Paternal uniparental disomy of chromosome 14

Summary

Paternal uniparental disomy of chromosome 14 (MONDO:0011975) is a disease with 3 cohort genes.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Cohort genes: 3
• ClinVar variants: 5
• Phenotypes (HPO): 120

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		37	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

120 HPO clinical features (Orphanet curated; top 50 by frequency):

HPO ID	Term	Frequency
HP:0006665	Coat hanger sign of ribs	Obligate (100%)
HP:0001263	Global developmental delay	Very frequent (80-99%)
HP:0001561	Polyhydramnios	Very frequent (80-99%)
HP:0001999	Abnormal facial shape	Very frequent (80-99%)
HP:0006267	Large placenta	Very frequent (80-99%)
HP:0011968	Feeding difficulties	Very frequent (80-99%)
HP:0000158	Macroglossia	Frequent (30-79%)
HP:0000278	Retrognathia	Frequent (30-79%)
HP:0000470	Short neck	Frequent (30-79%)
HP:0000767	Pectus excavatum	Frequent (30-79%)
HP:0000924	Abnormality of the skeletal system	Frequent (30-79%)
HP:0001371	Flexion contracture	Frequent (30-79%)
HP:0001510	Growth delay	Frequent (30-79%)
HP:0001540	Diastasis recti	Frequent (30-79%)
HP:0001622	Premature birth	Frequent (30-79%)
HP:0002002	Deep philtrum	Frequent (30-79%)
HP:0002751	Kyphoscoliosis	Frequent (30-79%)
HP:0002866	Hypoplastic iliac wing	Frequent (30-79%)
HP:0002878	Respiratory failure	Frequent (30-79%)
HP:0005257	Thoracic hypoplasia	Frequent (30-79%)
HP:0005268	Spontaneous abortion	Frequent (30-79%)
HP:0005280	Depressed nasal bridge	Frequent (30-79%)
HP:0008551	Microtia	Frequent (30-79%)
HP:0008897	Postnatal growth retardation	Frequent (30-79%)
HP:0009826	Limb undergrowth	Frequent (30-79%)
HP:0011335	Frontal hirsutism	Frequent (30-79%)
HP:0011823	Chin with horizontal crease	Frequent (30-79%)
HP:0012745	Short palpebral fissure	Frequent (30-79%)
HP:0000028	Cryptorchidism	Occasional (5-29%)
HP:0000160	Narrow mouth	Occasional (5-29%)
HP:0000252	Microcephaly	Occasional (5-29%)
HP:0000260	Wide anterior fontanel	Occasional (5-29%)
HP:0000286	Epicanthus	Occasional (5-29%)
HP:0000303	Mandibular prognathia	Occasional (5-29%)
HP:0000322	Short philtrum	Occasional (5-29%)
HP:0000327	Hypoplasia of the maxilla	Occasional (5-29%)
HP:0000343	Long philtrum	Occasional (5-29%)
HP:0000347	Micrognathia	Occasional (5-29%)
HP:0000358	Posteriorly rotated ears	Occasional (5-29%)
HP:0000431	Wide nasal bridge	Occasional (5-29%)
HP:0000445	Wide nose	Occasional (5-29%)
HP:0000463	Anteverted nares	Occasional (5-29%)
HP:0000490	Deeply set eye	Occasional (5-29%)
HP:0000581	Blepharophimosis	Occasional (5-29%)
HP:0000773	Short ribs	Occasional (5-29%)
HP:0000774	Narrow chest	Occasional (5-29%)
HP:0000882	Hypoplastic scapulae	Occasional (5-29%)
HP:0000884	Prominent sternum	Occasional (5-29%)
HP:0000890	Long clavicles	Occasional (5-29%)
HP:0000907	Anterior rib cupping	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	paternal uniparental disomy of chromosome 14
Mondo ID	MONDO:0011975
MeSH	C536471
OMIM	608149
Orphanet	96334
ICD-11	1835121942
UMLS	C5680251
MedGen	1843450
GARD	0005409
Is cancer (heuristic)	no

Also known as: paternal uniparental disomy 14 · paternal uniparental disomy of chromosome 14 · paternal uniparental disomy of chromosome type 14 · UPD(14)pat

Data availability: 5 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 › multiple congenital anomalies due to 14q32.2 maternally expressed gene defect › paternal uniparental disomy of chromosome 14

Related subtypes (2): maternal 14q32.2 microdeletion syndrome, maternal 14q32.2 hypermethylation 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

5 retrieved; paginated sample, class counts are floors:

5 pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
162012	NC_000014.9:g.100804359_100812916del		Pathogenic	no assertion criteria provided
162009	NC_000014.9:g.100489287_100900640del411354	BEGAIN	Pathogenic	no assertion criteria provided
162007	NC_000014.9:g.100720531_100829298del108768	DLK1	Pathogenic	no assertion criteria provided
162011	NC_000014.9:g.100806482_101281031del474550	LOC132090209	Pathogenic	no assertion criteria provided
162014	NC_000014.9:g.100824888_100829190delins100833642_100833702	MEG3	Pathogenic	no assertion criteria provided

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 0 · Orphanet: 14 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
MEG3	Orphanet:254525	Temple syndrome due to paternal 14q32.2 microdeletion
MEG3	Orphanet:254528	Kagami-Ogata syndrome due to maternal 14q32.2 microdeletion
MEG3	Orphanet:254531	Temple syndrome due to paternal 14q32.2 hypomethylation
MEG3	Orphanet:254534	Kagami-Ogata syndrome due to maternal 14q32.2 hypermethylation
MEG3	Orphanet:96184	Temple syndrome due to maternal uniparental disomy of chromosome 14
MEG3	Orphanet:96334	Kagami-Ogata syndrome due to paternal uniparental disomy of chromosome 14
DLK1	Orphanet:254525	Temple syndrome due to paternal 14q32.2 microdeletion
DLK1	Orphanet:254528	Kagami-Ogata syndrome due to maternal 14q32.2 microdeletion
DLK1	Orphanet:254531	Temple syndrome due to paternal 14q32.2 hypomethylation
DLK1	Orphanet:254534	Kagami-Ogata syndrome due to maternal 14q32.2 hypermethylation
DLK1	Orphanet:650077	Genetic central precocious puberty in female
DLK1	Orphanet:650097	Genetic central precocious puberty in male
DLK1	Orphanet:96184	Temple syndrome due to maternal uniparental disomy of chromosome 14
DLK1	Orphanet:96334	Kagami-Ogata syndrome due to paternal uniparental disomy of chromosome 14

Cohort genes → proteins

3 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	3

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
MEG3	HGNC:14575	ENSG00000214548		maternally expressed 3	clinvar
BEGAIN	HGNC:24163	ENSG00000183092	Q9BUH8	Brain-enriched guanylate kinase-associated protein	clinvar
DLK1	HGNC:2907	ENSG00000185559	P80370	Protein delta homolog 1	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
BEGAIN	Brain-enriched guanylate kinase-associated protein	May sustain the structure of the postsynaptic density (PSD).
DLK1	Protein delta homolog 1	May have a role in neuroendocrine differentiation.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 3 · 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	3	1.8×	0.174

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
MEG3	Other/Unknown	no
BEGAIN	Other/Unknown	no		Tjap1/BEGAIN
DLK1	Other/Unknown	no		EGF-type_Asp/Asn_hydroxyl_site, EGF, EGF-like_Ca-bd_dom

Expression context

Cohort genes with no expression data: 0.

3 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)	3
unknown	0

Top tissues across cohort

Tissue	Cohort genes
cerebellar hemisphere	2
right hemisphere of cerebellum	2
adenohypophysis	1
cerebellar cortex	1
adrenal cortex	1
right adrenal gland	1
right adrenal gland cortex	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
MEG3	265	ubiquitous	marker	adenohypophysis, right hemisphere of cerebellum, cerebellar hemisphere
BEGAIN	181	broad	marker	right hemisphere of cerebellum, cerebellar hemisphere, cerebellar cortex
DLK1	199	broad	marker	right adrenal gland cortex, right adrenal gland, adrenal cortex

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
BEGAIN	1,615
DLK1	186
MEG3	0

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
DLK1	P80370	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
BEGAIN	Q9BUH8	57.19

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 4. Enrichment computed across 3 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
Activated NOTCH1 Transmits Signal to the Nucleus	1	178.4×	0.014	DLK1
Protein-protein interactions at synapses	1	132.8×	0.014	BEGAIN
Neurexins and neuroligins	1	98.5×	0.014	BEGAIN
Neuronal System	1	22.1×	0.045	BEGAIN

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
evoked excitatory postsynaptic potential	1	8426.0×	9e-04	BEGAIN
regulation of bone remodeling	1	1404.3×	0.003	DLK1
positive regulation of bone resorption	1	495.6×	0.005	DLK1
negative regulation of ossification	1	312.1×	0.006	DLK1
positive regulation of osteoclast differentiation	1	290.6×	0.006	DLK1
negative regulation of Notch signaling pathway	1	216.1×	0.006	DLK1
negative regulation of osteoblast differentiation	1	147.8×	0.008	DLK1
cell differentiation	1	14.6×	0.068	DLK1

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 3 evidence-associated genes (33%) 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
DLK1	FEDRATINIB

Top cohort targets by molecule count

Symbol	Molecules	Max phase
DLK1	15	4
MEG3	0	0
BEGAIN	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
FEDRATINIB	4	DLK1
AXITINIB	4	DLK1
NERATINIB	4	DLK1
BOSUTINIB	4	DLK1
SUNITINIB	4	DLK1
CRIZOTINIB	4	DLK1
CEP-1347	3	DLK1
DOVITINIB	3	DLK1
LESTAURTINIB	3	DLK1
SU-014813	2	DLK1
TOZASERTIB	2	DLK1
PELITINIB	2	DLK1
KW-2449	1	DLK1
GDC-0134	1	DLK1
AST-487	1	DLK1

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
DLK1	51	Binding:51

Pharmacogenomics

Cohort genes with a PharmGKB record: 3; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

15 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)
FEDRATINIB	4	DLK1
AXITINIB	4	DLK1
NERATINIB	4	DLK1
BOSUTINIB	4	DLK1
SUNITINIB	4	DLK1
CRIZOTINIB	4	DLK1
CEP-1347	3	DLK1
DOVITINIB	3	DLK1
LESTAURTINIB	3	DLK1
SU-014813	2	DLK1
TOZASERTIB	2	DLK1
PELITINIB	2	DLK1
KW-2449	1	DLK1
GDC-0134	1	DLK1
AST-487	1	DLK1

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	DLK1
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	2	MEG3, BEGAIN

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)
MEG3	0	—
BEGAIN	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.