Distal tetrasomy 15q

Summary

Distal tetrasomy 15q (MONDO:0013918) is a disease with 2 cohort genes.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Cohort genes: 2
• ClinVar variants: 2
• Phenotypes (HPO): 45

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		23	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

45 HPO clinical features (Orphanet curated; top 45 by frequency):

HPO ID	Term	Frequency
HP:0000218	High palate	Very frequent (80-99%)
HP:0001263	Global developmental delay	Very frequent (80-99%)
HP:0001507	Growth abnormality	Very frequent (80-99%)
HP:0001999	Abnormal facial shape	Very frequent (80-99%)
HP:0000077	Abnormality of the kidney	Frequent (30-79%)
HP:0000126	Hydronephrosis	Frequent (30-79%)
HP:0000278	Retrognathia	Frequent (30-79%)
HP:0000316	Hypertelorism	Frequent (30-79%)
HP:0000347	Micrognathia	Frequent (30-79%)
HP:0000369	Low-set ears	Frequent (30-79%)
HP:0000506	Telecanthus	Frequent (30-79%)
HP:0000929	Abnormal skull morphology	Frequent (30-79%)
HP:0001252	Hypotonia	Frequent (30-79%)
HP:0001328	Specific learning disability	Frequent (30-79%)
HP:0001363	Craniosynostosis	Frequent (30-79%)
HP:0001520	Large for gestational age	Frequent (30-79%)
HP:0003517	Birth length greater than 97th percentile	Frequent (30-79%)
HP:0000034	Hydrocele testis	Occasional (5-29%)
HP:0000085	Horseshoe kidney	Occasional (5-29%)
HP:0000113	Polycystic kidney dysplasia	Occasional (5-29%)
HP:0000238	Hydrocephalus	Occasional (5-29%)
HP:0000378	Cupped ear	Occasional (5-29%)
HP:0000407	Sensorineural hearing impairment	Occasional (5-29%)
HP:0000486	Strabismus	Occasional (5-29%)
HP:0000766	Abnormal sternum morphology	Occasional (5-29%)
HP:0000811	Abnormal external genitalia	Occasional (5-29%)
HP:0001131	Corneal dystrophy	Occasional (5-29%)
HP:0001166	Arachnodactyly	Occasional (5-29%)
HP:0001305	Dandy-Walker malformation	Occasional (5-29%)
HP:0001371	Flexion contracture	Occasional (5-29%)
HP:0001511	Intrauterine growth retardation	Occasional (5-29%)
HP:0001627	Abnormal heart morphology	Occasional (5-29%)
HP:0001631	Atrial septal defect	Occasional (5-29%)
HP:0001643	Patent ductus arteriosus	Occasional (5-29%)
HP:0002089	Pulmonary hypoplasia	Occasional (5-29%)
HP:0002650	Scoliosis	Occasional (5-29%)
HP:0002667	Nephroblastoma	Occasional (5-29%)
HP:0002808	Kyphosis	Occasional (5-29%)
HP:0003396	Syringomyelia	Occasional (5-29%)
HP:0008551	Microtia	Occasional (5-29%)
HP:0010946	Dilatation of the renal pelvis	Occasional (5-29%)
HP:0011039	Abnormality of the helix	Occasional (5-29%)
HP:0012304	Hypoplastic aortic arch	Occasional (5-29%)
HP:0012385	Camptodactyly	Occasional (5-29%)
HP:0100790	Hernia	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	distal tetrasomy 15q
Mondo ID	MONDO:0013918
OMIM	614846
Orphanet	314588
UMLS	C3553858
MedGen	766772
GARD	0017424
Is cancer (heuristic)	no

Also known as: distal tetrasomy type 15q · tetrasomy 15(q25-qter) · tetrasomy 15q26 · tetrasomy type 15Q26

Data availability: 2 ClinVar variants.

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-intellectual disability › 15q overgrowth syndrome › distal tetrasomy 15q

Related subtypes (1): distal trisomy 15q

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 pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1703689	Single allele	APBA2	Pathogenic	no assertion criteria provided
1703688	GRCh37/hg19 9p22.1-q33.1(chr9:19356861-119513311)	ABCA1	Uncertain significance	no assertion criteria provided

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 0 · Orphanet: 2 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
ABCA1	Orphanet:31150	Tangier disease
ABCA1	Orphanet:425	Apolipoprotein A-I deficiency

Cohort genes → proteins

2 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
ABCA1	HGNC:29	ENSG00000165029	O95477	Phospholipid-transporting ATPase ABCA1	clinvar
APBA2	HGNC:579	ENSG00000034053	Q99767	Amyloid-beta A4 precursor protein-binding family A member 2	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
ABCA1	Phospholipid-transporting ATPase ABCA1	Catalyzes the translocation of specific phospholipids from the cytoplasmic to the extracellular/lumenal leaflet of membrane coupled to the hydrolysis of ATP.
APBA2	Amyloid-beta A4 precursor protein-binding family A member 2	Putative function in synaptic vesicle exocytosis by binding to STXBP1, an essential component of the synaptic vesicle exocytotic machinery.

Protein-family classification

Druggable: 1 · Difficult: 1 · Unknown: 0 · 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
Transporter	1	38.9×	0.051
Scaffold/PPI	1	8.6×	0.112

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
ABCA1	Transporter	yes		ABC_transporter-like_ATP-bd, AAA+_ATPase, ABC2_TM
APBA2	Scaffold/PPI	no		PDZ, PTB/PI_dom, PH-like_dom_sf

Expression context

Cohort genes with no expression data: 0.

2 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)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
adrenal tissue	1
left adrenal gland	1
skin of hip	1
cerebellum	1
right hemisphere of cerebellum	1
superior frontal gyrus	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
ABCA1	272	ubiquitous	marker	adrenal tissue, skin of hip, left adrenal gland
APBA2	131	ubiquitous	marker	superior frontal gyrus, right hemisphere of cerebellum, cerebellum

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
ABCA1	3,551
APBA2	2,193

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
ABCA1	O95477	7

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
APBA2	Q99767	59.74

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 19. Enrichment computed across 2 evidence-associated genes (2 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 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Defective ABCA1 causes TGD	1	2855.0×	0.007	ABCA1
HDL assembly	1	713.8×	0.013	ABCA1
Plasma lipoprotein assembly	1	356.9×	0.018	ABCA1
ABC transporter disorders	1	219.6×	0.019	ABCA1
NR1H2 and NR1H3-mediated signaling	1	196.9×	0.019	ABCA1
NR1H3 & NR1H2 regulate gene expression linked to cholesterol transport and efflux	1	154.3×	0.020	ABCA1
Protein-protein interactions at synapses	1	132.8×	0.020	APBA2
Plasma lipoprotein assembly, remodeling, and clearance	1	114.2×	0.021	ABCA1
Neurexins and neuroligins	1	98.5×	0.021	APBA2
Regulation of lipid metabolism by PPARalpha	1	70.5×	0.025	ABCA1
Disorders of transmembrane transporters	1	69.6×	0.025	ABCA1
Signaling by Nuclear Receptors	1	51.0×	0.031	ABCA1
PPARA activates gene expression	1	47.2×	0.031	ABCA1
Neuronal System	1	22.1×	0.061	APBA2
Metabolism of lipids	1	15.8×	0.079	ABCA1
Transport of small molecules	1	12.6×	0.093	ABCA1
Disease	1	6.5×	0.164	ABCA1
Metabolism	1	5.8×	0.174	ABCA1
Signal Transduction	1	5.1×	0.187	ABCA1

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
response to vitamin B3	1	4213.0×	0.003	ABCA1
regulation of high-density lipoprotein particle assembly	1	4213.0×	0.003	ABCA1
positive regulation of high-density lipoprotein particle assembly	1	4213.0×	0.003	ABCA1
signal release	1	2808.7×	0.003	ABCA1
peptide secretion	1	2106.5×	0.003	ABCA1
response to laminar fluid shear stress	1	2106.5×	0.003	ABCA1
lipoprotein biosynthetic process	1	1404.3×	0.004	ABCA1
high-density lipoprotein particle assembly	1	842.6×	0.005	ABCA1
export across plasma membrane	1	842.6×	0.005	ABCA1
negative regulation of cholesterol storage	1	766.0×	0.005	ABCA1
regulation of Cdc42 protein signal transduction	1	702.2×	0.005	ABCA1
negative regulation of macrophage derived foam cell differentiation	1	648.1×	0.005	ABCA1
intracellular cholesterol transport	1	648.1×	0.005	ABCA1
protein transmembrane transport	1	648.1×	0.005	ABCA1
phospholipid efflux	1	561.7×	0.005	ABCA1
phospholipid homeostasis	1	495.6×	0.005	ABCA1
reverse cholesterol transport	1	468.1×	0.005	ABCA1
cellular response to low-density lipoprotein particle stimulus	1	443.5×	0.005	ABCA1
cellular response to cholesterol	1	421.3×	0.005	ABCA1
phagocytosis, engulfment	1	337.0×	0.006	ABCA1
platelet dense granule organization	1	337.0×	0.006	ABCA1
positive regulation of cholesterol efflux	1	312.1×	0.006	ABCA1
phospholipid translocation	1	312.1×	0.006	ABCA1
cellular response to cytokine stimulus	1	271.8×	0.007	ABCA1
cholesterol efflux	1	263.3×	0.007	ABCA1
presynaptic modulation of chemical synaptic transmission	1	227.7×	0.007	APBA2
lysosome organization	1	153.2×	0.010	ABCA1
protein secretion	1	131.7×	0.012	ABCA1
endosomal transport	1	122.1×	0.012	ABCA1
cellular response to xenobiotic stimulus	1	120.4×	0.012	ABCA1

Therapeutics

Drug target analysis

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

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
ABCA1	0	0
APBA2	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
ABCA1	2	Binding:2

Pharmacogenomics

Cohort genes with a PharmGKB record: 2; 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	1	ABCA1
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	APBA2

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)
ABCA1	2	—
APBA2	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.