Nijmegen breakage syndrome

Summary

Nijmegen breakage syndrome (MONDO:0009623) is a disease caused by NBN (GenCC Definitive), with 3 cohort genes and 3 clinical trials. Top therapeutic interventions include treosulfan.

At a glance

• Prevalence: Unknown (Worldwide) [Orphanet-validated]
• Causal gene: NBN (GenCC Definitive)
• Cohort genes: 3
• ClinVar variants: 2,995
• Phenotypes (HPO): 49
• Clinical trials: 3

Clinical features

Epidemiology

Prevalence records

7 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Point prevalence	<1 / 1 000 000	0.7	Russian Federation	Validated
Point prevalence	1-9 / 1 000 000	3.1	Poland	Validated
Point prevalence	1-9 / 1 000 000	3.1	Czech Republic	Validated
Point prevalence	1-9 / 1 000 000	2.6	Slovakia	Validated
Point prevalence	1-9 / 1 000 000	2.3	Belarus	Validated
Point prevalence	1-9 / 1 000 000	1.3	Ukraine	Validated
Prevalence at birth	1-9 / 100 000	1	Worldwide	Not yet validated

Signs & symptoms

Clinical features (HPO)

49 HPO clinical features (Orphanet curated; top 49 by frequency):

HPO ID	Term	Frequency
HP:0000252	Microcephaly	Very frequent (80-99%)
HP:0000271	Abnormality of the face	Very frequent (80-99%)
HP:0000278	Retrognathia	Very frequent (80-99%)
HP:0000294	Low anterior hairline	Very frequent (80-99%)
HP:0000340	Sloping forehead	Very frequent (80-99%)
HP:0000364	Hearing abnormality	Very frequent (80-99%)
HP:0000400	Macrotia	Very frequent (80-99%)
HP:0000426	Prominent nasal bridge	Very frequent (80-99%)
HP:0000444	Convex nasal ridge	Very frequent (80-99%)
HP:0000448	Prominent nose	Very frequent (80-99%)
HP:0000470	Short neck	Very frequent (80-99%)
HP:0000582	Upslanted palpebral fissure	Very frequent (80-99%)
HP:0001268	Mental deterioration	Very frequent (80-99%)
HP:0001595	Abnormality of the hair	Very frequent (80-99%)
HP:0001873	Thrombocytopenia	Very frequent (80-99%)
HP:0001878	Hemolytic anemia	Very frequent (80-99%)
HP:0001890	Autoimmune hemolytic anemia	Very frequent (80-99%)
HP:0002002	Deep philtrum	Very frequent (80-99%)
HP:0002023	Anal atresia	Very frequent (80-99%)
HP:0002025	Anal stenosis	Very frequent (80-99%)
HP:0002028	Chronic diarrhea	Very frequent (80-99%)
HP:0002205	Recurrent respiratory infections	Very frequent (80-99%)
HP:0003220	Abnormality of chromosome stability	Very frequent (80-99%)
HP:0004322	Short stature	Very frequent (80-99%)
HP:0004326	Cachexia	Very frequent (80-99%)
HP:0005280	Depressed nasal bridge	Very frequent (80-99%)
HP:0005425	Recurrent sinopulmonary infections	Very frequent (80-99%)
HP:0006532	Recurrent pneumonia	Very frequent (80-99%)
HP:0007018	Attention deficit hyperactivity disorder	Very frequent (80-99%)
HP:0011362	Abnormal hair quantity	Very frequent (80-99%)
HP:0012732	Anorectal anomaly	Very frequent (80-99%)
HP:0002664	Neoplasm	Frequent (30-79%)
HP:0100515	Pollakisuria	Frequent (30-79%)
HP:0000175	Cleft palate	Occasional (5-29%)
HP:0000492	Abnormal eyelid morphology	Occasional (5-29%)
HP:0000992	Cutaneous photosensitivity	Occasional (5-29%)
HP:0001324	Muscle weakness	Occasional (5-29%)
HP:0001480	Freckling	Occasional (5-29%)
HP:0002269	Abnormality of neuronal migration	Occasional (5-29%)
HP:0002488	Acute leukemia	Occasional (5-29%)
HP:0002665	Lymphoma	Occasional (5-29%)
HP:0002859	Rhabdomyosarcoma	Occasional (5-29%)
HP:0002878	Respiratory failure	Occasional (5-29%)
HP:0003011	Abnormality of the musculature	Occasional (5-29%)
HP:0003202	Skeletal muscle atrophy	Occasional (5-29%)
HP:0009733	Glioma	Occasional (5-29%)
HP:0012190	T-cell lymphoma	Occasional (5-29%)
HP:0012191	B-cell lymphoma	Occasional (5-29%)
HP:0100335	Non-midline cleft of the upper lip	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	Nijmegen breakage syndrome
Mondo ID	MONDO:0009623
MeSH	D049932
OMIM	251260
Orphanet	647
DOID	DOID:7400
ICD-11	1925662580
NCIT	C4692
SNOMED CT	234638009
UMLS	C0398791
MedGen	140771
GARD	0003904
MedDRA	10067857
Is cancer (heuristic)	no

Also known as: AT V1 · ataxia-telangiectasia, variant 1 · Berlin breakage syndrome · immunodeficiency-microcephaly-chromosomal instability syndrome · microcephaly immunodeficiency lymphoreticuloma · microcephaly with normal intelligence immunodeficiency and lymphoreticular malignancies · NBS · NBs · Nijmegen breakage syndrome · Nonsyndromal microcephaly autosomal recessive with normal intelligence · Seemanova syndrome · Seemanova syndrome type 2

Data availability: 2,995 ClinVar variants · 5 GenCC gene-disease records · 26 cell lines.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › autosomal genetic disease › autosomal recessive disease › Nijmegen breakage syndrome

Related subtypes (218): immunodeficiency-centromeric instability-facial anomalies syndrome, hypercalcemia, infantile, Ochoa syndrome, autosomal recessive Ehlers-Danlos syndrome, vascular type, hydrolethalus syndrome, 3-M syndrome, isolated hyperchlorhidrosis, dacryocystitis-osteopoikilosis syndrome, Hutchinson-Gilford progeria syndrome, achalasia microcephaly syndrome, acrorenal syndrome, autosomal recessive, beta-ketothiolase deficiency, autosomal recessive Alport syndrome, Alstrom syndrome, microphthalmia with limb anomalies, camptodactyly-arthropathy-coxa vara-pericarditis syndrome, Behr syndrome, bifid nose, autosomal recessive, Bloom syndrome, Bowen-Conradi syndrome, camptodactyly with fibrous tissue hyperplasia and skeletal dysplasia, heart defects-limb shortening syndrome, autosomal recessive palmoplantar keratoderma and congenital alopecia, COFS syndrome, craniometaphyseal dysplasia, autosomal recessive, Fraser syndrome, cystic fibrosis, polycystic lipomembranous osteodysplasia with sclerosing leukoencephaly, persistent hyperplastic primary vitreous, autosomal recessive, Donnai-Barrow syndrome, Schöpf-Schulz-Passarge syndrome, cleft lip/palate-ectodermal dysplasia syndrome, Ellis-van Creveld syndrome, Wolcott-Rallison syndrome, autosomal recessive faciodigitogenital syndrome, acromesomelic dysplasia 2B, brittle cornea syndrome, triple-A syndrome, autosomal recessive humeroradial synostosis, multinucleated neurons-anhydramnios-renal dysplasia-cerebellar hypoplasia-hydranencephaly syndrome, hydrocephalus, nonsyndromic, autosomal recessive 1, autosomal recessive hydrocephalus due to congenital stenosis of aqueduct of Sylvius, hypertelorism, microtia, facial clefting syndrome, hypoparathyroidism-retardation-dysmorphism syndrome, Vici syndrome, Johanson-Blizzard syndrome, autosomal recessive Kenny-Caffey syndrome, Papillon-Lefevre disease, Haim-Munk syndrome, Laurence-Moon syndrome, Donohue syndrome, lipase deficiency, combined, autosomal recessive familial Mediterranean fever, thiamine-responsive megaloblastic anemia syndrome, cartilage-hair hypoplasia, pseudo-TORCH syndrome, Galloway-Mowat syndrome, mulibrey nanism, myotonia congenita, autosomal recessive, Schwartz-Jampel syndrome, proteosome-associated autoinflammatory syndrome, Netherton syndrome, Niemann-Pick disease type A, oculodentodigital dysplasia, autosomal recessive, odonto-onycho-dermal dysplasia, autosomal recessive omodysplasia, osteoporosis-pseudoglioma syndrome, Shwachman-Diamond syndrome, phenylketonuria, Bjornstad syndrome, Laron syndrome, autosomal recessive polycystic kidney disease, autosomal recessive inherited pseudoxanthoma elasticum, autosomal recessive multiple pterygium syndrome, rapadilino syndrome, short-rib thoracic dysplasia 9 with or without polydactyly, autosomal recessive Robinow syndrome, Sjogren-Larsson syndrome, scapuloperoneal spinal muscular atrophy, autosomal recessive, spondyloepiphyseal dysplasia tarda, autosomal recessive, inherited threoninemia, Pendred syndrome, autosomal recessive spondylocostal dysostosis, Werner syndrome, ABCD syndrome, Naxos disease, autosomal recessive amelia, human HOXA1 syndromes, sickle cell disease, autosomal recessive proximal renal tubular acidosis, hyper-IgM syndrome type 2, temtamy preaxial brachydactyly syndrome, TH-deficient dopa-responsive dystonia, craniosynostosis syndrome, autosomal recessive, Niemann-Pick disease type B, skin fragility-woolly hair-palmoplantar keratoderma syndrome, CoQ-responsive OXPHOS deficiency, familial adenomatous polyposis 2, Pierson syndrome, palmoplantar keratoderma-XX sex reversal-predisposition to squamous cell carcinoma syndrome, cardiomyopathy-hypotonia-lactic acidosis syndrome, PHARC syndrome, Kahrizi syndrome, cutis laxa with severe pulmonary, gastrointestinal and urinary anomalies, congenital prothrombin deficiency, immunodeficiency 31B, dyskeratosis congenita, autosomal recessive 2, dyskeratosis congenita, autosomal recessive 3, Nestor-Guillermo progeria syndrome, leukoencephalopathy with calcifications and cysts, mitochondrial pyruvate carrier deficiency, branched-chain keto acid dehydrogenase kinase deficiency, dyskeratosis congenita, autosomal recessive 5, hypohidrosis-enamel hypoplasia-palmoplantar keratoderma-intellectual disability syndrome, alacrima, achalasia, and intellectual disability syndrome, hyperlipoproteinemia, type 1D, microcephaly and chorioretinopathy 2, congenital stationary night blindness 1G, combined oxidative phosphorylation deficiency 29, hypermanganesemia with dystonia 2, growth retardation, intellectual developmental disorder, hypotonia, and hepatopathy, gnb5-related intellectual disability-cardiac arrhythmia syndrome, autosomal recessive spastic paraplegia type 78, autosomal recessive limb-girdle muscular dystrophy, Bardet-Biedl syndrome, autosomal recessive cerebellar ataxia, neuronopathy, distal hereditary motor, autosomal recessive, UV-sensitive syndrome, Ehlers-Danlos syndrome, kyphoscoliotic type 1, Cockayne syndrome, hyperphenylalaninemia due to tetrahydrobiopterin deficiency, leukoencephalopathy-palmoplantar keratoderma syndrome, autosomal recessive hypohidrotic ectodermal dysplasia, Warburg micro syndrome, autosomal recessive primary microcephaly, autosomal recessive progressive external ophthalmoplegia, Meier-Gorlin syndrome, autosomal recessive sideroblastic anemia, autosomal recessive intermediate Charcot-Marie-Tooth disease, Perrault syndrome, autosomal recessive hypophosphatemic rickets, de Barsy syndrome, leukocyte adhesion deficiency, Senior-Loken syndrome, autosomal recessive spastic ataxia, childhood-onset autosomal recessive myopathy with external ophthalmoplegia, autosomal recessive cerebral atrophy, GM3 synthase deficiency, autosomal recessive distal renal tubular acidosis, pigmentation defects-palmoplantar keratoderma-skin carcinoma syndrome, autosomal recessive brachyolmia, Aicardi-Goutieres syndrome, homocystinuria without methylmalonic aciduria, Niemann-Pick disease type C, nephronophthisis, autosomal recessive osteopetrosis, peroxisome biogenesis disorder, congenital non-bullous ichthyosiform erythroderma, Seckel syndrome, Usher syndrome, autosomal recessive cutis laxa type 1, autosomal recessive cutis laxa type 2, hearing loss, autosomal recessive, microcephaly, growth restriction, and increased sister chromatid exchange 2, encephalopathy, progressive, early-onset, with brain edema and/or leukoencephalopathy, 1, congenital vertebral-cardiac-renal anomalies syndrome, hair defect with photosensitivity and intellectual disability syndrome, autosomal recessive severe congenital neutropenia, severe combined immunodeficiency due to CARMIL2 deficiency, extraoral halitosis due to methanethiol oxidase deficiency, neurodevelopmental disorder with microcephaly, impaired language, epilepsy, and gait abnormalities, mitochondrial complex 2 deficiency, nuclear type 3, mitochondrial complex 2 deficiency, nuclear type 4, mismatch repair cancer syndrome, spondyloepimetaphyseal dysplasia with joint laxity, type 3, Kilquist syndrome, Duane anomaly-myopathy-scoliosis syndrome, autosomal recessive axonal charcot-marie-tooth disease due to copper metabolism defect, immune dysregulation-inflammatory bowel disease-arthritis-recurrent infections-lymphopenia syndrome, optic atrophy-ataxia-peripheral neuropathy-global developmental delay syndrome, congenital myopathy with reduced type 2 muscle fibers, NAD(P)HX dehydratase deficiency, autosomal recessive ocular albinism, ichthyosis linearis circumflexa, eosinophil peroxidase deficiency, hyperphenylalaninemia due to DNAJC12 deficiency, autosomal recessive epidermolytic ichthyosis, Ehlers-Danlos syndrome, classic-like, 2, joint laxity, short stature, and myopia, HELIX syndrome, auditory neuropathy-optic atrophy syndrome, glycosylphosphatidylinositol biosynthesis defect 15, neurodegeneration, childhood-onset, stress-induced, with variable ataxia and seizures, SCN4A-related myopathy, autosomal recessive, Uner Tan Syndrome, nephropathic cystinosis, Imerslund-Grasbeck syndrome type 1, Imerslund-Grasbeck syndrome type 2, permanent neonatal diabetes mellitus 1, growth hormone insensitivity with immune dysregulation 1, autosomal recessive, Rajab interstitial lung disease with brain calcifications 1, Roberts-SC phocomelia syndrome, neurodevelopmental disorder with microcephaly, impaired language, and gait abnormalities, RPE65-related recessive retinopathy, GUCY2D-related recessive retinopathy, autosomal recessive titinopathy, intellectual disability, autosomal recessive, ALPL-related autosomal recessive hypophosphatasia, spastic paraplegia 18b, autosomal recessive, CEP164-related ciliopathy, RP1-related recessive retinopathy, pseudohypoaldosteronism, type IB2, autosomal recessive, pseudohypoaldosteronism, type IB3, autosomal recessive, spastic paraplegia 30B, autosomal recessive, cerebral arteriopathy, autosomal recessive, with subcortical infarcts and leukoencephalopathy 1, brain small vessel disease 2B, autosomal recessive, IMPG1-related recessive retinopathy, PROM1-related recessive retinopathy

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:

292 uncertain significance, 119 likely benign, 56 conflicting classifications of pathogenicity, 56 pathogenic, 26 likely pathogenic, 26 pathogenic/likely pathogenic, 18 benign/likely benign, 7 benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1367856	NM_002485.5(NBN):c.1889C>A (p.Ser630Ter)	LOC126860438	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
142559	NM_002485.5(NBN):c.1903A>T (p.Lys635Ter)	LOC126860438	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1452252	NM_002485.5(NBN):c.1895G>A (p.Trp632Ter)	LOC126860438	Pathogenic	criteria provided, multiple submitters, no conflicts
1068887	NM_002485.5(NBN):c.580G>T (p.Glu194Ter)	NBN	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1068989	NM_002485.5(NBN):c.2172_2173delinsTT (p.Arg724_Gln725delinsSerTer)	NBN	Pathogenic	criteria provided, single submitter
1069236	NM_002485.5(NBN):c.1986_2001del (p.Val663fs)	NBN	Pathogenic	criteria provided, single submitter
1070578	NM_002485.5(NBN):c.113_114insGGCCGGGCGCGGTGGCTCACGCCTGTAATCCCAGCACTTTGGGAGGCCGAGGCGGGTGGATCATGAGGTCAGGAGATCGAGACCATCCTGGCTAACAAGGTGAAANNNNNNNNNNAAAAAAAAAAAAAAAAAAAAGAAAATGA (p.Asp38delinsGluAlaGlyArgGlyGlySerArgLeuTer)	NBN	Pathogenic	criteria provided, single submitter
1070710	NM_002485.5(NBN):c.520_521insT (p.Pro174fs)	NBN	Pathogenic	criteria provided, single submitter
1071046	NM_002485.5(NBN):c.1554del (p.Asp519fs)	NBN	Pathogenic	criteria provided, single submitter
1071444	NM_002485.5(NBN):c.157del (p.Ser53fs)	NBN	Pathogenic	criteria provided, single submitter
1072146	NM_002485.5(NBN):c.2051del (p.Asn684fs)	NBN	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1072454	NM_002485.5(NBN):c.48C>G (p.Tyr16Ter)	NBN	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1072536	NC_000008.10:g.(?90990438)(90990561_?)del	NBN	Pathogenic	criteria provided, single submitter
1072538	NC_000008.10:g.(?90958358)(90960130_?)del	NBN	Pathogenic	criteria provided, single submitter
1072539	NC_000008.10:g.(?90955471)(90976745_?)del	NBN	Pathogenic	criteria provided, single submitter
1072749	NM_002485.5(NBN):c.765_801del (p.Asn256fs)	NBN	Pathogenic	criteria provided, single submitter
1073031	NM_002485.5(NBN):c.1417C>T (p.Gln473Ter)	NBN	Pathogenic	criteria provided, multiple submitters, no conflicts
1073255	NM_002485.5(NBN):c.1939del (p.Ser647fs)	NBN	Pathogenic	criteria provided, single submitter
1073756	NM_002485.5(NBN):c.1106C>G (p.Ser369Ter)	NBN	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1073911	NM_002485.5(NBN):c.1496C>A (p.Ser499Ter)	NBN	Pathogenic	criteria provided, single submitter
1074632	NM_002485.5(NBN):c.2089G>T (p.Gly697Ter)	NBN	Pathogenic	criteria provided, single submitter
1075267	NM_002485.5(NBN):c.1234_1235del (p.Ser411_Asn412insTer)	NBN	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1075300	NM_002485.5(NBN):c.1993A>T (p.Lys665Ter)	NBN	Pathogenic	criteria provided, single submitter
1075344	NM_002485.5(NBN):c.1695_1698dup (p.Phe567fs)	NBN	Pathogenic	criteria provided, multiple submitters, no conflicts
1075360	NM_002485.5(NBN):c.1190C>G (p.Ser397Ter)	NBN	Pathogenic	criteria provided, single submitter
1075578	NM_002485.5(NBN):c.1362dup (p.Ile455fs)	NBN	Pathogenic	criteria provided, single submitter
1075823	NM_002485.5(NBN):c.228_231dup (p.Val78fs)	NBN	Pathogenic	criteria provided, multiple submitters, no conflicts
1075847	NM_002485.5(NBN):c.4del (p.Trp2fs)	NBN	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1076528	NM_002485.5(NBN):c.1778_1779insGGCCGGGCGCGGTGGCTCACGCCTGTAATCCCAGCACTTTGGGAGGCCGAGGCGGGTGGATCATGAGGTCAGGAGATCGAGACCATCCTGGCTAACAAGGTGAAACCCCNNNNNNNNNNAAAAAAAAAAAAAAAAAAAAGAAAAAGGCC (p.Pro593_Arg594insAlaGlyArgGlyGlySerArgLeuTer)	NBN	Pathogenic	criteria provided, single submitter
1076558	NM_002485.5(NBN):c.1192C>T (p.Gln398Ter)	NBN	Pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 8 · Orphanet: 6 · 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
NBN	Definitive	Autosomal recessive	Nijmegen breakage syndrome	8

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
NBN	Orphanet:1331	Familial prostate cancer
NBN	Orphanet:145	Hereditary breast and/or ovarian cancer syndrome
NBN	Orphanet:647	Nijmegen breakage syndrome
GCK	Orphanet:552	MODY
GCK	Orphanet:79299	Congenital glucokinase-related hyperinsulinism
GCK	Orphanet:99885	Isolated permanent neonatal diabetes mellitus

Cohort genes → proteins

3 cohort genes, 3 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	3

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
NBN	HGNC:7652	ENSG00000104320	O60934	Nibrin	gencc,clinvar
DECR1	HGNC:2753	ENSG00000104325	Q16698	2,4-dienoyl-CoA reductase [(3E)-enoyl-CoA-producing], mitochondrial	clinvar
GCK	HGNC:4195	ENSG00000106633	P35557	Hexokinase-4	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
NBN	Nibrin	Component of the MRN complex, which plays a central role in double-strand break (DSB) repair, DNA recombination, maintenance of telomere integrity and meiosis.
DECR1	2,4-dienoyl-CoA reductase [(3E)-enoyl-CoA-producing], mitochondrial	Auxiliary enzyme of beta-oxidation.
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: 2 · Difficult: 0 · Unknown: 1 · Druggable fraction: 0.67

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	9.2×	0.313
Enzyme (other)	1	4.0×	0.345
Other/Unknown	1	0.6×	0.914

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
NBN	Other/Unknown	no		FHA_dom, BRCT_dom, SMAD_FHA_dom_sf
DECR1	Enzyme (other)	yes	1.3.1.124	SDR_fam, NAD(P)-bd_dom_sf
GCK	Kinase	yes	2.7.1.1	Hexokinase, Hexokinase_BS, Hexokinase_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)	3
unknown	0

Top tissues across cohort

Tissue	Cohort genes
cauda epididymis	1
endometrium epithelium	1
mammary duct	1
heart right ventricle	1
left ventricle myocardium	1
right adrenal gland	1
adenohypophysis	1
islet of Langerhans	1
pituitary gland	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
NBN	299	ubiquitous	marker	endometrium epithelium, mammary duct, cauda epididymis
DECR1	296	ubiquitous	marker	left ventricle myocardium, heart right ventricle, right adrenal gland
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
DECR1	4,079
GCK	2,245
NBN	1,989

Structural data

PDB: 3 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
GCK	P35557	35
NBN	O60934	7
DECR1	Q16698	3

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 51. Enrichment computed across 3 evidence-associated genes (3 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 3 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	3806.7×	0.013	GCK
Sensing of DNA Double Strand Breaks	1	634.4×	0.020	NBN
mitochondrial fatty acid beta-oxidation of unsaturated fatty acids	1	634.4×	0.020	DECR1
Defective homologous recombination repair (HRR) due to PALB2 loss of function	1	317.2×	0.020	NBN
HDR through MMEJ (alt-NHEJ)	1	292.8×	0.020	NBN
Diseases of DNA Double-Strand Break Repair	1	271.9×	0.020	NBN
Defective homologous recombination repair (HRR) due to BRCA2 loss of function	1	271.9×	0.020	NBN
Resolution of D-Loop Structures	1	211.5×	0.020	NBN
Diseases of DNA repair	1	190.3×	0.020	NBN
Regulation of gene expression in beta cells	1	173.0×	0.020	GCK
DNA Double Strand Break Response	1	158.6×	0.020	NBN
Impaired BRCA2 binding to PALB2	1	152.3×	0.020	NBN
Defective homologous recombination repair (HRR) due to BRCA1 loss of function	1	141.0×	0.020	NBN
Defective HDR through Homologous Recombination Repair (HRR) due to PALB2 loss of BRCA1 binding function	1	141.0×	0.020	NBN
Defective HDR through Homologous Recombination Repair (HRR) due to PALB2 loss of BRCA2/RAD51/RAD51C binding function	1	141.0×	0.020	NBN
Resolution of D-loop Structures through Synthesis-Dependent Strand Annealing (SDSA)	1	131.3×	0.020	NBN
Homologous DNA Pairing and Strand Exchange	1	126.9×	0.020	NBN
FOXO-mediated transcription of oxidative stress, metabolic and neuronal genes	1	126.9×	0.020	GCK
Regulation of Glucokinase by Glucokinase Regulatory Protein	1	119.0×	0.020	GCK
Defective TPR may confer susceptibility towards thyroid papillary carcinoma (TPC)	1	119.0×	0.020	GCK
Homology Directed Repair	1	102.9×	0.020	NBN
HDR through Homologous Recombination (HRR) or Single Strand Annealing (SSA)	1	102.9×	0.020	NBN
Impaired BRCA2 binding to RAD51	1	102.9×	0.020	NBN
Resolution of D-loop Structures through Holliday Junction Intermediates	1	100.2×	0.020	NBN
HDR through Single Strand Annealing (SSA)	1	97.6×	0.020	NBN
Meiosis	1	95.2×	0.020	NBN
Glycolysis	1	95.2×	0.020	GCK
Presynaptic phase of homologous DNA pairing and strand exchange	1	90.6×	0.020	NBN
DNA Double-Strand Break Repair	1	82.8×	0.021	NBN
Reproduction	1	63.4×	0.026	NBN

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
telomere maintenance via telomere trimming	1	2808.7×	0.007	NBN
telomeric 3’ overhang formation	1	1404.3×	0.007	NBN
negative regulation of telomere capping	1	1123.5×	0.007	NBN
blastocyst growth	1	936.2×	0.007	NBN
glucose catabolic process	1	802.5×	0.007	GCK
protection from non-homologous end joining at telomere	1	802.5×	0.007	NBN
DNA strand resection involved in replication fork processing	1	702.2×	0.007	NBN
telomere maintenance in response to DNA damage	1	624.1×	0.007	NBN
regulation of potassium ion transport	1	624.1×	0.007	GCK
R-loop processing	1	561.7×	0.007	NBN
double-strand break repair via alternative nonhomologous end joining	1	561.7×	0.007	NBN
DNA double-strand break processing	1	510.7×	0.007	NBN
NADP+ metabolic process	1	510.7×	0.007	GCK
cellular response to leptin stimulus	1	510.7×	0.007	GCK
homologous recombination	1	468.1×	0.007	NBN
t-circle formation	1	468.1×	0.007	NBN
glucose 6-phosphate metabolic process	1	432.1×	0.007	GCK
regulation of glycolytic process	1	401.2×	0.007	GCK
regulation of DNA-templated DNA replication initiation	1	351.1×	0.007	NBN
protein localization to site of double-strand break	1	351.1×	0.007	NBN
positive regulation of glycogen biosynthetic process	1	330.4×	0.007	GCK
isotype switching	1	280.9×	0.008	NBN
mitotic G2/M transition checkpoint	1	267.5×	0.008	NBN
negative regulation of gluconeogenesis	1	267.5×	0.008	GCK
calcium ion import	1	267.5×	0.008	GCK
canonical glycolysis	1	234.1×	0.008	GCK
intracellular glucose homeostasis	1	193.7×	0.010	GCK
positive regulation of telomere maintenance	1	170.2×	0.011	NBN
mitotic G2 DNA damage checkpoint signaling	1	147.8×	0.012	NBN
DNA damage checkpoint signaling	1	130.6×	0.012	NBN

Therapeutics

Drugs indicated for this disease

No approved or late-stage (phase ≥3) drug is indicated for this disease; the following are in earlier-phase trials only.

Earlier-phase candidates (phase 2, investigational — efficacy not yet established): Treosulfan.

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 1 · Undrugged: 2

Druggability breadth: 3 of 3 evidence-associated genes (100%) 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
NBN	0	0
DECR1	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): 2.

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

Symbol	Assays	Type breakdown
GCK	228	Binding:226, ADMET:1, Functional:1
NBN	2	Binding:2
DECR1	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
DECR1	1.3.1.124	2,4-dienoyl-CoA reductase [(3E)-enoyl-CoA-producing]
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: 3; 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	1	DECR1
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	NBN

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
NBN	2	—
DECR1	1	—

Clinical trials & evidence

Clinical trials

Clinical trials: 3.

Phase distribution (across all retrieved trials)

Phase	Trials
PHASE2	3

Top trials by phase / activity

NCT	Phase	Status	Title
NCT06198842	PHASE2	RECRUITING	Low Dose Treosulfan Based Conditioning Regimen and PTCy in HSCT for Nijmegen Breakage Syndrome
NCT07316595	PHASE2	NOT_YET_RECRUITING	Study of Treosulfan-Based Conditioning for HSCT in Nijmegen Breakage Syndrome
NCT04400045	PHASE2	UNKNOWN	Low Dose Treosulfan Based Conditioning Regimen in HSCT for Nijmegen Breakage Syndrome

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
TREOSULFAN	4	3