Mandibular hypoplasia-deafness-progeroid syndrome

Summary

Mandibular hypoplasia-deafness-progeroid syndrome (MONDO:0014157) is a disease caused by POLD1 (GenCC Definitive), with 1 cohort gene.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: POLD1 (GenCC Definitive)
• Cohort genes: 1
• ClinVar variants: 182

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		21	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Identifiers

Disease identifiers

Field	Value
Canonical name	mandibular hypoplasia-deafness-progeroid syndrome
Mondo ID	MONDO:0014157
OMIM	615381
Orphanet	363649
UMLS	C3715192
MedGen	811623
GARD	0010989
Is cancer (heuristic)	no

Also known as: mandibular hypoplasia, deafness, progeroid features · mandibular hypoplasia, deafness, progeroid features, and lipodystrophy syndrome · mandibular hypoplasia-hearing loss-progeroid syndrome · MDP syndrome · MDPL

Data availability: 182 ClinVar variants · 7 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › progeroid syndrome › mandibular hypoplasia-deafness-progeroid syndrome

Related subtypes (15): Hutchinson-Gilford progeria syndrome, Wiedemann-Rautenstrauch syndrome, Werner syndrome, progeroid facial appearance with hand anomalies, XFE progeroid syndrome, Fontaine progeroid syndrome, Nestor-Guillermo progeria syndrome, progeroid and marfanoid aspect-lipodystrophy syndrome, Cockayne syndrome, mandibuloacral dysplasia progeroid syndrome, achalasia-progeroid syndrome, Fischer-Zirnsak progeroid syndrome, Marbach-Rustad progeroid syndrome, RECON progeroid syndrome, Garg-Mishra progeroid 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

182 retrieved; paginated sample, class counts are floors:

70 uncertain significance, 68 conflicting classifications of pathogenicity, 23 benign/likely benign, 11 likely benign, 9 benign, 1 pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
60775	NM_002691.4(POLD1):c.1809CTC[1] (p.Ser605del)	POLD1	Pathogenic	criteria provided, multiple submitters, no conflicts
1301641	NM_002691.4(POLD1):c.3199G>A (p.Glu1067Lys)	POLD1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1981775	NM_002691.4(POLD1):c.3304C>T (p.Pro1102Ser)	POLD1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
220938	NM_002691.4(POLD1):c.2017G>A (p.Glu673Lys)	POLD1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
221136	NM_002691.4(POLD1):c.961G>A (p.Gly321Ser)	POLD1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
221152	NM_002691.4(POLD1):c.778A>G (p.Ile260Val)	POLD1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
221166	NM_002691.4(POLD1):c.773C>T (p.Thr258Met)	POLD1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
225288	NM_002691.4(POLD1):c.208G>T (p.Val70Phe)	POLD1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
239224	NM_002691.4(POLD1):c.1157G>A (p.Arg386His)	POLD1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
239228	NM_002691.4(POLD1):c.1295G>A (p.Arg432Gln)	POLD1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
239230	NM_002691.4(POLD1):c.1322C>T (p.Thr441Met)	POLD1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
239244	NM_002691.4(POLD1):c.1562G>A (p.Arg521Gln)	POLD1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
239267	NM_002691.4(POLD1):c.203G>A (p.Gly68Glu)	POLD1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
239283	NM_002691.4(POLD1):c.2317G>A (p.Ala773Thr)	POLD1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
239285	NM_002691.4(POLD1):c.2327G>A (p.Arg776Gln)	POLD1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
239286	NM_002691.4(POLD1):c.232C>T (p.Arg78Cys)	POLD1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
239299	NM_002691.4(POLD1):c.2560G>A (p.Asp854Asn)	POLD1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
239314	NM_002691.4(POLD1):c.2861C>G (p.Thr954Arg)	POLD1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
239334	NM_002691.4(POLD1):c.3218+5G>A	POLD1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
239345	NM_002691.4(POLD1):c.353C>T (p.Ser118Phe)	POLD1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
239350	NM_002691.4(POLD1):c.497G>A (p.Arg166Gln)	POLD1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
239357	NM_002691.4(POLD1):c.583C>T (p.Arg195Ter)	POLD1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
239370	NM_002691.4(POLD1):c.820G>A (p.Ala274Thr)	POLD1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
246444	NM_002691.4(POLD1):c.713C>T (p.Thr238Met)	POLD1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
246453	NM_002691.4(POLD1):c.2360C>T (p.Pro787Leu)	POLD1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
246491	NM_002691.4(POLD1):c.2677G>A (p.Asp893Asn)	POLD1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
389988	NM_002691.4(POLD1):c.273A>G (p.Thr91=)	POLD1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
391420	NM_002691.4(POLD1):c.2772C>T (p.Tyr924=)	POLD1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
407957	NM_002691.4(POLD1):c.1294C>G (p.Arg432Gly)	POLD1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
407959	NM_002691.4(POLD1):c.233G>A (p.Arg78His)	POLD1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 15 · 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
POLD1	Definitive	Autosomal dominant	mandibular hypoplasia-deafness-progeroid syndrome	15

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
POLD1	Orphanet:363649	Mandibular hypoplasia-deafness-progeroid features-lipodystrophy syndrome
POLD1	Orphanet:440437	Familial colorectal cancer Type X
POLD1	Orphanet:447877	Polymerase proofreading-related polyposis

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
POLD1	HGNC:9175	ENSG00000062822	P28340	DNA polymerase delta catalytic subunit	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
POLD1	DNA polymerase delta catalytic subunit	As the catalytic component of the trimeric (Pol-delta3 complex) and tetrameric DNA polymerase delta complexes (Pol-delta4 complex), plays a crucial role in high fidelity genome replication, including in lagging strand synthesis, and repair.

Protein-family classification

Druggable: 0 · Difficult: 1 · Unknown: 0 · 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
Transcription factor	1	8.3×	0.121

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
POLD1	Transcription factor	no	2.7.7.7	DNA-dir_DNA_pol_B_exonuc, DNA-dir_DNA_pol_B_multi_dom, DNA-dir_DNA_pol_B

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
mucosa of transverse colon	1
primordial germ cell in gonad	1
ventricular zone	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
POLD1	134	ubiquitous	marker	mucosa of transverse colon, ventricular zone, primordial germ cell in gonad

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
POLD1	4,000

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
POLD1	P28340	6

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 18. 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	POLD1
Mismatch repair (MMR) directed by MSH2:MSH6 (MutSalpha)	1	815.7×	0.003	POLD1
Mismatch repair (MMR) directed by MSH2:MSH3 (MutSbeta)	1	815.7×	0.003	POLD1
Polymerase switching	1	815.7×	0.003	POLD1
Removal of the Flap Intermediate	1	815.7×	0.003	POLD1
Processive synthesis on the C-strand of the telomere	1	761.3×	0.003	POLD1
Telomere C-strand (Lagging Strand) Synthesis	1	761.3×	0.003	POLD1
Cytosolic iron-sulfur cluster assembly	1	761.3×	0.003	POLD1
Removal of the Flap Intermediate from the C-strand	1	634.4×	0.003	POLD1
PCNA-Dependent Long Patch Base Excision Repair	1	519.1×	0.003	POLD1
Gap-filling DNA repair synthesis and ligation in GG-NER	1	439.2×	0.004	POLD1
Polymerase switching on the C-strand of the telomere	1	423.0×	0.004	POLD1
Recognition of DNA damage by PCNA-containing replication complex	1	380.7×	0.004	POLD1
Termination of translesion DNA synthesis	1	346.1×	0.004	POLD1
Dual Incision in GG-NER	1	259.6×	0.005	POLD1
HDR through Homologous Recombination (HRR)	1	190.3×	0.006	POLD1
Gap-filling DNA repair synthesis and ligation in TC-NER	1	178.4×	0.006	POLD1
Dual incision in TC-NER	1	173.0×	0.006	POLD1

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
DNA replication proofreading	1	5617.3×	0.001	POLD1
error-free translesion synthesis	1	3370.4×	0.001	POLD1
nucleotide-excision repair, DNA gap filling	1	2808.7×	0.001	POLD1
base-excision repair, gap-filling	1	1123.5×	0.002	POLD1
DNA synthesis involved in DNA repair	1	936.2×	0.002	POLD1
fatty acid homeostasis	1	936.2×	0.002	POLD1
DNA biosynthetic process	1	802.5×	0.002	POLD1
DNA-templated DNA replication	1	561.7×	0.003	POLD1
response to UV	1	366.4×	0.004	POLD1
cellular response to UV	1	295.6×	0.004	POLD1
DNA replication	1	165.2×	0.007	POLD1
DNA repair	1	63.8×	0.016	POLD1

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
POLD1	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
POLD1	8	Binding:8

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
POLD1	2.7.7.7	DNA-directed DNA polymerase

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	POLD1

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)
POLD1	8	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.