Richieri Costa-Pereira syndrome

Summary

Richieri Costa-Pereira syndrome (MONDO:0009998) is a disease caused by EIF4A3 (GenCC Definitive), with 1 cohort gene.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: EIF4A3 (GenCC Definitive)
• Cohort genes: 1
• ClinVar variants: 4
• Phenotypes (HPO): 29

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		33	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

29 HPO clinical features (Orphanet curated; top 29 by frequency):

HPO ID	Term	Frequency
HP:0000308	Microretrognathia	Very frequent (80-99%)
HP:0000377	Abnormal pinna morphology	Very frequent (80-99%)
HP:0001762	Talipes equinovarus	Very frequent (80-99%)
HP:0006355	Agenesis of mandibular central incisor	Very frequent (80-99%)
HP:0009601	Aplasia/Hypoplasia of the thumb	Very frequent (80-99%)
HP:0010109	Short hallux	Very frequent (80-99%)
HP:0000201	Pierre-Robin sequence	Frequent (30-79%)
HP:0000690	Agenesis of maxillary lateral incisor	Frequent (30-79%)
HP:0001245	Small thenar eminence	Frequent (30-79%)
HP:0001609	Hoarse voice	Frequent (30-79%)
HP:0002643	Neonatal respiratory distress	Frequent (30-79%)
HP:0002984	Hypoplasia of the radius	Frequent (30-79%)
HP:0003038	Fibular hypoplasia	Frequent (30-79%)
HP:0004209	Clinodactyly of the 5th finger	Frequent (30-79%)
HP:0004322	Short stature	Frequent (30-79%)
HP:0004987	Mesomelic leg shortening	Frequent (30-79%)
HP:0005011	Mesomelic arm shortening	Frequent (30-79%)
HP:0005736	Short tibia	Frequent (30-79%)
HP:0006536	Airway obstruction	Frequent (30-79%)
HP:0008872	Feeding difficulties in infancy	Frequent (30-79%)
HP:0009237	Short 5th finger	Frequent (30-79%)
HP:0010752	Cleft mandible	Frequent (30-79%)
HP:0012789	Hypoplasia of the calcaneus	Frequent (30-79%)
HP:0200154	Agenesis of mandibular lateral incisor	Frequent (30-79%)
HP:0000193	Bifid uvula	Occasional (5-29%)
HP:0001328	Specific learning disability	Occasional (5-29%)
HP:0008744	Abnormal aryepiglottic fold morphology	Occasional (5-29%)
HP:0010565	Aplasia/Hypoplasia of the Epiglottis	Occasional (5-29%)
HP:0011051	Agenesis of premolar	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	Richieri Costa-Pereira syndrome
Mondo ID	MONDO:0009998
MeSH	C535677
OMIM	268305
Orphanet	3102
ICD-11	107084177
SNOMED CT	723998001
UMLS	C1849348
MedGen	336581
GARD	0004718
Is cancer (heuristic)	no

Also known as: Richieri Costa Pereira syndrome · Richieri Costa-Pereira syndrome · Richieri-Costa and Pereira form of acrofacial dysostosis · short stature, Robin sequence, cleft mandible, pre/postaxial hand anomalies, and clubfoot · short stature-Pierre Robin sequence-cleft mandible-hand anomalies clubfoot syndrome · short stature-Pierre Robin syndrome-cleft mandible-hand anomalies clubfoot syndrome

Data availability: 4 ClinVar variants · 5 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 › Richieri Costa-Pereira 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, 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, Fontaine progeroid syndrome, 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

4 retrieved; paginated sample, class counts are floors:

4 pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
101500	NM_014740.4(EIF4A3):c.-98_-81delinsTCGGCAGCGGCACAGCGAGG[13]	EIF4A3	Pathogenic	no assertion criteria provided
101501	NG_046916.1:g.5125_5142delinsTCGGCAGCGGCACAGCGAGG[12]	EIF4A3	Pathogenic	no assertion criteria provided
101502	NM_014740.4(EIF4A3):c.-98_-81del18insTCGGCAGCGGCACAGCGAGG[10]	EIF4A3	Pathogenic	no assertion criteria provided
101503	NM_014740.4(EIF4A3):c.809A>G (p.Asp270Gly)	EIF4A3	Pathogenic	no assertion criteria provided

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 5 · 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
EIF4A3	Definitive	Autosomal recessive	Richieri Costa-Pereira syndrome	5

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
EIF4A3	Orphanet:3102	Richieri Costa-Pereira 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
EIF4A3	HGNC:18683	ENSG00000141543	P38919	Eukaryotic initiation factor 4A-III	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
EIF4A3	Eukaryotic initiation factor 4A-III	ATP-dependent RNA helicase.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 0 · Druggable fraction: 1.0

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
Enzyme (other)	1	12.0×	0.083

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
EIF4A3	Enzyme (other)	yes	3.6.4.13	RNA-helicase_DEAD-box_CS, Helicase_C-like, DEAD/DEAH_box_helicase_dom

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
endometrium epithelium	1
primordial germ cell in gonad	1
type B pancreatic cell	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
EIF4A3	294	ubiquitous	marker	type B pancreatic cell, primordial germ cell in gonad, endometrium epithelium

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
EIF4A3	6,202

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
EIF4A3	P38919	22

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 11. 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
Z-decay: degradation of maternal mRNAs by zygotically expressed factors	1	951.7×	0.009	EIF4A3
Deadenylation of mRNA	1	439.2×	0.009	EIF4A3
M-decay: degradation of maternal mRNAs by maternally stored factors	1	326.3×	0.009	EIF4A3
Dengue Virus Genome Translation and Replication	1	317.2×	0.009	EIF4A3
mRNA 3’-end processing	1	196.9×	0.010	EIF4A3
Transport of Mature mRNA derived from an Intron-Containing Transcript	1	152.3×	0.010	EIF4A3
ISG15 antiviral mechanism	1	150.3×	0.010	EIF4A3
Nonsense Mediated Decay (NMD) enhanced by the Exon Junction Complex (EJC)	1	97.6×	0.014	EIF4A3
Regulation of expression of SLITs and ROBOs	1	69.2×	0.018	EIF4A3
mRNA Splicing - Major Pathway	1	54.6×	0.020	EIF4A3
Dengue Virus-Host Interactions	1	45.7×	0.022	EIF4A3

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
cellular response to selenite ion	1	16852.0×	4e-04	EIF4A3
negative regulation of selenocysteine incorporation	1	16852.0×	4e-04	EIF4A3
regulation of translation at postsynapse, modulating synaptic transmission	1	5617.3×	9e-04	EIF4A3
regulation of nuclear-transcribed mRNA catabolic process, nonsense-mediated decay	1	3370.4×	0.001	EIF4A3
cellular response to brain-derived neurotrophic factor stimulus	1	1872.4×	0.002	EIF4A3
negative regulation of excitatory postsynaptic potential	1	1296.3×	0.002	EIF4A3
exploration behavior	1	648.1×	0.003	EIF4A3
embryonic cranial skeleton morphogenesis	1	581.1×	0.003	EIF4A3
associative learning	1	481.5×	0.003	EIF4A3
nuclear-transcribed mRNA catabolic process, nonsense-mediated decay	1	468.1×	0.003	EIF4A3
mRNA export from nucleus	1	295.6×	0.005	EIF4A3
positive regulation of translation	1	227.7×	0.005	EIF4A3
negative regulation of translation	1	195.9×	0.006	EIF4A3
rRNA processing	1	141.6×	0.008	EIF4A3
mRNA splicing, via spliceosome	1	91.6×	0.011	EIF4A3

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
EIF4A3	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
EIF4A3	26	Binding:26

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
EIF4A3	3.6.4.13	RNA helicase

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	1	EIF4A3
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	0

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)
EIF4A3	26	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.