Ataxia telangiectasia

Summary

Ataxia telangiectasia (MONDO:0008840) is a disease caused by ATM (GenCC Definitive), with 8 cohort genes and 33 clinical trials. Top therapeutic interventions include clonidine, dexamethasone sodium phosphate, and levacetylleucine.

At a glance

• Prevalence: 1-9 / 1 000 000 (Europe) [Orphanet-validated]
• Causal gene: ATM (GenCC Definitive)
• Cohort genes: 8
• ClinVar variants: 14,327
• Phenotypes (HPO): 37
• Clinical trials: 33

Clinical features

Epidemiology

Prevalence records

8 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Point prevalence	1-9 / 1 000 000	0.49	Europe	Validated
Point prevalence	1-9 / 1 000 000	0.4	Norway	Validated
Point prevalence	1-9 / 1 000 000	0.15	Portugal	Validated
Point prevalence	1-9 / 1 000 000	0.25	France	Validated
Point prevalence	1-9 / 100 000	1.19	Italy	Validated
Prevalence at birth	1-5 / 10 000	10	Norway	Validated
Prevalence at birth	1-9 / 100 000	1.7	United States	Validated
Point prevalence	1-9 / 1 000 000	0.25	United Kingdom	Not yet validated

Signs & symptoms

Clinical features (HPO)

37 HPO clinical features (Orphanet curated; top 37 by frequency):

HPO ID	Term	Frequency
HP:0000147	Polycystic ovaries	Very frequent (80-99%)
HP:0000486	Strabismus	Very frequent (80-99%)
HP:0000496	Abnormality of eye movement	Very frequent (80-99%)
HP:0000639	Nystagmus	Very frequent (80-99%)
HP:0000823	Delayed puberty	Very frequent (80-99%)
HP:0001251	Ataxia	Very frequent (80-99%)
HP:0001288	Gait disturbance	Very frequent (80-99%)
HP:0001337	Tremor	Very frequent (80-99%)
HP:0001888	Lymphopenia	Very frequent (80-99%)
HP:0002167	Abnormality of speech or vocalization	Very frequent (80-99%)
HP:0002205	Recurrent respiratory infections	Very frequent (80-99%)
HP:0002216	Premature graying of hair	Very frequent (80-99%)
HP:0002715	Abnormality of the immune system	Very frequent (80-99%)
HP:0002721	Immunodeficiency	Very frequent (80-99%)
HP:0002910	Elevated circulating hepatic transaminase concentration	Very frequent (80-99%)
HP:0003220	Abnormality of chromosome stability	Very frequent (80-99%)
HP:0004313	Decreased circulating antibody level	Very frequent (80-99%)
HP:0005374	Cellular immunodeficiency	Very frequent (80-99%)
HP:0007495	Prematurely aged appearance	Very frequent (80-99%)
HP:0010515	Aplasia/Hypoplasia of the thymus	Very frequent (80-99%)
HP:0100022	Abnormality of movement	Very frequent (80-99%)
HP:0100579	Mucosal telangiectasiae	Very frequent (80-99%)
HP:0100585	Telangiectasia of the skin	Very frequent (80-99%)
HP:0000819	Diabetes mellitus	Frequent (30-79%)
HP:0001250	Seizure	Frequent (30-79%)
HP:0001257	Spasticity	Frequent (30-79%)
HP:0001260	Dysarthria	Frequent (30-79%)
HP:0002664	Neoplasm	Frequent (30-79%)
HP:0003202	Skeletal muscle atrophy	Frequent (30-79%)
HP:0004322	Short stature	Frequent (30-79%)
HP:0005599	Hypopigmentation of hair	Frequent (30-79%)
HP:0000035	Abnormal testis morphology	Occasional (5-29%)
HP:0001508	Failure to thrive	Occasional (5-29%)
HP:0005978	Type II diabetes mellitus	Occasional (5-29%)
HP:0007565	Multiple cafe-au-lait spots	Occasional (5-29%)
HP:0008065	Aplasia/Hypoplasia of the skin	Occasional (5-29%)
HP:0100543	Cognitive impairment	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	ataxia telangiectasia
Mondo ID	MONDO:0008840
MeSH	D001260
OMIM	208900
Orphanet	100
DOID	DOID:12704
NCIT	C2887
SNOMED CT	68504005
UMLS	C0004135
MedGen	439
GARD	0005862
MedDRA	10003594
NORD	816
Is cancer (heuristic)	no

Also known as: AT · AT1 · ataxia - telangiectasia · ataxia telangiectasia · ataxia telangiectasia syndrome · cerebello-oculocutaneous telangiectasia · immunodeficiency with ataxia telangiectasia · Louis-Bar syndrome

Data availability: 14,327 ClinVar variants · 8 GenCC gene-disease records · 341 cell lines.

Disease family

An umbrella term covering 1 Mondo subtype.

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › immunodeficiency disease › combined immunodeficiency › ataxia telangiectasia

Related subtypes (32): combined immunodeficiency due to ZAP70 deficiency, X-linked immunodeficiency with magnesium defect, Epstein-Barr virus infection and neoplasia, combined immunodeficiency due to moesin deficiency, Wiskott-Aldrich syndrome, MHC class I deficiency, combined immunodeficiency due to STK4 deficiency, combined immunodeficiency due to MALT1 deficiency, combined immunodeficiency due to OX40 deficiency, combined immunodeficiency due to CD3gamma deficiency, combined immunodeficiency due to CTPS1 deficiency, combined immunodeficiency due to CRAC channel dysfunction, severe combined immunodeficiency, non-SCID combined immunodeficiency, combined immunodeficiency due to RELA haploinsufficiency, combined immunodeficiency due to GINS1 deficiency, combined immunodeficiency syndrome, combined immunodeficiency due to POLE2 deficiency, autosomal recessive combined immunodeficiency due to complete IL6ST deficiency, autosomal recessive combined immunodeficiency due to partial IL6ST deficiency, autosomal dominant combined immunodeficiency due to partial IL6ST deficiency, autosomal recessive combined immunodeficiency due to IL6R deficiency, autosomal dominant combined immunodeficiency due to ERBIN deficiency, combined immunodeficiency due to TBX1 deficiency, RAC2-related combined immunodeficiency-bronchiectasis-cancer-predisposing syndrome, combined immunodeficiency due to dimerization defective IKAROS mutation, late-onset combined immunodeficiency due to ICOSL deficiency, combined immunodeficiency-hypogammaglobulinemia-skeletal anomalies syndrome due to IKBKA deficiency, early-onset combined immunodeficiency with low ig due to dominant negative IKAROS mutation, combined immunodeficiency with low Ig due to BCL10 deficiency, IRF4-related combined immunodeficiency, NFATC1-related combined immunodeficiency, POLD3-related combined immunodeficiency

Subtypes (1): ataxia-telangiectasia with generalized skin pigmentation and early death

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:

375 uncertain significance, 137 pathogenic, 35 conflicting classifications of pathogenicity, 21 likely pathogenic, 19 pathogenic/likely pathogenic, 9 likely benign, 4 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1075501	NC_000011.9:g.(?94153285)(111965700_?)del	AASDHPPT	Pathogenic	criteria provided, single submitter
1013733	NM_000051.4(ATM):c.3248A>G (p.His1083Arg)	ATM	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1027442	NM_000051.4(ATM):c.2152dup (p.Cys718fs)	ATM	Pathogenic	criteria provided, multiple submitters, no conflicts
1062106	NM_000051.4(ATM):c.5217_5231del (p.Asn1739_Thr1743del)	ATM	Pathogenic	criteria provided, single submitter
1066028	NM_000051.4(ATM):c.2638+1G>T	ATM	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1066285	NM_000051.4(ATM):c.8151+1G>A	ATM	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1066672	NM_000051.4(ATM):c.7307+1G>A	ATM	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1067957	NM_000051.4(ATM):c.1802+1G>T	ATM	Pathogenic	criteria provided, single submitter
1068029	NM_000051.4(ATM):c.4436+1G>A	ATM	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1068261	NM_000051.4(ATM):c.7788+1G>A	ATM	Pathogenic	criteria provided, multiple submitters, no conflicts
1068370	NM_000051.4(ATM):c.7515+1G>T	ATM	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1068534	NM_000051.4(ATM):c.6242T>A (p.Leu2081Ter)	ATM	Pathogenic	criteria provided, multiple submitters, no conflicts
1068555	NM_000051.4(ATM):c.3216del (p.Val1073fs)	ATM	Pathogenic	criteria provided, single submitter
1068579	NM_000051.4(ATM):c.8785A>T (p.Arg2929Ter)	ATM	Pathogenic	criteria provided, single submitter
1068697	NM_000051.4(ATM):c.1276del (p.Ser426fs)	ATM	Pathogenic	criteria provided, single submitter
1068740	NM_000051.4(ATM):c.935_936insTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTNNNATCCGCCCGCCTCGGCCTCCCAAAGTGCTGGGATTACAGGCGTGAGCCACCGCGCCCGGCCCTTT (p.Leu312fs)	ATM	Pathogenic	criteria provided, single submitter
1068798	NM_000051.4(ATM):c.6080T>G (p.Leu2027Ter)	ATM	Pathogenic	criteria provided, single submitter
1068803	NM_000051.4(ATM):c.3455_3456del (p.Ser1152fs)	ATM	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1068838	NM_000051.4(ATM):c.6295del (p.His2099fs)	ATM	Pathogenic	criteria provided, single submitter
1069119	NM_000051.4(ATM):c.3105_3106del (p.Phe1036fs)	ATM	Pathogenic	criteria provided, single submitter
1069197	NM_000051.4(ATM):c.1179G>A (p.Trp393Ter)	ATM	Pathogenic	criteria provided, multiple submitters, no conflicts
1069441	NM_000051.4(ATM):c.1262C>G (p.Ser421Ter)	ATM	Pathogenic	criteria provided, multiple submitters, no conflicts
1069467	NM_000051.4(ATM):c.3076del (p.Trp1026fs)	ATM	Pathogenic	criteria provided, single submitter
1069521	NM_000051.4(ATM):c.8556T>G (p.Tyr2852Ter)	ATM	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1069556	NC_000011.9:g.(?108178614)(108178721_?)del	ATM	Pathogenic	criteria provided, single submitter
1069557	NC_000011.9:g.(?108190675)(108190791_?)del	ATM	Pathogenic	criteria provided, single submitter
1069558	NC_000011.9:g.(?108196027)(108196281_?)del	ATM	Pathogenic	criteria provided, single submitter
1069559	NC_000011.9:g.(?108204603)(108204705_?)del	ATM	Pathogenic	criteria provided, single submitter
1069594	NM_000051.4(ATM):c.6616C>T (p.Gln2206Ter)	ATM	Pathogenic	criteria provided, single submitter
1069643	NM_000051.4(ATM):c.1966del (p.Thr656fs)	ATM	Pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 14 · Orphanet: 23 · 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
ATM	Definitive	Autosomal recessive	ataxia telangiectasia	14

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
ATM	Orphanet:100	Ataxia-telangiectasia
ATM	Orphanet:1331	Familial prostate cancer
ATM	Orphanet:145	Hereditary breast and/or ovarian cancer syndrome
ATM	Orphanet:227535	Hereditary breast cancer
ATM	Orphanet:370109	Ataxia-telangiectasia variant
ATM	Orphanet:440437	Familial colorectal cancer Type X
ATM	Orphanet:52416	Mantle cell lymphoma
ATM	Orphanet:67038	B-cell chronic lymphocytic leukemia
BRAF	Orphanet:1340	Cardiofaciocutaneous syndrome
BRAF	Orphanet:146	Differentiated thyroid carcinoma
BRAF	Orphanet:251615	Pilomyxoid astrocytoma
BRAF	Orphanet:389	Langerhans cell histiocytosis
BRAF	Orphanet:500	Noonan syndrome with multiple lentigines
BRAF	Orphanet:54595	Craniopharyngioma
BRAF	Orphanet:58017	Classic hairy cell leukemia
BRAF	Orphanet:626	Large/giant congenital melanocytic nevus
BRAF	Orphanet:648	Noonan syndrome
BRAF	Orphanet:840	Syringocystadenoma papilliferum
BRAF	Orphanet:96253	Cushing disease
MSH2	Orphanet:144	Lynch syndrome
MSH2	Orphanet:252202	Constitutional mismatch repair deficiency syndrome
NPAT	Orphanet:440437	Familial colorectal cancer Type X
ACAT1	Orphanet:134	Beta-ketothiolase deficiency

Cohort genes → proteins

8 cohort genes, 8 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	8

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
ATM	HGNC:795	ENSG00000149311	Q13315	Serine-protein kinase ATM	gencc,clinvar
BRAF	HGNC:1097	ENSG00000157764	P15056	Serine/threonine-protein kinase B-raf	clinvar
SOAT1	HGNC:11177	ENSG00000057252	P35610	Sterol O-acyltransferase 1	clinvar
AASDHPPT	HGNC:14235	ENSG00000149313	Q9NRN7	L-aminoadipate-semialdehyde dehydrogenase-phosphopantetheinyl transferase	clinvar
C11orf65	HGNC:28519	ENSG00000166323	Q8NCR3	Protein MFI	clinvar
MSH2	HGNC:7325	ENSG00000095002	P43246	DNA mismatch repair protein Msh2	clinvar
NPAT	HGNC:7896	ENSG00000149308	Q14207	Protein NPAT	clinvar
ACAT1	HGNC:93	ENSG00000075239	P24752	Acetyl-CoA acetyltransferase, mitochondrial	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
ATM	Serine-protein kinase ATM	Serine/threonine protein kinase which activates checkpoint signaling upon double strand breaks (DSBs), apoptosis and genotoxic stresses such as ionizing ultraviolet A light (UVA), thereby acting as a DNA damage sensor.
BRAF	Serine/threonine-protein kinase B-raf	Protein kinase involved in the transduction of mitogenic signals from the cell membrane to the nucleus.
SOAT1	Sterol O-acyltransferase 1	Catalyzes the formation of fatty acid-cholesterol esters, which are less soluble in membranes than cholesterol.
AASDHPPT	L-aminoadipate-semialdehyde dehydrogenase-phosphopantetheinyl transferase	Catalyzes the post-translational modification of target proteins by phosphopantetheine.
C11orf65	Protein MFI	Acts as an inhibitor of mitochondrial fission.
MSH2	DNA mismatch repair protein Msh2	Component of the post-replicative DNA mismatch repair system (MMR).
NPAT	Protein NPAT	Transcription regulator required for progression through the G1 and S phases of the cell cycle and for S phase entry.
ACAT1	Acetyl-CoA acetyltransferase, mitochondrial	This is one of the enzymes that catalyzes the last step of the mitochondrial beta-oxidation pathway, an aerobic process breaking down fatty acids into acetyl-CoA.

Protein-family classification

Druggable: 4 · Difficult: 0 · Unknown: 4 · 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	2	6.9×	0.094
Enzyme (other)	2	3.0×	0.209
Other/Unknown	4	0.9×	0.755

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
ATM	Kinase	yes	2.7.11.1	PI3/4_kinase_cat_dom, PIK-rel_kinase_FAT, FATC_dom
BRAF	Kinase	yes	2.7.10.2	Prot_kinase_dom, Ser-Thr/Tyr_kinase_cat_dom, PKC_DAG/PE
SOAT1	Enzyme (other)	yes	2.3.1.26	MBOAT_fam, Oat_ACAT_DAG_ARE, Sterol_acyltranf_meta
AASDHPPT	Enzyme (other)	yes	2.7.8.7	4-PPantetheinyl_Trfase_dom, 4-PPantetheinyl_Trfase_dom_sf, P-Pant_transferase_sf
C11orf65	Other/Unknown	no
MSH2	Other/Unknown	no		DNA_mismatch_repair_MutS_C, DNA_mismatch_repair_MutS-lik_N, DNA_mismatch_repair_MutS_core
NPAT	Other/Unknown	no		LisH, NPAT_C, NPAT_LisH
ACAT1	Other/Unknown	no		Thiolase, Thiolase-like, Thiolase_AS

Expression context

Cohort genes with no expression data: 0.

8 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)	8
unknown	0

Top tissues across cohort

Tissue	Cohort genes
calcaneal tendon	3
colonic epithelium	2
sperm	2
secondary oocyte	2
corpus callosum	1
buccal mucosa cell	1
adrenal tissue	1
right adrenal gland	1
right adrenal gland cortex	1
choroid plexus epithelium	1
cortical plate	1
left testis	1
right testis	1
oocyte	1
ventricular zone	1
male germ line stem cell (sensu Vertebrata) in testis	1
nephron tubule	1
renal medulla	1
skeletal muscle tissue of rectus abdominis	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
ATM	286	ubiquitous	marker	calcaneal tendon, colonic epithelium, corpus callosum
BRAF	265	ubiquitous	marker	buccal mucosa cell, colonic epithelium, calcaneal tendon
SOAT1	266	ubiquitous	marker	adrenal tissue, right adrenal gland cortex, right adrenal gland
AASDHPPT	297	ubiquitous	marker	cortical plate, sperm, choroid plexus epithelium
C11orf65	163	ubiquitous	marker	sperm, left testis, right testis
MSH2	278	ubiquitous	marker	secondary oocyte, oocyte, ventricular zone
NPAT	279	ubiquitous	marker	secondary oocyte, calcaneal tendon, male germ line stem cell (sensu Vertebrata) in testis
ACAT1	294	ubiquitous	marker	nephron tubule, skeletal muscle tissue of rectus abdominis, renal medulla

Protein interactions among cohort

Intra-cohort edges: 4.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
BRAF	7,394
ATM	7,383
MSH2	4,537
ACAT1	2,836
SOAT1	2,327
NPAT	2,123
AASDHPPT	1,734
C11orf65	312

Intra-cohort edges

A	B	Sources
ACAT1	NPAT	string_interaction
ATM	MSH2	string_interaction
ATM	NPAT	string_interaction
C11orf65	NPAT	string_interaction

Structural data

PDB: 6 · AlphaFold-only: 2 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
BRAF	P15056	131
MSH2	P43246	30
ATM	Q13315	14
ACAT1	P24752	7
SOAT1	P35610	5
AASDHPPT	Q9NRN7	3

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
C11orf65	Q8NCR3	74.69
NPAT	Q14207	44.62

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 128. Enrichment computed across 8 evidence-associated genes (6 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 6 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Diseases of DNA repair	2	190.3×	0.006	ATM, MSH2
Beta-ketothiolase deficiency	1	1903.3×	0.017	ACAT1
TP53 Regulates Transcription of DNA Repair Genes	2	60.4×	0.017	ATM, MSH2
Disease	4	8.7×	0.017	ATM, BRAF, MSH2, ACAT1
Defective Mismatch Repair Associated With MSH3	1	951.7×	0.022	MSH2
Defective Mismatch Repair Associated With MSH6	1	951.7×	0.022	MSH2
Defective Mismatch Repair Associated With MSH2	1	634.4×	0.022	MSH2
Mismatch Repair	1	475.8×	0.022	MSH2
Diseases of Mismatch Repair (MMR)	1	475.8×	0.022	MSH2
Utilization of Ketone Bodies	1	475.8×	0.022	ACAT1
Signaling by MRAS-complex mutants	1	475.8×	0.022	BRAF
DNA Repair	2	32.8×	0.022	ATM, MSH2
Signalling to p38 via RIT and RIN	1	380.7×	0.023	BRAF
Negative feedback regulation of MAPK pathway	1	317.2×	0.023	BRAF
Sensing of DNA Double Strand Breaks	1	317.2×	0.023	ATM
Ketone body metabolism	1	317.2×	0.023	ACAT1
Diseases of branched-chain amino acid catabolism	1	317.2×	0.023	ACAT1
ARMS-mediated activation	1	271.9×	0.023	BRAF
Prolonged ERK activation events	1	237.9×	0.023	BRAF
Synthesis of Ketone Bodies	1	237.9×	0.023	ACAT1
SHOC2 M1731 mutant abolishes MRAS complex function	1	237.9×	0.023	BRAF
Gain-of-function MRAS complexes activate RAF signaling	1	237.9×	0.023	BRAF
Transcriptional Regulation by TP53	2	20.7×	0.023	ATM, MSH2
Signaling by FGFR3	1	190.3×	0.027	BRAF
Signaling by FGFR4	1	173.0×	0.027	BRAF
Frs2-mediated activation	1	158.6×	0.027	BRAF
TP53 Regulates Transcription of Caspase Activators and Caspases	1	158.6×	0.027	ATM
Pexophagy	1	158.6×	0.027	ATM
Defective homologous recombination repair (HRR) due to PALB2 loss of function	1	158.6×	0.027	ATM
Mismatch repair (MMR) directed by MSH2:MSH6 (MutSalpha)	1	135.9×	0.027	MSH2

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 8 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
somatic recombination of immunoglobulin genes involved in immune response	1	2106.5×	0.012	MSH2
metanephric proximal convoluted tubule development	1	2106.5×	0.012	ACAT1
propionyl-CoA biosynthetic process	1	2106.5×	0.012	ACAT1
obsolete L-lysine biosynthetic process via aminoadipic acid	1	1053.2×	0.012	AASDHPPT
establishment of RNA localization to telomere	1	1053.2×	0.012	ATM
establishment of protein-containing complex localization to telomere	1	1053.2×	0.012	ATM
positive regulation of telomerase catalytic core complex assembly	1	1053.2×	0.012	ATM
pre-B cell allelic exclusion	1	702.2×	0.012	ATM
10-formyltetrahydrofolate catabolic process	1	702.2×	0.012	AASDHPPT
CD4-positive or CD8-positive, alpha-beta T cell lineage commitment	1	702.2×	0.012	BRAF
cellular response to nitrosative stress	1	702.2×	0.012	ATM
obsolete ketone body metabolic process	1	702.2×	0.012	ACAT1
somatic recombination of immunoglobulin gene segments	1	526.6×	0.012	MSH2
B cell mediated immunity	1	526.6×	0.012	MSH2
acetyl-CoA catabolic process	1	526.6×	0.012	ACAT1
ketone body catabolic process	1	526.6×	0.012	ACAT1
coenzyme A metabolic process	1	421.3×	0.012	ACAT1
peptidyl-serine autophosphorylation	1	421.3×	0.012	ATM
positive regulation of amyloid precursor protein biosynthetic process	1	421.3×	0.012	SOAT1
maintenance of DNA repeat elements	1	421.3×	0.012	MSH2
cell cycle G1/S phase transition	1	421.3×	0.012	NPAT
positive regulation of axon regeneration	1	421.3×	0.012	BRAF
negative regulation of mitochondrial fission	1	421.3×	0.012	C11orf65
negative regulation of telomere capping	1	421.3×	0.012	ATM
negative regulation of synaptic vesicle exocytosis	1	421.3×	0.012	BRAF
mitotic recombination	1	351.1×	0.012	MSH2
L-isoleucine catabolic process	1	351.1×	0.012	ACAT1
regulation of telomere maintenance via telomerase	1	351.1×	0.012	ATM
CD4-positive, alpha-beta T cell differentiation	1	351.1×	0.012	BRAF
positive regulation of isotype switching to IgA isotypes	1	351.1×	0.012	MSH2

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): Niacinamide, Trenonacog Alfa, Triheptanoin.

Drug target analysis

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

Druggability breadth: 6 of 8 evidence-associated genes (75%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Genes with an approved drug

The molecule shown is one approved compound that hits the gene — not necessarily a drug of choice or one indicated for this disease.

Symbol	Example approved molecule
ATM	AMIODARONE HYDROCHLORIDE
BRAF	VEMURAFENIB
SOAT1	PROGESTERONE
ACAT1	MITOTANE

Top cohort targets by molecule count

Symbol	Molecules	Max phase
BRAF	48	4
ATM	35	4
SOAT1	6	4
ACAT1	5	4
AASDHPPT	0	0
C11orf65	0	0
MSH2	0	0
NPAT	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
AMIODARONE HYDROCHLORIDE	4	ATM
FURAZOLIDONE	4	ATM
ESTRADIOL ACETATE	4	ATM
NAFTIFINE HYDROCHLORIDE	4	ATM
METHYSERGIDE MALEATE	4	ATM
AMITRIPTYLINE HYDROCHLORIDE	4	ATM
XYLOMETAZOLINE HYDROCHLORIDE	4	ATM
FLUVOXAMINE MALEATE	4	ATM
ESTRADIOL VALERATE	4	ATM
PERMETHRIN	4	ATM
MITOTANE	4	ACAT1, ATM
TICLOPIDINE HYDROCHLORIDE	4	ATM
ENOXIMONE	4	ATM
METHYLENE BLUE ANHYDROUS	4	ATM
DITHIAZANINE IODIDE	4	ATM
ETHACRYNIC ACID	4	ATM
SECNIDAZOLE	4	ATM
MENADIONE	4	ATM
FENOFIBRATE	4	ATM
DIPYRIDAMOLE	4	ATM
VEMURAFENIB	4	BRAF
PONATINIB	4	BRAF
FEDRATINIB	4	BRAF
SORAFENIB	4	BRAF
DASATINIB ANHYDROUS	4	BRAF
RUXOLITINIB	4	BRAF
INFIGRATINIB PHOSPHATE	4	BRAF
INFIGRATINIB	4	BRAF
REGORAFENIB	4	BRAF
DABRAFENIB	4	BRAF

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 4.

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

Symbol	Assays	Type breakdown
BRAF	1,442	Binding:1400, Functional:37, ADMET:5
ATM	240	Binding:233, Functional:5, ADMET:2
SOAT1	136	Binding:127, Functional:8, ADMET:1
ACAT1	12	Binding:12
MSH2	9	Binding:9
AASDHPPT	2	Binding:2

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
ATM	2.7.11.1	non-specific serine/threonine protein kinase
BRAF	2.7.10.2, 2.7.11.1	non-specific protein-tyrosine kinase, non-specific serine/threonine protein kinase
SOAT1	2.3.1.26	sterol O-acyltransferase
AASDHPPT	2.7.8.7	holo-[acyl-carrier-protein] synthase

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
ATM	240
BRAF	1,442
SOAT1	136

Pharmacogenomics

Cohort genes with a PharmGKB record: 8; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

29 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)
AMIODARONE HYDROCHLORIDE	4	ATM
FURAZOLIDONE	4	ATM
ESTRADIOL ACETATE	4	ATM
NAFTIFINE HYDROCHLORIDE	4	ATM
METHYSERGIDE MALEATE	4	ATM
AMITRIPTYLINE HYDROCHLORIDE	4	ATM
XYLOMETAZOLINE HYDROCHLORIDE	4	ATM
FLUVOXAMINE MALEATE	4	ATM
PERMETHRIN	4	ATM
MITOTANE	4	ACAT1, ATM
TICLOPIDINE HYDROCHLORIDE	4	ATM
ENOXIMONE	4	ATM
METHYLENE BLUE ANHYDROUS	4	ATM
DITHIAZANINE IODIDE	4	ATM
ETHACRYNIC ACID	4	ATM
SECNIDAZOLE	4	ATM
MENADIONE	4	ATM
FENOFIBRATE	4	ATM
DIPYRIDAMOLE	4	ATM
VEMURAFENIB	4	BRAF
PONATINIB	4	BRAF
FEDRATINIB	4	BRAF
SORAFENIB	4	BRAF
DASATINIB ANHYDROUS	4	BRAF
RUXOLITINIB	4	BRAF
INFIGRATINIB PHOSPHATE	4	BRAF
INFIGRATINIB	4	BRAF
REGORAFENIB	4	BRAF
DABRAFENIB	4	BRAF

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	4	ATM, BRAF, SOAT1, ACAT1
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	1	AASDHPPT
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	3	C11orf65, MSH2, NPAT

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)
NPAT	0	ACAT1
AASDHPPT	2	—
C11orf65	0	—
MSH2	9	—

Clinical trials & evidence

Clinical trials

Clinical trials: 33.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	18
PHASE3	5
PHASE2	5
PHASE4	2
PHASE1/PHASE2	1
EARLY_PHASE1	1
PHASE1	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT01052623	PHASE4	UNKNOWN	Status of Growth Hormone/ Insulin-like Growth Factor-1 (GH/IGF-1) Axis and Growth Failure in Ataxia Telangiectasia (AT)
NCT02733679	PHASE4	COMPLETED	Response of Individuals With Ataxia-Telangiectasia to Metformin and Pioglitazone
NCT06673056	PHASE3	ACTIVE_NOT_RECRUITING	A Pivotal Study of N-Acetyl-L-Leucine on Ataxia-Telangiectasia (A-T)
NCT00656409	PHASE3	COMPLETED	Conjugate Pneumococcal Vaccine in Ataxia Telangiectasia (AT)
NCT03563053	PHASE3	TERMINATED	Extension Treatment Using EryDex System in Patients With AT Who Participated in the ATTeST-IEDAT-02-2015 Study
NCT06193200	PHASE3	COMPLETED	Evaluate the Neurological Effects of EryDex on Subjects With A-T
NCT06664853	PHASE3	TERMINATED	Open-Label Extension of EryDex Study IEDAT-04-2022
NCT04870866	PHASE2	ACTIVE_NOT_RECRUITING	NAD Supplementation to Prevent Progressive Neurological Disease in Ataxia Telangiectasia
NCT07215416	PHASE1/PHASE2	RECRUITING	Safety and Efficacy of Mutation-targeted Precision Genetic Therapy for Ataxia-Telangiectasia (A-T)
NCT03759678	PHASE2	TERMINATED	N-Acetyl-L-Leucine for Ataxia-Telangiectasia (A-T)
NCT03962114	PHASE2	COMPLETED	Effects of Vitamin B3 in Patients With Ataxia Telangiectasia
NCT04513002	PHASE2	COMPLETED	Ataxia-telangiectasia: Treating Mitochondrial Dysfunction With a Novel Form of Anaplerosis
NCT04887311	PHASE2	UNKNOWN	MBM-01 (Tempol) for the Treatment of Ataxia Telangiectasia
NCT05531890	PHASE1	UNKNOWN	Comparative Bioavailability of Betamethasone Oral Solution Metered Spray (GTX-102) in Healthy Subjects
NCT00640003	EARLY_PHASE1	COMPLETED	Baclofen Treatment of Ataxia Telangiectasia
NCT01793168	Not specified	RECRUITING	Rare Disease Patient Registry & Natural History Study - Coordination of Rare Diseases at Sanford
NCT05692596	Not specified	ACTIVE_NOT_RECRUITING	The Pancreas Interception Center (PIC) for Early Detection, Prevention, and Novel Therapeutics
NCT00187057	Not specified	COMPLETED	Study for Treatment of Cancer in Children With Ataxia-telangiectasia
NCT00951886	Not specified	UNKNOWN	The Validity of Forced Expiratory Maneuvers in Ataxia Telangiectasia Studied Longitudinally
NCT01075438	Not specified	UNKNOWN	Immunogenicity of Pneumococcal Vaccines in Ataxia-telangiectasia Patients
NCT01942850	Not specified	COMPLETED	International Ataxia Rating Scale in Younger Patients
NCT02285348	Not specified	COMPLETED	Oxidative Stress, Low Grade Inflammation, Tissue Breakdown and Biomarkers in Cerebrospinal Fluid of A-T
NCT02309632	Not specified	WITHDRAWN	Pancreatic Cancer Screening of High-Risk Individuals in Arkansas
NCT02345135	Not specified	COMPLETED	Susceptibility to Infections in Ataxia Telangiectasia
NCT02345200	Not specified	COMPLETED	Body Composition and Hormonal Status in Ataxia Telangiectasia
NCT03357978	Not specified	UNKNOWN	Susceptibility to Infections, Tumor Risk and Liver Disease in Patients With Ataxia Telangiectasia
NCT04037189	Not specified	UNKNOWN	Treatment of Leukemia and Lymphoma in Children With Ataxia Telangiectasia
NCT04605523	Not specified	UNKNOWN	Neurofilament Light- Chain in Ataxia Telangiectasia
NCT04991701	Not specified	UNKNOWN	A National Retrospective Population Based Cohort Study of the Natural History of Ataxia Telangiectasia
NCT05252819	Not specified	COMPLETED	Whole Body MRI for Cancer Surveillance in A-T
NCT05471310	Not specified	COMPLETED	Videoocular Assessment of Eye Movement Activity in an Ataxia Telangiectasia
NCT05692622	Not specified	UNKNOWN	Home-based Complex Intervention for Children With Ataxia Telangiectasia
NCT06324877	Not specified	UNKNOWN	Ataxia-telangiectasia: Treating Mitochondrial Dysfunction With Nicotinamide Riboside

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
CLONIDINE	4	2
DEXAMETHASONE SODIUM PHOSPHATE	4	2
LEVACETYLLEUCINE	4	2
BACLOFEN	4	1
ESTRADIOL VALERATE	4	1
NIACIN	4	1
NIACINAMIDE	4	1
PIOGLITAZONE	4	1
PROCARBAZINE	4	1
SOMATROPIN	4	1
TRIHEPTANOIN	4	1
VINBLASTINE	4	1
NICOTINAMIDE RIBOSIDE	3	2
TRENONACOG ALFA	3	1
CHEMBL1200637	0	2
CHEMBL4743806	0	2
CHEMBL4788494	0	1