Ataxia-telangiectasia-like disorder 1

Summary

Ataxia-telangiectasia-like disorder 1 (MONDO:0024557) is a disease caused by MRE11 (GenCC Definitive), with 1 cohort gene.

At a glance

• Prevalence: Unknown (Worldwide)
• Causal gene: MRE11 (GenCC Definitive)
• Cohort genes: 1
• ClinVar variants: 377
• Phenotypes (HPO): 34

Clinical features

Signs & symptoms

Clinical features (HPO)

34 HPO clinical features (Orphanet curated; top 34 by frequency):

HPO ID	Term	Frequency
HP:0001251	Ataxia	Very frequent (80-99%)
HP:0000298	Mask-like facies	Frequent (30-79%)
HP:0000514	Slow saccadic eye movements	Frequent (30-79%)
HP:0000657	Oculomotor apraxia	Frequent (30-79%)
HP:0001260	Dysarthria	Frequent (30-79%)
HP:0001272	Cerebellar atrophy	Frequent (30-79%)
HP:0001290	Generalized hypotonia	Frequent (30-79%)
HP:0001310	Dysmetria	Frequent (30-79%)
HP:0001315	Reduced tendon reflexes	Frequent (30-79%)
HP:0001320	Cerebellar vermis hypoplasia	Frequent (30-79%)
HP:0001332	Dystonia	Frequent (30-79%)
HP:0002066	Gait ataxia	Frequent (30-79%)
HP:0002072	Chorea	Frequent (30-79%)
HP:0002080	Intention tremor	Frequent (30-79%)
HP:0002198	Dilated fourth ventricle	Frequent (30-79%)
HP:0002310	Orofacial dyskinesia	Frequent (30-79%)
HP:0003438	Absent Achilles reflex	Frequent (30-79%)
HP:0100953	Enlarged interhemispheric fissure	Frequent (30-79%)
HP:0000617	Abnormality of ocular smooth pursuit	Occasional (5-29%)
HP:0000640	Gaze-evoked nystagmus	Occasional (5-29%)
HP:0000641	Dysmetric saccades	Occasional (5-29%)
HP:0000750	Delayed speech and language development	Occasional (5-29%)
HP:0000815	Hypergonadotropic hypogonadism	Occasional (5-29%)
HP:0001336	Myoclonus	Occasional (5-29%)
HP:0001382	Joint hypermobility	Occasional (5-29%)
HP:0001761	Pes cavus	Occasional (5-29%)
HP:0002075	Dysdiadochokinesis	Occasional (5-29%)
HP:0002307	Drooling	Occasional (5-29%)
HP:0002359	Frequent falls	Occasional (5-29%)
HP:0006801	Hyperactive deep tendon reflexes	Occasional (5-29%)
HP:0007141	Sensorimotor neuropathy	Occasional (5-29%)
HP:0010544	Vertical nystagmus	Occasional (5-29%)
HP:0040010	Small posterior fossa	Occasional (5-29%)
HP:0004322	Short stature	Very rare (<1-4%)

Identifiers

Disease identifiers

Field	Value
Canonical name	ataxia-telangiectasia-like disorder 1
Mondo ID	MONDO:0024557
OMIM	604391
Orphanet	251347
DOID	DOID:0081384
NCIT	C132224
UMLS	C4012790
MedGen	861227
GARD	0017209
Is cancer (heuristic)	no

Also known as: ataxia - telangiectasia-like disorder caused by mutation in MRE11 · ataxia-telangiectasia-like disorder 1 · ataxia-telangiectasia-like disorder caused by mutation in MRE11 · ATLD1 · MRE11 ataxia - telangiectasia-like disorder · MRE11 ataxia-telangiectasia-like disorder

Data availability: 377 ClinVar variants · 5 GenCC gene-disease records · 2 cell lines.

Disease family

Classification path: disease › human disease › disease by body system or component › nervous system disorder › central nervous system disorder › neurodegenerative disease › inherited neurodegenerative disorder › ataxia-telangiectasia-like disorder › ataxia-telangiectasia-like disorder 1

Related subtypes (2): ataxia, early-onset, with oculomotor apraxia and hypoalbuminemia, ataxia-telangiectasia-like disorder 2

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

377 retrieved; paginated sample, class counts are floors:

191 uncertain significance, 59 conflicting classifications of pathogenicity, 43 pathogenic/likely pathogenic, 40 likely pathogenic, 22 benign, 11 benign/likely benign, 6 likely benign, 5 pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1073861	NM_005591.4(MRE11):c.1280dup (p.Leu427fs)	MRE11	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1260482	NM_005591.4(MRE11):c.1100_1131del (p.Val367fs)	MRE11	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1323291	NM_005591.4(MRE11):c.1018del (p.Ile340fs)	MRE11	Pathogenic	criteria provided, single submitter
1323292	NM_005591.4(MRE11):c.403-2A>T	MRE11	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1323293	NM_005591.4(MRE11):c.1552dup (p.Glu518fs)	MRE11	Pathogenic	criteria provided, single submitter
140936	NM_005591.4(MRE11):c.845+2T>A	MRE11	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
140941	NM_005591.4(MRE11):c.1516G>T (p.Glu506Ter)	MRE11	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
140953	NM_005591.4(MRE11):c.1090C>T (p.Arg364Ter)	MRE11	Pathogenic	criteria provided, multiple submitters, no conflicts
141533	NM_005591.4(MRE11):c.1927-2A>G	MRE11	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
141542	NM_005591.4(MRE11):c.923dup (p.Met309fs)	MRE11	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1681558	NM_005591.4(MRE11):c.1888C>T (p.Gln630Ter)	MRE11	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1681596	NM_005591.4(MRE11):c.1096C>T (p.Arg366Ter)	MRE11	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1799665	NM_005591.4(MRE11):c.1532dup (p.Asn511fs)	MRE11	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1800330	NM_005591.4(MRE11):c.1441dup (p.Thr481fs)	MRE11	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1800442	NM_005591.4(MRE11):c.939del (p.Val313_Leu314insTer)	MRE11	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
184445	NM_005591.4(MRE11):c.1726C>T (p.Arg576Ter)	MRE11	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
184556	NM_005591.4(MRE11):c.1222dup (p.Thr408fs)	MRE11	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
185530	NM_005591.4(MRE11):c.504_511del (p.Leu169fs)	MRE11	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
186193	NM_005591.4(MRE11):c.1135dup (p.Leu379fs)	MRE11	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
187174	NM_005591.4(MRE11):c.1867+2T>C	MRE11	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
216094	NM_005591.4(MRE11):c.1143del (p.Phe381fs)	MRE11	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
216095	NM_005591.4(MRE11):c.1441del (p.Thr481fs)	MRE11	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
224574	NM_005591.4(MRE11):c.229G>T (p.Glu77Ter)	MRE11	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
230014	NM_005591.4(MRE11):c.659+1G>A	MRE11	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
231449	NM_005591.4(MRE11):c.1447C>T (p.Arg483Ter)	MRE11	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
233090	NM_005591.4(MRE11):c.1633_1640del (p.Leu545fs)	MRE11	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
233262	NM_005591.4(MRE11):c.806C>G (p.Ser269Ter)	MRE11	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2451357	NM_005591.4(MRE11):c.784del (p.Tyr262fs)	MRE11	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2676681	NM_005591.4(MRE11):c.1458_1461del (p.Lys486fs)	MRE11	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2676685	NM_005591.4(MRE11):c.1127del (p.Phe376fs)	MRE11	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 8 · Orphanet: 3 · 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
MRE11	Definitive	Autosomal recessive	ataxia-telangiectasia-like disorder 1	8

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
MRE11	Orphanet:145	Hereditary breast and/or ovarian cancer syndrome
MRE11	Orphanet:240760	Nijmegen breakage syndrome-like disorder
MRE11	Orphanet:251347	Ataxia-telangiectasia-like disorder

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
MRE11	HGNC:7230	ENSG00000020922	P49959	Double-strand break repair protein MRE11	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
MRE11	Double-strand break repair protein MRE11	Core 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: 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)
MRE11	Other/Unknown	no		Mre11, Calcineurin-like_PHP, Mre11_DNA-bd

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
calcaneal tendon	1
oocyte	1
secondary oocyte	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
MRE11	254	ubiquitous	marker	calcaneal tendon, oocyte, secondary oocyte

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
MRE11	3,932

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
MRE11	P49959	10

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 49. 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
Sensing of DNA Double Strand Breaks	1	1903.3×	0.007	MRE11
STING mediated induction of host immune responses	1	1038.2×	0.007	MRE11
Defective homologous recombination repair (HRR) due to PALB2 loss of function	1	951.7×	0.007	MRE11
HDR through MMEJ (alt-NHEJ)	1	878.5×	0.007	MRE11
IRF3-mediated induction of type I IFN	1	815.7×	0.007	MRE11
Diseases of DNA Double-Strand Break Repair	1	815.7×	0.007	MRE11
Defective homologous recombination repair (HRR) due to BRCA2 loss of function	1	815.7×	0.007	MRE11
Resolution of D-Loop Structures	1	634.4×	0.007	MRE11
Diseases of DNA repair	1	571.0×	0.007	MRE11
DNA Double Strand Break Response	1	475.8×	0.007	MRE11
Impaired BRCA2 binding to PALB2	1	456.8×	0.007	MRE11
Defective homologous recombination repair (HRR) due to BRCA1 loss of function	1	423.0×	0.007	MRE11
Defective HDR through Homologous Recombination Repair (HRR) due to PALB2 loss of BRCA1 binding function	1	423.0×	0.007	MRE11
Defective HDR through Homologous Recombination Repair (HRR) due to PALB2 loss of BRCA2/RAD51/RAD51C binding function	1	423.0×	0.007	MRE11
Resolution of D-loop Structures through Synthesis-Dependent Strand Annealing (SDSA)	1	393.8×	0.007	MRE11
Homologous DNA Pairing and Strand Exchange	1	380.7×	0.007	MRE11
Homology Directed Repair	1	308.6×	0.007	MRE11
HDR through Homologous Recombination (HRR) or Single Strand Annealing (SSA)	1	308.6×	0.007	MRE11
Impaired BRCA2 binding to RAD51	1	308.6×	0.007	MRE11
Resolution of D-loop Structures through Holliday Junction Intermediates	1	300.5×	0.007	MRE11
HDR through Single Strand Annealing (SSA)	1	292.8×	0.007	MRE11
Meiosis	1	285.5×	0.007	MRE11
Cytosolic sensors of pathogen-associated DNA	1	285.5×	0.007	MRE11
Presynaptic phase of homologous DNA pairing and strand exchange	1	271.9×	0.008	MRE11
DNA Double-Strand Break Repair	1	248.3×	0.008	MRE11
Reproduction	1	190.3×	0.010	MRE11
HDR through Homologous Recombination (HRR)	1	190.3×	0.010	MRE11
Nonhomologous End-Joining (NHEJ)	1	167.9×	0.010	MRE11
DNA Damage/Telomere Stress Induced Senescence	1	163.1×	0.010	MRE11
Recruitment and ATM-mediated phosphorylation of repair and signaling proteins at DNA double strand breaks	1	146.4×	0.011	MRE11

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
mitochondrial double-strand break repair via homologous recombination	1	16852.0×	0.002	MRE11
regulation of mitotic recombination	1	8426.0×	0.002	MRE11
telomeric 3’ overhang formation	1	4213.0×	0.002	MRE11
meiotic DNA double-strand break formation	1	2407.4×	0.002	MRE11
DNA strand resection involved in replication fork processing	1	2106.5×	0.002	MRE11
negative regulation of double-strand break repair via nonhomologous end joining	1	2106.5×	0.002	MRE11
R-loop processing	1	1685.2×	0.002	MRE11
DNA double-strand break processing	1	1532.0×	0.002	MRE11
homologous recombination	1	1404.3×	0.002	MRE11
mitotic intra-S DNA damage checkpoint signaling	1	936.2×	0.003	MRE11
mitotic G2/M transition checkpoint	1	802.5×	0.003	MRE11
sister chromatid cohesion	1	766.0×	0.003	MRE11
telomere maintenance via telomerase	1	732.7×	0.003	MRE11
homologous chromosome pairing at meiosis	1	601.9×	0.003	MRE11
reciprocal meiotic recombination	1	561.7×	0.003	MRE11
positive regulation of telomere maintenance	1	510.7×	0.003	MRE11
mitotic G2 DNA damage checkpoint signaling	1	443.5×	0.004	MRE11
double-strand break repair via nonhomologous end joining	1	421.3×	0.004	MRE11
positive regulation of double-strand break repair	1	343.9×	0.004	MRE11
DNA recombination	1	337.0×	0.004	MRE11
telomere maintenance	1	267.5×	0.005	MRE11
double-strand break repair	1	203.0×	0.006	MRE11
double-strand break repair via homologous recombination	1	156.0×	0.008	MRE11
cell population proliferation	1	102.8×	0.011	MRE11
DNA repair	1	63.8×	0.017	MRE11
DNA damage response	1	53.5×	0.019	MRE11
negative regulation of apoptotic process	1	34.8×	0.029	MRE11

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 1 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
MRE11	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
MRE11	36	Binding:36

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	MRE11

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)
MRE11	36	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.