Ataxia-telangiectasia-like disorder 2

Summary

Ataxia-telangiectasia-like disorder 2 (MONDO:0014399) is a disease with 1 cohort gene.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Cohort genes: 1
• ClinVar variants: 2
• Phenotypes (HPO): 16

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		4	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

16 HPO clinical features (Orphanet curated; top 16 by frequency):

HPO ID	Term	Frequency
HP:0000365	Hearing impairment	Very frequent (80-99%)
HP:0000613	Photophobia	Very frequent (80-99%)
HP:0000992	Cutaneous photosensitivity	Very frequent (80-99%)
HP:0001263	Global developmental delay	Very frequent (80-99%)
HP:0002066	Gait ataxia	Very frequent (80-99%)
HP:0002180	Neurodegeneration	Very frequent (80-99%)
HP:0100585	Telangiectasia of the skin	Very frequent (80-99%)
HP:0001256	Intellectual disability, mild	Frequent (30-79%)
HP:0004322	Short stature	Frequent (30-79%)
HP:0007763	Retinal telangiectasia	Frequent (30-79%)
HP:0031087	Absent pubertal growth spurt	Frequent (30-79%)
HP:0000252	Microcephaly	Occasional (5-29%)
HP:0000776	Congenital diaphragmatic hernia	Occasional (5-29%)
HP:0001272	Cerebellar atrophy	Occasional (5-29%)
HP:0002664	Neoplasm	Occasional (5-29%)
HP:0010864	Intellectual disability, severe	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	ataxia-telangiectasia-like disorder 2
Mondo ID	MONDO:0014399
OMIM	615919
Orphanet	438134
DOID	DOID:0081385
UMLS	C4014676
MedGen	863113
GARD	0017736
Is cancer (heuristic)	no

Also known as: ataxia-telangiectasia-like disorder 2 · ataxia-telangiectasia-like disorder type 2 · ATLD2

Data availability: 2 ClinVar variants · 3 GenCC gene-disease records.

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 2

Related subtypes (2): ataxia, early-onset, with oculomotor apraxia and hypoalbuminemia, ataxia-telangiectasia-like disorder 1

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

2 retrieved; paginated sample, class counts are floors:

1 uncertain significance, 1 likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
803596	NM_182649.2(PCNA):c.443G>C (p.Cys148Ser)	PCNA	Likely pathogenic	criteria provided, multiple submitters, no conflicts
143043	NM_182649.2(PCNA):c.683G>T (p.Ser228Ile)	PCNA	Uncertain significance	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 4 · Orphanet: 1 · 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
PCNA	Supportive	Autosomal recessive	ataxia-telangiectasia-like disorder 2	4

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
PCNA	Orphanet:438134	PCNA-related progressive neurodegenerative photosensitivity syndrome

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
PCNA	HGNC:8729	ENSG00000132646	P12004	DNA sliding clamp PCNA	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
PCNA	DNA sliding clamp PCNA	Confers DNA tethering and processivity to DNA polymerases and other proteins.

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)
PCNA	Other/Unknown	no		Pr_cel_nuc_antig, Pr_cel_nuc_antig_N, Pr_cel_nuc_antig_C

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
ganglionic eminence	1
oocyte	1
secondary oocyte	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
PCNA	287	ubiquitous	marker	oocyte, secondary oocyte, ganglionic eminence

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
PCNA	6,079

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
PCNA	P12004	102

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 26. 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
Processive synthesis on the lagging strand	1	1142.0×	0.003	PCNA
Mismatch repair (MMR) directed by MSH2:MSH6 (MutSalpha)	1	815.7×	0.003	PCNA
Mismatch repair (MMR) directed by MSH2:MSH3 (MutSbeta)	1	815.7×	0.003	PCNA
Polymerase switching	1	815.7×	0.003	PCNA
Removal of the Flap Intermediate	1	815.7×	0.003	PCNA
Processive synthesis on the C-strand of the telomere	1	761.3×	0.003	PCNA
Telomere C-strand (Lagging Strand) Synthesis	1	761.3×	0.003	PCNA
Translesion synthesis by REV1	1	713.8×	0.003	PCNA
Translesion synthesis by POLI	1	671.8×	0.003	PCNA
Removal of the Flap Intermediate from the C-strand	1	634.4×	0.003	PCNA
Translesion synthesis by POLK	1	634.4×	0.003	PCNA
Translesion Synthesis by POLH	1	601.0×	0.003	PCNA
TP53 Regulates Transcription of Genes Involved in G2 Cell Cycle Arrest	1	601.0×	0.003	PCNA
Transcription of E2F targets under negative control by DREAM complex	1	543.8×	0.003	PCNA
PCNA-Dependent Long Patch Base Excision Repair	1	519.1×	0.003	PCNA
Gap-filling DNA repair synthesis and ligation in GG-NER	1	439.2×	0.004	PCNA
Polymerase switching on the C-strand of the telomere	1	423.0×	0.004	PCNA
Recognition of DNA damage by PCNA-containing replication complex	1	380.7×	0.004	PCNA
G1/S-Specific Transcription	1	356.9×	0.004	PCNA
Termination of translesion DNA synthesis	1	346.1×	0.004	PCNA
Dual Incision in GG-NER	1	259.6×	0.005	PCNA
SUMOylation of DNA replication proteins	1	248.3×	0.005	PCNA
E3 ubiquitin ligases ubiquitinate target proteins	1	193.6×	0.006	PCNA
HDR through Homologous Recombination (HRR)	1	190.3×	0.006	PCNA
Gap-filling DNA repair synthesis and ligation in TC-NER	1	178.4×	0.006	PCNA
Dual incision in TC-NER	1	173.0×	0.006	PCNA

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
mitotic telomere maintenance via semi-conservative replication	1	5617.3×	0.002	PCNA
leading strand elongation	1	4213.0×	0.002	PCNA
response to L-glutamate	1	1685.2×	0.003	PCNA
estrous cycle	1	1404.3×	0.003	PCNA
response to dexamethasone	1	1203.7×	0.003	PCNA
base-excision repair, gap-filling	1	1123.5×	0.003	PCNA
translesion synthesis	1	936.2×	0.003	PCNA
response to cadmium ion	1	732.7×	0.004	PCNA
mismatch repair	1	648.1×	0.004	PCNA
positive regulation of DNA replication	1	581.1×	0.004	PCNA
liver regeneration	1	510.7×	0.004	PCNA
replication fork processing	1	421.3×	0.004	PCNA
positive regulation of DNA repair	1	358.6×	0.005	PCNA
cellular response to UV	1	295.6×	0.005	PCNA
cellular response to xenobiotic stimulus	1	240.7×	0.006	PCNA
cellular response to hydrogen peroxide	1	234.1×	0.006	PCNA
response to estradiol	1	198.3×	0.006	PCNA
epithelial cell differentiation	1	175.5×	0.007	PCNA
chromatin organization	1	99.1×	0.011	PCNA
heart development	1	78.8×	0.013	PCNA
negative regulation of transcription by RNA polymerase II	1	17.7×	0.056	PCNA

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 1 evidence-associated genes (100%) 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
PCNA	LIOTHYRONINE

Top cohort targets by molecule count

Symbol	Molecules	Max phase
PCNA	5	4

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
LIOTHYRONINE	4	PCNA
TIRATRICOL	3	PCNA
MOLIBRESIB	2	PCNA
3,5-DIIODOTHYROPROPIONIC ACID	2	PCNA
THYROPROPIC ACID	2	PCNA

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
PCNA	21	Binding:21

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

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)
LIOTHYRONINE	4	PCNA
TIRATRICOL	3	PCNA
MOLIBRESIB	2	PCNA
3,5-DIIODOTHYROPROPIONIC ACID	2	PCNA
THYROPROPIC ACID	2	PCNA

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	PCNA
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	0

Undrugged target profiles

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

Clinical trials & evidence

Clinical trials

Clinical trials: 0.