Pancytopenia-developmental delay syndrome

Summary

Pancytopenia-developmental delay syndrome (MONDO:0014317) is a disease caused by ERCC6L2 (GenCC Definitive), with 2 cohort genes.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: ERCC6L2 (GenCC Definitive)
• Cohort genes: 2
• ClinVar variants: 61

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		3	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Identifiers

Disease identifiers

Field	Value
Canonical name	pancytopenia-developmental delay syndrome
Mondo ID	MONDO:0014317
OMIM	615715
Orphanet	401764
UMLS	C3810350
MedGen	816680
GARD	0017655
Is cancer (heuristic)	no

Also known as: BMFS2 · bone marrow failure syndrome 2 · bone marrow failure syndrome type 2 · pancytopenia-developmental delay syndrome · Trilineage bone marrow failure-developmental delay syndrome

Data availability: 61 ClinVar variants · 5 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › immune system disorder › bone marrow disorder › bone marrow failure syndrome › pancytopenia-developmental delay syndrome

Related subtypes (7): autosomal dominant aplasia and myelodysplasia, bone marrow failure syndrome 3, bone marrow failure syndrome 4, bone marrow failure syndrome 6, AMED syndrome, digenic, bone marrow failure syndrome 5, Ziegler-Huang syndrome

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

61 retrieved; paginated sample, class counts are floors:

21 uncertain significance, 12 benign, 7 benign/likely benign, 6 pathogenic, 6 likely pathogenic, 4 conflicting classifications of pathogenicity, 4 likely benign, 1 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
125449	NM_020207.7(ERCC6L2):c.1930C>T (p.Arg644Ter)	ERCC6L2	Pathogenic	criteria provided, multiple submitters, no conflicts
125450	NM_020207.7(ERCC6L2):c.1203_1206del (p.Thr402fs)	ERCC6L2	Pathogenic	no assertion criteria provided
1390409	NM_020207.7(ERCC6L2):c.1987C>T (p.Arg663Ter)	ERCC6L2	Pathogenic	criteria provided, multiple submitters, no conflicts
421974	NM_020207.7(ERCC6L2):c.19C>T (p.Gln7Ter)	ERCC6L2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
4278127	NM_020207.7(ERCC6L2):c.3569C>A (p.Ser1190Ter)	ERCC6L2	Pathogenic	criteria provided, single submitter
619039	NM_020207.7(ERCC6L2):c.2156del (p.Gly719fs)	ERCC6L2	Pathogenic	criteria provided, multiple submitters, no conflicts
585929	NM_000162.5(GCK):c.952G>A (p.Gly318Arg)	GCK	Pathogenic	reviewed by expert panel
1324347	NM_020207.7(ERCC6L2):c.1682_1683del (p.Glu561fs)	ERCC6L2	Likely pathogenic	criteria provided, single submitter
2627470	NM_020207.7(ERCC6L2):c.1948-1G>A	ERCC6L2	Likely pathogenic	criteria provided, single submitter
3064086	NM_020207.7(ERCC6L2):c.3276dup (p.Cys1093fs)	ERCC6L2	Likely pathogenic	criteria provided, single submitter
3390963	NM_020207.7(ERCC6L2):c.2158_2159dup (p.Pro721fs)	ERCC6L2	Likely pathogenic	criteria provided, single submitter
4280022	NM_020207.7(ERCC6L2):c.2195_2198del (p.Asp732fs)	ERCC6L2	Likely pathogenic	criteria provided, single submitter
813930	NM_020207.7(ERCC6L2):c.3492+2T>G	ERCC6L2	Likely pathogenic	criteria provided, single submitter
1034369	NM_020207.7(ERCC6L2):c.163T>G (p.Leu55Val)	ERCC6L2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1054208	NM_020207.7(ERCC6L2):c.4090A>C (p.Thr1364Pro)	ERCC6L2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1557140	NM_020207.7(ERCC6L2):c.789-6_789-3del	ERCC6L2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
728402	NM_020207.7(ERCC6L2):c.379C>G (p.Gln127Glu)	ERCC6L2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1032068	NM_020207.7(ERCC6L2):c.1097G>A (p.Gly366Asp)	ERCC6L2	Uncertain significance	criteria provided, single submitter
1034368	NM_020207.7(ERCC6L2):c.1772A>G (p.Asn591Ser)	ERCC6L2	Uncertain significance	criteria provided, multiple submitters, no conflicts
1047574	NM_020207.7(ERCC6L2):c.1099T>C (p.Trp367Arg)	ERCC6L2	Uncertain significance	criteria provided, multiple submitters, no conflicts
1053992	NM_020207.7(ERCC6L2):c.2855G>A (p.Arg952Lys)	ERCC6L2	Uncertain significance	criteria provided, multiple submitters, no conflicts
1349569	NM_020207.7(ERCC6L2):c.2620A>G (p.Ile874Val)	ERCC6L2	Uncertain significance	criteria provided, multiple submitters, no conflicts
1479907	NM_020207.7(ERCC6L2):c.283C>G (p.Pro95Ala)	ERCC6L2	Uncertain significance	criteria provided, multiple submitters, no conflicts
1495370	NM_020207.7(ERCC6L2):c.3712T>C (p.Ser1238Pro)	ERCC6L2	Uncertain significance	criteria provided, multiple submitters, no conflicts
1504849	NM_020207.7(ERCC6L2):c.2512A>G (p.Lys838Glu)	ERCC6L2	Uncertain significance	criteria provided, multiple submitters, no conflicts
1518312	NM_020207.7(ERCC6L2):c.1555C>A (p.His519Asn)	ERCC6L2	Uncertain significance	criteria provided, multiple submitters, no conflicts
1522327	NM_020207.7(ERCC6L2):c.333T>A (p.Asn111Lys)	ERCC6L2	Uncertain significance	criteria provided, multiple submitters, no conflicts
1675071	NM_020207.7(ERCC6L2):c.2657C>T (p.Thr886Ile)	ERCC6L2	Uncertain significance	criteria provided, multiple submitters, no conflicts
1927352	NM_020207.7(ERCC6L2):c.3674G>C (p.Arg1225Thr)	ERCC6L2	Uncertain significance	criteria provided, multiple submitters, no conflicts
3001234	NM_020207.7(ERCC6L2):c.2245G>A (p.Glu749Lys)	ERCC6L2	Uncertain significance	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 5 · Orphanet: 5 · 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
ERCC6L2	Definitive	Autosomal recessive	pancytopenia-developmental delay syndrome	5

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
ERCC6L2	Orphanet:319465	Inherited acute myeloid leukemia
ERCC6L2	Orphanet:401764	Pancytopenia-developmental delay syndrome
GCK	Orphanet:552	MODY
GCK	Orphanet:79299	Congenital glucokinase-related hyperinsulinism
GCK	Orphanet:99885	Isolated permanent neonatal diabetes mellitus

Cohort genes → proteins

2 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
ERCC6L2	HGNC:26922	ENSG00000182150	Q5T890	DNA excision repair protein ERCC-6-like 2	gencc,clinvar
GCK	HGNC:4195	ENSG00000106633	P35557	Hexokinase-4	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
ERCC6L2	DNA excision repair protein ERCC-6-like 2	Promotes double-strand break (DSB) end-joining and facilitates programmed recombination by controlling how DNA ends are joined in a spatially oriented manner during repair.
GCK	Hexokinase-4	Catalyzes the phosphorylation of hexose, such as D-glucose, D-fructose and D-mannose, to hexose 6-phosphate (D-glucose 6-phosphate, D-fructose 6-phosphate and D-mannose 6-phosphate, respectively).

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 1 · Druggable fraction: 0.5

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
Kinase	1	13.9×	0.142
Other/Unknown	1	0.9×	0.805

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
ERCC6L2	Other/Unknown	no		SNF2_N, Helicase_C-like, DNA/RNA_helicase_DEAH_CS
GCK	Kinase	yes	2.7.1.1	Hexokinase, Hexokinase_BS, Hexokinase_N

Expression context

Cohort genes with no expression data: 0.

2 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)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
Brodmann (1909) area 23	1
endothelial cell	1
epithelial cell of pancreas	1
adenohypophysis	1
islet of Langerhans	1
pituitary gland	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
ERCC6L2	255	ubiquitous	marker	epithelial cell of pancreas, Brodmann (1909) area 23, endothelial cell
GCK	155	tissue_specific	marker	pituitary gland, adenohypophysis, islet of Langerhans

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
ERCC6L2	2,705
GCK	2,245

Structural data

PDB: 2 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
GCK	P35557	35
ERCC6L2	Q5T890	2

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 6. Enrichment computed across 2 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
Defective GCK causes maturity-onset diabetes of the young 2 (MODY2)	1	11420.0×	5e-04	GCK
Regulation of gene expression in beta cells	1	519.1×	0.003	GCK
FOXO-mediated transcription of oxidative stress, metabolic and neuronal genes	1	380.7×	0.003	GCK
Regulation of Glucokinase by Glucokinase Regulatory Protein	1	356.9×	0.003	GCK
Defective TPR may confer susceptibility towards thyroid papillary carcinoma (TPC)	1	356.9×	0.003	GCK
Glycolysis	1	285.5×	0.004	GCK

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
glucose catabolic process	1	1203.7×	0.005	GCK
regulation of potassium ion transport	1	936.2×	0.005	GCK
double-strand break repair via classical nonhomologous end joining	1	842.6×	0.005	ERCC6L2
NADP+ metabolic process	1	766.0×	0.005	GCK
cellular response to leptin stimulus	1	766.0×	0.005	GCK
glucose 6-phosphate metabolic process	1	648.1×	0.005	GCK
regulation of glycolytic process	1	601.9×	0.005	GCK
positive regulation of glycogen biosynthetic process	1	495.6×	0.005	GCK
negative regulation of gluconeogenesis	1	401.2×	0.005	GCK
calcium ion import	1	401.2×	0.005	GCK
canonical glycolysis	1	351.1×	0.006	GCK
intracellular glucose homeostasis	1	290.6×	0.006	GCK
interstrand cross-link repair	1	216.1×	0.007	ERCC6L2
cellular response to reactive oxygen species	1	205.5×	0.007	ERCC6L2
regulation of insulin secretion	1	195.9×	0.007	GCK
glycolytic process	1	191.5×	0.007	GCK
glucose metabolic process	1	127.7×	0.009	GCK
response to glucose	1	127.7×	0.009	GCK
positive regulation of insulin secretion	1	127.7×	0.009	GCK
cellular response to insulin stimulus	1	85.1×	0.013	GCK
glucose homeostasis	1	65.3×	0.016	GCK
DNA damage response	1	26.8×	0.037	ERCC6L2

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 2 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
GCK	5	2
ERCC6L2	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
PIRAGLIATIN	2	GCK
NERIGLIATIN	2	GCK
PF-04991532	2	GCK
AZD-1656	2	GCK
MK-0941 FREE BASE	2	GCK

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
GCK	228	Binding:226, ADMET:1, Functional:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
GCK	2.7.1.1	hexokinase

Cohort genes with high screening signal

≥100 ChEMBL assays — a studied-ness signal; see Therapeutics for approved-drug status.

Symbol	ChEMBL assays
GCK	228

Pharmacogenomics

Cohort genes with a PharmGKB record: 2; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

5 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.

Compound	Max phase	Cohort target (bioactivity)
PIRAGLIATIN	2	GCK
NERIGLIATIN	2	GCK
PF-04991532	2	GCK
AZD-1656	2	GCK
MK-0941 FREE BASE	2	GCK

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	1	GCK
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	ERCC6L2

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)
ERCC6L2	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.