Nijmegen breakage syndrome-like disorder

Summary

Nijmegen breakage syndrome-like disorder (MONDO:0013118) is a disease caused by RAD50 (GenCC Strong), with 2 cohort genes.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: RAD50 (GenCC Strong)
• Cohort genes: 2
• ClinVar variants: 423

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

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

Identifiers

Disease identifiers

Field	Value
Canonical name	Nijmegen breakage syndrome-like disorder
Mondo ID	MONDO:0013118
MeSH	C567767
OMIM	613078
Orphanet	240760
ICD-11	1014526672
NCIT	C153178
SNOMED CT	766753005
UMLS	C2751318
MedGen	442700
GARD	0017184
Is cancer (heuristic)	no

Also known as: microcephaly and chromosomal instability without immunodeficiency · NBs-like disorder · NBSLD · Nijmegen breakage syndrome-like disorder · RAD50 deficiency

Data availability: 423 ClinVar variants · 4 GenCC gene-disease records · 1 cell line.

Disease family

Classification path: disease › human disease › disease by developmental or physiological process › disorder of development or morphogenesis › developmental defect during embryogenesis › multiple congenital anomalies/dysmorphic syndrome › multiple congenital anomalies/dysmorphic syndrome without intellectual disability › Nijmegen breakage syndrome-like disorder

Related subtypes (167): Treacher-Collins syndrome, branchio-oto-renal syndrome, acrorenal syndrome, Townes-Brocks syndrome, Ascher syndrome, brachytelephalangy-dysmorphism-Kallmann syndrome, branchiooculofacial syndrome, Gordon syndrome, cataract-aberrant oral frenula-growth delay syndrome, cherubism, Alagille syndrome, cleft palate-lateral synechia syndrome, blepharocheilodontic syndrome, craniofacial-deafness-hand syndrome, cryptomicrotia-brachydactyly-excess fingertip arch syndrome, Beare-Stevenson cutis gyrata syndrome, Cyprus facial-neuromusculoskeletal syndrome, deafness-craniofacial syndrome, short stature-valvular heart disease-characteristic facies syndrome, 3-M syndrome, external auditory canal atresia-vertical talus-hypertelorism syndrome, femoral-facial syndrome, multinodular goiter-cystic kidney-polydactyly syndrome, hand-foot-genital syndrome, Bencze syndrome, oculoauriculovertebral spectrum with radial defects, Holt-Oram syndrome, mullerian duct anomalies-limb anomalies syndrome, Aase-Smith syndrome, LADD syndrome, Noonan syndrome with multiple lentigines, median nodule of the upper lip, Nager acrofacial dysostosis, Marshall syndrome, Binder syndrome, Schilbach-Rott syndrome, nasopalpebral lipoma-coloboma syndrome, autosomal dominant prognathism, short stature-craniofacial anomalies-genital hypoplasia syndrome, radial hypoplasia-triphalangeal thumbs-hypospadias-maxillary diastema syndrome, scalp-ear-nipple syndrome, flat face-microstomia-ear anomaly syndrome, Czeizel-Losonci syndrome, otospondylomegaepiphyseal dysplasia, autosomal dominant, ventricular extrasystoles with syncopal episodes-perodactyly-robin sequence syndrome, posterior fusion of lumbosacral vertebrae-blepharoptosis syndrome, acrofacial dysostosis, Weyers type, Freeman-Sheldon syndrome, Ackerman syndrome, acro-renal-mandibular syndrome, acrocraniofacial dysostosis, PAGOD syndrome, alar cartilages hypoplasia-coloboma-telecanthus syndrome, microcephaly-albinism-digital anomalies syndrome, fetal akinesia deformation sequence, Cooper-Jabs syndrome, Barber-Say syndrome, Beemer-Ertbruggen syndrome, blepharophimosis-ptosis-esotropia-syndactyly-short stature syndrome, camptodactyly syndrome, Guadalajara type 1, camptodactyly syndrome, Guadalajara type 2, heart defects-limb shortening syndrome, Verloove Vanhorick-Brubakk syndrome, Juberg-Hayward syndrome, heart defect - tongue hamartoma - polysyndactyly syndrome, Fraser syndrome, split hand-foot malformation 1 with sensorineural hearing loss, von Voss-Cherstvoy syndrome, autosomal recessive faciodigitogenital syndrome, gingival fibromatosis-facial dysmorphism syndrome, Fibulo-ulnar hypoplasia-renal anomalies syndrome, frontofacionasal dysplasia, genito-palato-cardiac syndrome, Hirschsprung disease-hearing loss-polydactyly syndrome, Holzgreve-Wagner-Rehder syndrome, hydrocephaly-tall stature-joint laxity syndrome, McKusick-Kaufman syndrome, acrofrontofacionasal dysostosis 2, Vici syndrome, Donohue syndrome, Dahlberg-Borer-Newcomer syndrome, macrosomia-microphthalmia-cleft palate syndrome, mesomelic dwarfism-cleft palate-camptodactyly syndrome, Nijmegen breakage syndrome, lethal congenital contracture syndrome 1, Richieri Costa-da Silva syndrome, Keipert syndrome, nephrosis-deafness-urinary tract-digital malformations syndrome, ichthyosis-oral and digital anomalies syndrome, otoonychoperoneal syndrome, PHAVER syndrome, polysyndactyly-cardiac malformation syndrome, postaxial acrofacial dysostosis, autosomal recessive multiple pterygium syndrome, rapadilino syndrome, renal-genital-middle ear anomalies, Richieri Costa-Pereira syndrome, SHORT syndrome, tetraamelia-multiple malformations syndrome, thymic-renal-anal-lung dysplasia, trigonocephaly-bifid nose-acral anomalies syndrome, white forelock with malformations, syndactyly-telecanthus-anogenital and renal malformations syndrome, Abruzzo-Erickson syndrome, CHILD syndrome, pentalogy of Cantrell, atrioventricular defect-blepharophimosis-radial and anal defect syndrome, short tarsus-absence of lower eyelashes syndrome, PARC syndrome, CODAS syndrome, pectus excavatum-macrocephaly-dysplastic nails syndrome, velo-facial-skeletal syndrome, anophthalmia plus syndrome, van den Ende-Gupta syndrome, absent tibia-polydactyly-arachnoid cyst syndrome, diaphragmatic defect-limb deficiency-skull defect syndrome, cleft lip/palate-intestinal malrotation-cardiopathy syndrome, Matthew-Wood syndrome, microcephaly-cardiac defect-lung malsegmentation syndrome, dislocation of the hip-dysmorphism syndrome, short stature-auditory canal atresia-mandibular hypoplasia-skeletal anomalies syndrome, grange syndrome, camptodactyly, myopia, and fibrosis of the medial rectus muscle of eye, arhinia, choanal atresia, and microphthalmia, anonychia-microcephaly syndrome, developmental malformations-deafness-dystonia syndrome, lethal congenital contracture syndrome 2, craniolenticulosutural dysplasia, 8q22.1 microdeletion syndrome, Braddock syndrome, choanal atresia-hearing loss-cardiac defects-craniofacial dysmorphism syndrome, BNAR syndrome, Frias syndrome, lethal congenital contracture syndrome 3, Fontaine progeroid syndrome, microcephaly-facio-cardio-skeletal syndrome, Hadziselimovic type, Warsaw breakage syndrome, even-plus syndrome, split-foot malformation-mesoaxial polydactyly syndrome, anophthalmia-megalocornea-cardiopathy-skeletal anomalies syndrome, digitotalar dysmorphism, heart-hand syndrome type 2, night blindness-skeletal anomalies-dysmorphism syndrome, Charlie M syndrome, facial dysmorphism-anorexia-cachexia-eye and skin anomalies syndrome, cleft lip-retinopathy syndrome, Cole-Carpenter syndrome, progressive non-infectious anterior vertebral fusion, dysmorphism-pectus carinatum-joint laxity syndrome, Hirschsprung disease-type D brachydactyly syndrome, mandibuloacral dysplasia, contractures - webbed neck - micrognathia - hypoplastic nipples syndrome, Thomas syndrome, Waardenburg syndrome, Weill-Marchesani syndrome, branchiootic syndrome, auricular abnormalities-cleft lip with or without cleft palate-ocular abnormalities syndrome, Axenfeld-Rieger syndrome, macrostomia-preauricular tags-external ophthalmoplegia syndrome, pelvis syndrome, Fanconi anemia, van der Woude syndrome, hypertrichosis-acromegaloid facial appearance syndrome, 49,XYYYY syndrome, congenital vertebral-cardiac-renal anomalies syndrome, structural heart defects and renal anomalies syndrome, Greig cephalopolysyndactyly-contiguous gene 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

423 retrieved; paginated sample, class counts are floors:

196 uncertain significance, 67 pathogenic/likely pathogenic, 60 conflicting classifications of pathogenicity, 28 likely pathogenic, 25 pathogenic, 20 likely benign, 16 benign/likely benign, 11 benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1064538	NM_005732.4(RAD50):c.2524G>A (p.Val842Ile)	RAD50	Pathogenic	no assertion criteria provided
1069196	NM_005732.4(RAD50):c.2767C>T (p.Gln923Ter)	RAD50	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1072155	NM_005732.4(RAD50):c.62dup (p.Asp21fs)	RAD50	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1074013	NM_005732.4(RAD50):c.193dup (p.Thr65fs)	RAD50	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
126999	NM_005732.4(RAD50):c.1114C>T (p.Gln372Ter)	RAD50	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
127997	NM_005732.4(RAD50):c.1393C>T (p.Gln465Ter)	RAD50	Pathogenic	criteria provided, multiple submitters, no conflicts
128015	NM_005732.4(RAD50):c.2983_2986del (p.Glu995fs)	RAD50	Pathogenic	criteria provided, multiple submitters, no conflicts
128024	NM_005732.4(RAD50):c.3G>A (p.Met1Ile)	RAD50	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1323513	NM_005732.4(RAD50):c.2620A>T (p.Lys874Ter)	RAD50	Pathogenic	criteria provided, multiple submitters, no conflicts
1323514	NM_005732.4(RAD50):c.2395C>T (p.Gln799Ter)	RAD50	Pathogenic	criteria provided, multiple submitters, no conflicts
1362564	NM_005732.4(RAD50):c.139G>T (p.Glu47Ter)	RAD50	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
140899	NM_005732.4(RAD50):c.399_400del (p.Ala134fs)	RAD50	Pathogenic	criteria provided, multiple submitters, no conflicts
1410757	NM_005732.4(RAD50):c.1370del (p.Leu457fs)	RAD50	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
141646	NM_005732.4(RAD50):c.1958C>A (p.Ser653Ter)	RAD50	Pathogenic	criteria provided, multiple submitters, no conflicts
141677	NM_005732.4(RAD50):c.2789_2792del (p.Ile930fs)	RAD50	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
141877	NM_005732.4(RAD50):c.1969+1G>A	RAD50	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
141896	NM_005732.4(RAD50):c.904G>T (p.Glu302Ter)	RAD50	Pathogenic	criteria provided, multiple submitters, no conflicts
142556	NM_005732.4(RAD50):c.1722dup (p.Gln575fs)	RAD50	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
143015	NM_005732.4(RAD50):c.2498_2499del (p.Gln833fs)	RAD50	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1453893	NM_005732.4(RAD50):c.2095_2113dup (p.Leu705delinsGlnTer)	RAD50	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1456267	NM_005732.4(RAD50):c.3458_3459dup (p.Thr1154fs)	RAD50	Pathogenic	criteria provided, single submitter
1779896	NM_005732.4(RAD50):c.1777A>T (p.Arg593Ter)	RAD50	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
184469	NM_005732.4(RAD50):c.1237C>T (p.Gln413Ter)	RAD50	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
184917	NM_005732.4(RAD50):c.2202del (p.Pro734_Met735insTer)	RAD50	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
185010	NM_005732.4(RAD50):c.687del (p.Ser229fs)	RAD50	Pathogenic	criteria provided, multiple submitters, no conflicts
185058	NM_005732.4(RAD50):c.2517dup (p.Asp840fs)	RAD50	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
185222	NM_005732.4(RAD50):c.756+2T>C	RAD50	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
185458	NM_005732.4(RAD50):c.3209del (p.Asn1070fs)	RAD50	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
187117	NM_005732.4(RAD50):c.412C>T (p.Arg138Ter)	RAD50	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
187444	NM_005732.4(RAD50):c.1270_1271del (p.Leu424fs)	RAD50	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 5 · Orphanet: 2 · 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
RAD50	Strong	Autosomal recessive	Nijmegen breakage syndrome-like disorder	5

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
RAD50	Orphanet:145	Hereditary breast and/or ovarian cancer syndrome
RAD50	Orphanet:240760	Nijmegen breakage syndrome-like disorder

Cohort genes → proteins

2 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
RAD50	HGNC:9816	ENSG00000113522	Q92878	DNA repair protein RAD50	gencc,clinvar
TH2LCRR	HGNC:40495	ENSG00000223442		T helper type 2 locus control region associated RNA	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
RAD50	DNA repair protein RAD50	Component of the MRN complex, which plays a central role in double-strand break (DSB) repair, DNA recombination, maintenance of telomere integrity and meiosis.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 2 · 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	2	1.8×	0.312

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
RAD50	Other/Unknown	no		Rad50_eukaryotes, Zn_hook_RAD50, P-loop_NTPase
TH2LCRR	Other/Unknown	no

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)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
calcaneal tendon	1
colonic epithelium	1
corpus callosum	1
left testis	1
right testis	1
sperm	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
RAD50	134	ubiquitous	marker	corpus callosum, calcaneal tendon, colonic epithelium
TH2LCRR	158		yes	sperm, left testis, right testis

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
RAD50	2,552
TH2LCRR	0

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
RAD50	Q92878	6

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 21. 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
Sensing of DNA Double Strand Breaks	1	1903.3×	0.006	RAD50
HDR through MMEJ (alt-NHEJ)	1	878.5×	0.006	RAD50
Impaired BRCA2 binding to PALB2	1	456.8×	0.006	RAD50
Defective homologous recombination repair (HRR) due to BRCA1 loss of function	1	423.0×	0.006	RAD50
Defective HDR through Homologous Recombination Repair (HRR) due to PALB2 loss of BRCA1 binding function	1	423.0×	0.006	RAD50
Defective HDR through Homologous Recombination Repair (HRR) due to PALB2 loss of BRCA2/RAD51/RAD51C binding function	1	423.0×	0.006	RAD50
Resolution of D-loop Structures through Synthesis-Dependent Strand Annealing (SDSA)	1	393.8×	0.006	RAD50
Homologous DNA Pairing and Strand Exchange	1	380.7×	0.006	RAD50
Impaired BRCA2 binding to RAD51	1	308.6×	0.006	RAD50
Resolution of D-loop Structures through Holliday Junction Intermediates	1	300.5×	0.006	RAD50
HDR through Single Strand Annealing (SSA)	1	292.8×	0.006	RAD50
Presynaptic phase of homologous DNA pairing and strand exchange	1	271.9×	0.006	RAD50
HDR through Homologous Recombination (HRR)	1	190.3×	0.008	RAD50
Nonhomologous End-Joining (NHEJ)	1	167.9×	0.008	RAD50
DNA Damage/Telomere Stress Induced Senescence	1	163.1×	0.008	RAD50
Recruitment and ATM-mediated phosphorylation of repair and signaling proteins at DNA double strand breaks	1	146.4×	0.008	RAD50
Differentiation of naive CD4+ T cells to T helper 2 cells (Th2 cells)	1	146.4×	0.008	RAD50
Meiotic recombination	1	129.8×	0.009	RAD50
G2/M DNA damage checkpoint	1	120.2×	0.009	RAD50
Regulation of TP53 Activity through Phosphorylation	1	117.7×	0.009	RAD50
Processing of DNA double-strand break ends	1	114.2×	0.009	RAD50

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
regulation of mitotic recombination	1	8426.0×	0.001	RAD50
telomeric 3’ overhang formation	1	4213.0×	0.001	RAD50
chromosome organization involved in meiotic cell cycle	1	3370.4×	0.001	RAD50
negative regulation of telomere capping	1	3370.4×	0.001	RAD50
DNA strand resection involved in replication fork processing	1	2106.5×	0.002	RAD50
R-loop processing	1	1685.2×	0.002	RAD50
telomere maintenance via recombination	1	1532.0×	0.002	RAD50
DNA double-strand break processing	1	1532.0×	0.002	RAD50
homologous recombination	1	1404.3×	0.002	RAD50
mitotic G2/M transition checkpoint	1	802.5×	0.002	RAD50
telomere maintenance via telomerase	1	732.7×	0.002	RAD50
reciprocal meiotic recombination	1	561.7×	0.003	RAD50
positive regulation of telomere maintenance	1	510.7×	0.003	RAD50
positive regulation of double-strand break repair	1	343.9×	0.004	RAD50
DNA recombination	1	337.0×	0.004	RAD50
telomere maintenance	1	267.5×	0.005	RAD50
double-strand break repair	1	203.0×	0.006	RAD50
double-strand break repair via homologous recombination	1	156.0×	0.007	RAD50
DNA repair	1	63.8×	0.016	RAD50
DNA damage response	1	53.5×	0.019	RAD50

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
RAD50	1	2
TH2LCRR	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
MOLIBRESIB	2	RAD50

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
RAD50	7	Binding:7

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

1 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)
MOLIBRESIB	2	RAD50

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	RAD50
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	TH2LCRR

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)
TH2LCRR	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.