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

600 retrieved; paginated sample, class counts are floors:

330 likely benign, 157 uncertain significance, 49 pathogenic, 24 likely pathogenic, 16 pathogenic/likely pathogenic, 12 benign, 6 conflicting classifications of pathogenicity, 5 benign/likely benign, 1 not provided

ClinVar	Variant (HGVS)	Gene	Classification	Review
1070011	NC_000010.10:g.(?14953179)(14961841_?)del	DCLRE1C	Pathogenic	criteria provided, single submitter
1070012	NC_000010.10:g.(?14946600)(14951339_?)del	DCLRE1C	Pathogenic	criteria provided, single submitter
1070013	NC_000010.10:g.(?14981789)(14996029_?)del	DCLRE1C	Pathogenic	criteria provided, single submitter
1070925	NM_001033855.3(DCLRE1C):c.1259_1266dup (p.Glu423fs)	DCLRE1C	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1071047	NM_001033855.3(DCLRE1C):c.1299_1306dup (p.Cys436Ter)	DCLRE1C	Pathogenic	criteria provided, multiple submitters, no conflicts
1071466	NM_001033855.3(DCLRE1C):c.671del (p.Gly224fs)	DCLRE1C	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1071845	NM_001033855.3(DCLRE1C):c.629del (p.Tyr210fs)	DCLRE1C	Pathogenic	criteria provided, single submitter
1074072	NM_001033855.3(DCLRE1C):c.1316_1317del (p.Glu439fs)	DCLRE1C	Pathogenic	criteria provided, single submitter
1075444	NM_001033855.3(DCLRE1C):c.511_512delinsTG (p.Pro171Ter)	DCLRE1C	Pathogenic	criteria provided, single submitter
1163043	NM_001033855.3(DCLRE1C):c.1670_1671del (p.Thr557fs)	DCLRE1C	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1322192	NM_001033855.3(DCLRE1C):c.571C>T (p.Arg191Ter)	DCLRE1C	Pathogenic	reviewed by expert panel
1324212	NM_001033855.3(DCLRE1C):c.1628_1632del (p.Ile543fs)	DCLRE1C	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1353520	NM_001033855.3(DCLRE1C):c.1585_1588dup (p.Thr530fs)	DCLRE1C	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1368634	NM_001033855.3(DCLRE1C):c.816T>A (p.Cys272Ter)	DCLRE1C	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1370296	NM_001033855.3(DCLRE1C):c.1313_1317del (p.Ala438fs)	DCLRE1C	Pathogenic	criteria provided, single submitter
1375314	NM_001033855.3(DCLRE1C):c.1467G>A (p.Trp489Ter)	DCLRE1C	Pathogenic	criteria provided, single submitter
1376240	NM_001033855.3(DCLRE1C):c.1665_1666del (p.Asp556fs)	DCLRE1C	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1378789	NM_001033855.3(DCLRE1C):c.1543G>T (p.Gly515Ter)	DCLRE1C	Pathogenic	criteria provided, single submitter
1386133	NM_001033855.3(DCLRE1C):c.1507_1508del (p.Ser503fs)	DCLRE1C	Pathogenic	criteria provided, single submitter
1388521	NM_001033855.3(DCLRE1C):c.310_313del	DCLRE1C	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1406894	NC_000010.10:g.(?14977452)(14978602_?)del	DCLRE1C	Pathogenic	criteria provided, single submitter
1440557	NM_001033855.3(DCLRE1C):c.1558_1559del (p.Lys520fs)	DCLRE1C	Pathogenic	criteria provided, single submitter
1451198	NM_001033855.3(DCLRE1C):c.1502_1503dup (p.Glu502fs)	DCLRE1C	Pathogenic	criteria provided, single submitter
1452422	NM_001033855.3(DCLRE1C):c.1221C>G (p.Tyr407Ter)	DCLRE1C	Pathogenic	criteria provided, single submitter
1452686	NC_000010.10:g.(?14978527)(14978602_?)del	DCLRE1C	Pathogenic	criteria provided, single submitter
1453056	NM_001033855.3(DCLRE1C):c.1545dup (p.Ser516fs)	DCLRE1C	Pathogenic	criteria provided, single submitter
1453673	NM_001033855.3(DCLRE1C):c.1442del (p.Lys481fs)	DCLRE1C	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1453759	NM_001033855.3(DCLRE1C):c.801G>A (p.Trp267Ter)	DCLRE1C	Pathogenic	criteria provided, single submitter
1455217	NC_000010.10:g.(?14995891)(14996441_?)del	DCLRE1C	Pathogenic	criteria provided, single submitter
1455220	NC_000010.10:g.(?14989514)(14996441_?)del	DCLRE1C	Pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 7 · Orphanet: 7 · 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
DCLRE1C	Definitive	Autosomal recessive	severe combined immunodeficiency due to DCLRE1C deficiency	7

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
DCLRE1C	Orphanet:275	Severe combined immunodeficiency due to DCLRE1C deficiency
DCLRE1C	Orphanet:39041	Omenn syndrome
ARID1B	Orphanet:1465	Coffin-Siris syndrome
ARID1B	Orphanet:251056	6q25.2q25.3 microdeletion syndrome
LIG4	Orphanet:235	Dubowitz syndrome
LIG4	Orphanet:39041	Omenn syndrome
LIG4	Orphanet:99812	LIG4 syndrome

Cohort genes → proteins

4 cohort genes, 4 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	4

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
DCLRE1C	HGNC:17642	ENSG00000152457	Q96SD1	Protein artemis	gencc,clinvar
SUV39H2	HGNC:17287	ENSG00000152455	Q9H5I1	Histone-lysine N-methyltransferase SUV39H2	clinvar
ARID1B	HGNC:18040	ENSG00000049618	Q8NFD5	AT-rich interactive domain-containing protein 1B	clinvar
LIG4	HGNC:6601	ENSG00000174405	P49917	DNA ligase 4	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
DCLRE1C	Protein artemis	Nuclease involved in DNA non-homologous end joining (NHEJ); required for double-strand break repair and V(D)J recombination.
SUV39H2	Histone-lysine N-methyltransferase SUV39H2	Histone methyltransferase that specifically mediates trimethylation of ‘Lys-9’ of histone H3 (H3K9me3) using monomethylated H3 ‘Lys-9’ (H3K9me1) as substrate.
ARID1B	AT-rich interactive domain-containing protein 1B	Involved in transcriptional activation and repression of select genes by chromatin remodeling (alteration of DNA-nucleosome topology).
LIG4	DNA ligase 4	DNA ligase involved in DNA non-homologous end joining (NHEJ); required for double-strand break (DSB) repair and V(D)J recombination.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 3 · Druggable fraction: 0.25

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
Enzyme (other)	1	3.0×	0.404
Other/Unknown	3	1.3×	0.404

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
DCLRE1C	Other/Unknown	no		DRMBL, RibonucZ/Hydroxyglut_hydro
SUV39H2	Other/Unknown	no		Chromo/chromo_shadow_dom, SET_dom, Post-SET_dom
ARID1B	Other/Unknown	no		ARID_dom, BAF250/Osa, BAF250_C
LIG4	Enzyme (other)	yes	6.5.1.1	DNA_ligase_ATP-dep, BRCT_dom, DNA_ligase_ATP-dep_N

Expression context

Cohort genes with no expression data: 0.

3 cohort genes 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)	4
unknown	0

Top tissues across cohort

Tissue	Cohort genes
secondary oocyte	2
buccal mucosa cell	1
epithelium of nasopharynx	1
tendon of biceps brachii	1
male germ cell	1
sperm	1
bone marrow cell	1
colonic epithelium	1
sural nerve	1
endothelial cell	1
oocyte	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
DCLRE1C	284	ubiquitous	marker	buccal mucosa cell, tendon of biceps brachii, epithelium of nasopharynx
SUV39H2	216	ubiquitous	marker	sperm, secondary oocyte, male germ cell
ARID1B	256	ubiquitous	marker	bone marrow cell, colonic epithelium, sural nerve
LIG4	275	ubiquitous	yes	endothelial cell, oocyte, secondary oocyte

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
SUV39H2	2,654
LIG4	2,352
ARID1B	2,131
DCLRE1C	1,756

Intra-cohort edges

A	B	Sources
DCLRE1C	LIG4	intact, string_interaction

Structural data

PDB: 4 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
LIG4	P49917	31
DCLRE1C	Q96SD1	14
SUV39H2	Q9H5I1	2
ARID1B	Q8NFD5	2

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 20. Enrichment computed across 4 evidence-associated genes (4 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 4 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)	2	84.0×	0.004	DCLRE1C, LIG4
Chromatin organization	2	40.8×	0.007	SUV39H2, ARID1B
Chromatin modifying enzymes	2	36.1×	0.007	SUV39H2, ARID1B
2-LTR circle formation	1	407.9×	0.012	LIG4
Formation of the canonical BAF (cBAF) complex	1	158.6×	0.025	ARID1B
Formation of neuronal progenitor and neuronal BAF (npBAF and nBAF)	1	114.2×	0.029	ARID1B
Regulation of endogenous retroelements	1	92.1×	0.031	ARID1B
RUNX1 interacts with co-factors whose precise effect on RUNX1 targets is not known	1	75.1×	0.033	ARID1B
Regulation of MITF-M-dependent genes involved in pigmentation	1	66.4×	0.033	ARID1B
MITF-M-dependent gene expression	1	45.3×	0.042	ARID1B
PKMTs methylate histone lysines	1	40.2×	0.042	SUV39H2
RMTs methylate histone arginines	1	36.6×	0.042	ARID1B
Transcriptional regulation by RUNX1	1	36.6×	0.042	ARID1B
Regulation of endogenous retroelements by Piwi-interacting RNAs (piRNAs)	1	29.4×	0.046	ARID1B
MITF-M-regulated melanocyte development	1	28.6×	0.046	ARID1B
Epigenetic regulation of gene expression	1	17.8×	0.069	ARID1B
RNA Polymerase II Transcription	1	5.6×	0.195	ARID1B
Gene expression (Transcription)	1	4.5×	0.229	ARID1B
Generic Transcription Pathway	1	3.8×	0.249	ARID1B
Developmental Biology	1	3.6×	0.249	ARID1B

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 4 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
V(D)J recombination	2	1053.2×	7e-05	DCLRE1C, LIG4
double-strand break repair via nonhomologous end joining	2	210.7×	1e-03	DCLRE1C, LIG4
establishment of integrated proviral latency	1	4213.0×	0.005	LIG4
positive regulation of chromosome organization	1	2106.5×	0.007	LIG4
pro-B cell differentiation	1	1053.2×	0.008	LIG4
T cell receptor V(D)J recombination	1	1053.2×	0.008	LIG4
DN2 thymocyte differentiation	1	1053.2×	0.008	LIG4
chromatin remodeling	2	36.5×	0.008	SUV39H2, ARID1B
nucleotide-excision repair, DNA gap filling	1	702.2×	0.009	LIG4
immunoglobulin V(D)J recombination	1	702.2×	0.009	LIG4
epigenetic programming in the zygotic pronuclei	1	468.1×	0.012	SUV39H2
double-strand break repair via classical nonhomologous end joining	1	421.3×	0.012	LIG4
single strand break repair	1	351.1×	0.013	LIG4
cellular response to lithium ion	1	280.9×	0.015	LIG4
response to X-ray	1	221.7×	0.018	LIG4
isotype switching	1	210.7×	0.018	LIG4
DNA biosynthetic process	1	200.6×	0.018	LIG4
regulation of G0 to G1 transition	1	168.5×	0.019	ARID1B
regulation of nucleotide-excision repair	1	150.5×	0.019	ARID1B
response to gamma radiation	1	145.3×	0.019	LIG4
positive regulation of neurogenesis	1	145.3×	0.019	LIG4
chromosome organization	1	145.3×	0.019	LIG4
regulation of mitotic metaphase/anaphase transition	1	123.9×	0.020	ARID1B
base-excision repair	1	117.0×	0.020	LIG4
positive regulation of T cell differentiation	1	113.9×	0.020	ARID1B
interstrand cross-link repair	1	108.0×	0.020	DCLRE1C
response to ionizing radiation	1	102.8×	0.020	DCLRE1C
T cell differentiation in thymus	1	102.8×	0.020	LIG4
cellular response to ionizing radiation	1	102.8×	0.020	LIG4
negative regulation of gene expression, epigenetic	1	100.3×	0.020	SUV39H2

Therapeutics

Drug target analysis

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

Druggability breadth: 2 of 4 evidence-associated genes (50%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
DCLRE1C	0	0
SUV39H2	0	0
ARID1B	0	0
LIG4	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
SUV39H2	62	Binding:61, Functional:1
LIG4	2	Binding:2

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
LIG4	6.5.1.1	DNA ligase (ATP)

Pharmacogenomics

Cohort genes with a PharmGKB record: 4; 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	1	LIG4
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	3	DCLRE1C, SUV39H2, ARID1B

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
DCLRE1C	0	—
SUV39H2	62	—
ARID1B	0	—
LIG4	2	—

Clinical trials & evidence

Clinical trials

Clinical trials: 1.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT03655223	Not specified	ENROLLING_BY_INVITATION	Early Check: Expanded Screening in Newborns