Fontaine progeroid syndrome

Summary

Fontaine progeroid syndrome (MONDO:0012853) is a disease caused by variants in SLC25A24 and SLC25A4, with 2 cohort genes.

At a glance

• Causal genes: SLC25A24 (GenCC Definitive), SLC25A4 (GenCC Strong)
• Cohort genes: 2
• ClinVar variants: 13

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	Fontaine progeroid syndrome
Mondo ID	MONDO:0012853
MeSH	C537290
OMIM	233500, 612289
Orphanet	2095, 2963, 697101
DOID	DOID:0051067
SNOMED CT	205800003
UMLS	C2676780
MedGen	394125
GARD	0004497
NORD	1201
Is cancer (heuristic)	no

Also known as: craniofacial dysostosis, hypertrichosis, hypoplasia of labia majora · craniofacial dysostosis, hypertrichosis, Hypoplasia of labia majora, dental and eye anomalies, patent ductus arteriosus, and normal intelligence · craniofacial dysostosis, patent ductus arteriosus, hypertrichosis, hypoplasia of labia majora, dental and eye anomalies · craniofacial dysostosis-genital, dental, cardiac anomalies syndrome · cranofacial dysostosis-hypertrichosis-hypoplasia of labia majora syndrome · dental and eye anomalies, patent ductus arteriosus, and normal intelligence · dental and eye anomalies-patent ductus arteriosus-normal intelligence syndrome · Fontaine progeroid syndrome · FPS · GCM syndrome · GCMS · Gorlin Chaudhry Moss syndrome · Gorlin-Chaudhry-Moss Syndrome · Gorlin-Chaudhry-Moss syndrome · Petty Laxova Wiedemann syndrome · Petty syndrome · Petty-Laxova-Wiedemann syndrome · progeroid syndrome congenital Petty type · progeroid syndrome Petty type · progeroid syndrome, congenital, Petty type (+1 more)

Data availability: 13 ClinVar variants · 6 GenCC gene-disease records.

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 without intellectual disability › Fontaine progeroid syndrome

Related subtypes (167): Treacher-Collins syndrome, branchio-oto-renal syndrome, acrorenal syndrome, Townes-Brocks syndrome, Ascher syndrome, brachytelephalangy-dysmorphism-Kallmann syndrome, branchiooculofacial syndrome, Gordon syndrome, cataract-aberrant oral frenula-growth delay syndrome, cherubism, Alagille syndrome, cleft palate-lateral synechia syndrome, blepharocheilodontic syndrome, craniofacial-deafness-hand syndrome, cryptomicrotia-brachydactyly-excess fingertip arch syndrome, Beare-Stevenson cutis gyrata syndrome, Cyprus facial-neuromusculoskeletal syndrome, deafness-craniofacial syndrome, short stature-valvular heart disease-characteristic facies syndrome, 3-M syndrome, external auditory canal atresia-vertical talus-hypertelorism syndrome, femoral-facial syndrome, multinodular goiter-cystic kidney-polydactyly syndrome, hand-foot-genital syndrome, Bencze syndrome, oculoauriculovertebral spectrum with radial defects, Holt-Oram syndrome, mullerian duct anomalies-limb anomalies syndrome, Aase-Smith syndrome, LADD syndrome, Noonan syndrome with multiple lentigines, median nodule of the upper lip, Nager acrofacial dysostosis, Marshall syndrome, Binder syndrome, Schilbach-Rott syndrome, nasopalpebral lipoma-coloboma syndrome, autosomal dominant prognathism, short stature-craniofacial anomalies-genital hypoplasia syndrome, radial hypoplasia-triphalangeal thumbs-hypospadias-maxillary diastema syndrome, scalp-ear-nipple syndrome, flat face-microstomia-ear anomaly syndrome, Czeizel-Losonci syndrome, otospondylomegaepiphyseal dysplasia, autosomal dominant, ventricular extrasystoles with syncopal episodes-perodactyly-robin sequence syndrome, posterior fusion of lumbosacral vertebrae-blepharoptosis syndrome, acrofacial dysostosis, Weyers type, Freeman-Sheldon syndrome, Ackerman syndrome, acro-renal-mandibular syndrome, acrocraniofacial dysostosis, PAGOD syndrome, alar cartilages hypoplasia-coloboma-telecanthus syndrome, microcephaly-albinism-digital anomalies syndrome, fetal akinesia deformation sequence, Cooper-Jabs syndrome, Barber-Say syndrome, Beemer-Ertbruggen syndrome, blepharophimosis-ptosis-esotropia-syndactyly-short stature syndrome, camptodactyly syndrome, Guadalajara type 1, camptodactyly syndrome, Guadalajara type 2, heart defects-limb shortening syndrome, Verloove Vanhorick-Brubakk syndrome, Juberg-Hayward syndrome, heart defect - tongue hamartoma - polysyndactyly syndrome, Fraser syndrome, split hand-foot malformation 1 with sensorineural hearing loss, von Voss-Cherstvoy syndrome, autosomal recessive faciodigitogenital syndrome, gingival fibromatosis-facial dysmorphism syndrome, Fibulo-ulnar hypoplasia-renal anomalies syndrome, frontofacionasal dysplasia, genito-palato-cardiac syndrome, Hirschsprung disease-hearing loss-polydactyly syndrome, Holzgreve-Wagner-Rehder syndrome, hydrocephaly-tall stature-joint laxity syndrome, McKusick-Kaufman syndrome, acrofrontofacionasal dysostosis 2, Vici syndrome, Donohue syndrome, Dahlberg-Borer-Newcomer syndrome, macrosomia-microphthalmia-cleft palate syndrome, mesomelic dwarfism-cleft palate-camptodactyly syndrome, Nijmegen breakage syndrome, lethal congenital contracture syndrome 1, Richieri Costa-da Silva syndrome, Keipert syndrome, nephrosis-deafness-urinary tract-digital malformations syndrome, ichthyosis-oral and digital anomalies syndrome, otoonychoperoneal syndrome, PHAVER syndrome, polysyndactyly-cardiac malformation syndrome, postaxial acrofacial dysostosis, autosomal recessive multiple pterygium syndrome, rapadilino syndrome, renal-genital-middle ear anomalies, Richieri Costa-Pereira syndrome, SHORT syndrome, tetraamelia-multiple malformations syndrome, thymic-renal-anal-lung dysplasia, trigonocephaly-bifid nose-acral anomalies syndrome, white forelock with malformations, syndactyly-telecanthus-anogenital and renal malformations syndrome, Abruzzo-Erickson syndrome, CHILD syndrome, pentalogy of Cantrell, atrioventricular defect-blepharophimosis-radial and anal defect syndrome, short tarsus-absence of lower eyelashes syndrome, PARC syndrome, CODAS syndrome, pectus excavatum-macrocephaly-dysplastic nails syndrome, velo-facial-skeletal syndrome, anophthalmia plus syndrome, van den Ende-Gupta syndrome, absent tibia-polydactyly-arachnoid cyst syndrome, diaphragmatic defect-limb deficiency-skull defect syndrome, cleft lip/palate-intestinal malrotation-cardiopathy syndrome, Matthew-Wood syndrome, microcephaly-cardiac defect-lung malsegmentation syndrome, dislocation of the hip-dysmorphism syndrome, short stature-auditory canal atresia-mandibular hypoplasia-skeletal anomalies syndrome, grange syndrome, camptodactyly, myopia, and fibrosis of the medial rectus muscle of eye, arhinia, choanal atresia, and microphthalmia, anonychia-microcephaly syndrome, developmental malformations-deafness-dystonia syndrome, lethal congenital contracture syndrome 2, craniolenticulosutural dysplasia, 8q22.1 microdeletion syndrome, Braddock syndrome, choanal atresia-hearing loss-cardiac defects-craniofacial dysmorphism syndrome, BNAR syndrome, Frias syndrome, lethal congenital contracture syndrome 3, microcephaly-facio-cardio-skeletal syndrome, Hadziselimovic type, Nijmegen breakage syndrome-like disorder, Warsaw breakage syndrome, even-plus syndrome, split-foot malformation-mesoaxial polydactyly syndrome, anophthalmia-megalocornea-cardiopathy-skeletal anomalies syndrome, digitotalar dysmorphism, heart-hand syndrome type 2, night blindness-skeletal anomalies-dysmorphism syndrome, Charlie M syndrome, facial dysmorphism-anorexia-cachexia-eye and skin anomalies syndrome, cleft lip-retinopathy syndrome, Cole-Carpenter syndrome, progressive non-infectious anterior vertebral fusion, dysmorphism-pectus carinatum-joint laxity syndrome, Hirschsprung disease-type D brachydactyly syndrome, mandibuloacral dysplasia, contractures - webbed neck - micrognathia - hypoplastic nipples syndrome, Thomas syndrome, Waardenburg syndrome, Weill-Marchesani syndrome, branchiootic syndrome, auricular abnormalities-cleft lip with or without cleft palate-ocular abnormalities syndrome, Axenfeld-Rieger syndrome, macrostomia-preauricular tags-external ophthalmoplegia syndrome, pelvis syndrome, Fanconi anemia, van der Woude syndrome, hypertrichosis-acromegaloid facial appearance syndrome, 49,XYYYY syndrome, congenital vertebral-cardiac-renal anomalies syndrome, structural heart defects and renal anomalies syndrome, Greig cephalopolysyndactyly-contiguous gene 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

13 retrieved; paginated sample, class counts are floors:

8 uncertain significance, 2 benign, 2 pathogenic, 1 likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
369980	NM_013386.5(SLC25A24):c.649C>T (p.Arg217Cys)	SLC25A24	Pathogenic	criteria provided, multiple submitters, no conflicts
370032	NM_013386.5(SLC25A24):c.650G>A (p.Arg217His)	SLC25A24	Pathogenic	criteria provided, multiple submitters, no conflicts
2435996	NM_013386.5(SLC25A24):c.1A>C (p.Met1Leu)	LOC112577470	Uncertain significance	criteria provided, single submitter
1032578	NM_013386.5(SLC25A24):c.812_822+1del	SLC25A24	Uncertain significance	criteria provided, single submitter
1683655	NM_013386.5(SLC25A24):c.424G>A (p.Val142Met)	SLC25A24	Uncertain significance	criteria provided, single submitter
2585298	NM_013386.5(SLC25A24):c.1346C>T (p.Pro449Leu)	SLC25A24	Uncertain significance	criteria provided, single submitter
3254910	NM_013386.5(SLC25A24):c.931G>T (p.Val311Phe)	SLC25A24	Uncertain significance	criteria provided, single submitter
3892454	NM_013386.5(SLC25A24):c.784G>A (p.Ala262Thr)	SLC25A24	Uncertain significance	criteria provided, single submitter
4077411	NM_013386.5(SLC25A24):c.970T>C (p.Tyr324His)	SLC25A24	Uncertain significance	no assertion criteria provided
4080073	NM_013386.5(SLC25A24):c.310+5G>A	SLC25A24	Uncertain significance	criteria provided, single submitter
1181064	NM_013386.5(SLC25A24):c.276A>G (p.Lys92=)	SLC25A24	Benign	criteria provided, multiple submitters, no conflicts
1246080	NM_013386.5(SLC25A24):c.398+45T>C	SLC25A24	Benign	criteria provided, multiple submitters, no conflicts
3064900	NM_013386.5(SLC25A24):c.202G>C (p.Asp68His)	SLC25A24	Likely benign	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 19 · Orphanet: 4 · 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
SLC25A24	Definitive	Autosomal dominant	Fontaine progeroid syndrome	5
SLC25A4	Strong	Autosomal dominant	Fontaine progeroid syndrome	14

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
SLC25A24	Orphanet:2095	Gorlin-Chaudhry-Moss syndrome
SLC25A24	Orphanet:2963	Progeroid syndrome, Petty type
SLC25A4	Orphanet:1369	Congenital cataract-hypertrophic cardiomyopathy-mitochondrial myopathy syndrome
SLC25A4	Orphanet:254892	Autosomal dominant progressive external ophthalmoplegia

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
SLC25A24	HGNC:20662	ENSG00000085491	Q6NUK1	Mitochondrial adenyl nucleotide antiporter SLC25A24	gencc,clinvar
SLC25A4	HGNC:10990	ENSG00000151729	P12235	ADP/ATP translocase 1	gencc

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
SLC25A24	Mitochondrial adenyl nucleotide antiporter SLC25A24	Electroneutral antiporter that mediates the transport of adenyl nucleotides through the inner mitochondrial membrane.
SLC25A4	ADP/ATP translocase 1	ADP:ATP antiporter that mediates import of ADP into the mitochondrial matrix for ATP synthesis, and export of ATP out to fuel the cell.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 2 · 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	2	1.8×	0.312

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
SLC25A24	Other/Unknown	no		EF_hand_dom, MCP, GDC-like
SLC25A4	Other/Unknown	no		MCP, ADT_euk_type, MCP_transmembrane

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)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
duodenum	1
islet of Langerhans	1
rectum	1
apex of heart	1
heart right ventricle	1
left ventricle myocardium	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
SLC25A24	138	ubiquitous	yes	rectum, duodenum, islet of Langerhans
SLC25A4	292	ubiquitous	marker	left ventricle myocardium, heart right ventricle, apex of heart

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
SLC25A4	3,085
SLC25A24	1,590

Intra-cohort edges

A	B	Sources
SLC25A24	SLC25A4	biogrid_interaction

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
SLC25A24	Q6NUK1	3

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
SLC25A4	P12235	92.07

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 16. Enrichment computed across 2 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
Mitochondrial Uncoupling	1	5710.0×	0.002	SLC25A4
Vpr-mediated induction of apoptosis by mitochondrial outer membrane permeabilization	1	3806.7×	0.002	SLC25A4
Interactions of Vpr with host cellular proteins	1	1427.5×	0.004	SLC25A4
Transport of nucleosides and free purine and pyrimidine bases across the plasma membrane	1	951.7×	0.004	SLC25A4
Host Interactions of HIV factors	1	335.9×	0.010	SLC25A4
Transport of vitamins, nucleosides, and related molecules	1	271.9×	0.010	SLC25A4
Protein localization	1	190.3×	0.012	SLC25A4
Mitochondrial protein import	1	167.9×	0.012	SLC25A4
HIV Infection	1	119.0×	0.015	SLC25A4
Aerobic respiration and respiratory electron transport	1	88.5×	0.018	SLC25A4
SLC-mediated transmembrane transport	1	59.2×	0.025	SLC25A4
Viral Infection Pathways	1	30.8×	0.043	SLC25A4
Transport of small molecules	1	25.1×	0.046	SLC25A4
Infectious disease	1	24.8×	0.046	SLC25A4
Disease	1	13.1×	0.082	SLC25A4
Metabolism	1	11.6×	0.086	SLC25A4

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
ADP transport	2	2106.5×	2e-06	SLC25A24, SLC25A4
mitochondrial ATP transmembrane transport	2	1872.4×	2e-06	SLC25A24, SLC25A4
adenine nucleotide transport	1	2106.5×	0.002	SLC25A24
mitochondrial ADP transmembrane transport	1	1685.2×	0.002	SLC25A4
ATP transport	1	702.2×	0.003	SLC25A24
regulation of mitochondrial membrane permeability	1	702.2×	0.003	SLC25A4
mitochondrial transport	1	601.9×	0.003	SLC25A24
positive regulation of mitophagy	1	561.7×	0.003	SLC25A4
negative regulation of mitochondrial outer membrane permeabilization involved in apoptotic signaling pathway	1	526.6×	0.003	SLC25A4
adaptive thermogenesis	1	526.6×	0.003	SLC25A4
negative regulation of necroptotic process	1	495.6×	0.003	SLC25A4
apoptotic mitochondrial changes	1	443.5×	0.003	SLC25A4
generation of precursor metabolites and energy	1	172.0×	0.007	SLC25A4
cellular response to calcium ion	1	100.3×	0.011	SLC25A24
cellular response to oxidative stress	1	77.3×	0.013	SLC25A24

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
SLC25A24	0	0
SLC25A4	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
SLC25A4	1	Binding:1

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	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	2	SLC25A24, SLC25A4

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)
SLC25A24	0	—
SLC25A4	1	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.