Tatton-Brown-Rahman overgrowth syndrome

Summary

Tatton-Brown-Rahman overgrowth syndrome (MONDO:0014382) is a disease caused by DNMT3A (GenCC Definitive), with 5 cohort genes.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: DNMT3A (GenCC Definitive)
• Cohort genes: 5
• ClinVar variants: 633
• Phenotypes (HPO): 40

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		17	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

40 HPO clinical features (Orphanet curated; top 40 by frequency):

HPO ID	Term	Frequency
HP:0000256	Macrocephaly	Very frequent (80-99%)
HP:0011407	Proportionate tall stature	Very frequent (80-99%)
HP:0000708	Atypical behavior	Frequent (30-79%)
HP:0001513	Obesity	Frequent (30-79%)
HP:0002342	Intellectual disability, moderate	Frequent (30-79%)
HP:0002751	Kyphoscoliosis	Frequent (30-79%)
HP:0008947	Floppy infant	Frequent (30-79%)
HP:0000028	Cryptorchidism	Occasional (5-29%)
HP:0000280	Coarse facial features	Occasional (5-29%)
HP:0000311	Round face	Occasional (5-29%)
HP:0000574	Thick eyebrow	Occasional (5-29%)
HP:0000739	Anxiety	Occasional (5-29%)
HP:0001250	Seizure	Occasional (5-29%)
HP:0001256	Intellectual disability, mild	Occasional (5-29%)
HP:0001382	Joint hypermobility	Occasional (5-29%)
HP:0001566	Widely-spaced maxillary central incisors	Occasional (5-29%)
HP:0001631	Atrial septal defect	Occasional (5-29%)
HP:0001831	Short toe	Occasional (5-29%)
HP:0002119	Ventriculomegaly	Occasional (5-29%)
HP:0002308	Chiari malformation	Occasional (5-29%)
HP:0002376	Developmental regression	Occasional (5-29%)
HP:0008094	Widely spaced toes	Occasional (5-29%)
HP:0010864	Intellectual disability, severe	Occasional (5-29%)
HP:0045025	Narrow palpebral fissure	Occasional (5-29%)
HP:0100753	Schizophrenia	Occasional (5-29%)
HP:0000303	Mandibular prognathia	Very rare (<1-4%)
HP:0000316	Hypertelorism	Very rare (<1-4%)
HP:0000718	Aggressive behavior	Very rare (<1-4%)
HP:0001537	Umbilical hernia	Very rare (<1-4%)
HP:0001643	Patent ductus arteriosus	Very rare (<1-4%)
HP:0001653	Mitral regurgitation	Very rare (<1-4%)
HP:0002000	Short columella	Very rare (<1-4%)
HP:0002002	Deep philtrum	Very rare (<1-4%)
HP:0002616	Aortic root aneurysm	Very rare (<1-4%)
HP:0003508	Proportionate short stature	Very rare (<1-4%)
HP:0005180	Tricuspid regurgitation	Very rare (<1-4%)
HP:0007302	Bipolar affective disorder	Very rare (<1-4%)
HP:0011688	Supraventricular tachycardia with an accessory connection mediated pathway	Very rare (<1-4%)
HP:0012324	Myeloid leukemia	Very rare (<1-4%)
HP:0100634	Neuroendocrine neoplasm	Very rare (<1-4%)

Identifiers

Disease identifiers

Field	Value
Canonical name	Tatton-Brown-Rahman overgrowth syndrome
Mondo ID	MONDO:0014382
OMIM	615879
Orphanet	404443
DOID	DOID:0112339
SNOMED CT	768843007
UMLS	C4014545
MedGen	862982
GARD	0017674
Is cancer (heuristic)	no

Also known as: DNMT3A-related overgrowth syndrome · tall stature-intellectual disability-facial dysmorphism syndrome · Tatton Brown Rahman Syndrome · Tatton-Brown-Rahman overgrowth syndrome · TATTON-BROWN-Rahman syndrome · TBRS

Data availability: 633 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-intellectual disability › Tatton-Brown-Rahman overgrowth syndrome

Related subtypes (337): Neu-Laxova syndrome, acrofacial dysostosis, Catania type, aortic arch anomaly-facial dysmorphism-intellectual disability syndrome, blepharonasofacial malformation syndrome, brachydactyly-nystagmus-cerebellar ataxia syndrome, craniofaciofrontodigital syndrome, uveal coloboma-cleft lip and palate-intellectual disability, Ramos-Arroyo syndrome, extrasystoles-short stature-hyperpigmentation-microcephaly syndrome, Floating-Harbor syndrome, Myhre syndrome, hirsutism-skeletal dysplasia-intellectual disability syndrome, Johnson neuroectodermal syndrome, KBG syndrome, trichorhinophalangeal syndrome type II, Lenz-Majewski hyperostotic dwarfism, Bannayan-Riley-Ruvalcaba syndrome, microcephaly-deafness-intellectual disability syndrome, ophthalmoplegia-intellectual disability-lingua scrotalis syndrome, omphalocele syndrome, Shprintzen-Goldberg type, Shprintzen-Goldberg syndrome, Smith-Magenis syndrome, delayed speech-facial asymmetry-strabismus-ear lobe creases syndrome, holoprosencephaly-radial heart renal anomalies syndrome, Wolf-Hirschhorn syndrome, pseudoprogeria syndrome, acrocallosal syndrome, acrofacial dysostosis Rodriguez type, agnathia-otocephaly complex, Stimmler syndrome, anencephaly 1, aniridia-renal agenesis-psychomotor retardation syndrome, Biemond syndrome type 2, bird headed-dwarfism, Montreal type, Bowen-Conradi syndrome, Elsahy-Waters syndrome, C syndrome, camptodactyly with fibrous tissue hyperplasia and skeletal dysplasia, Cohen syndrome, cortical blindness-intellectual disability-polydactyly syndrome, Costello syndrome, temtamy syndrome, cardiocranial syndrome, Pfeiffer type, facial dysmorphism-macrocephaly-myopia-Dandy-Walker malformation syndrome, Dubowitz syndrome, Bonnemann-Meinecke-Reich syndrome, epilepsy-telangiectasia syndrome, faciocardiorenal syndrome, fountain syndrome, Fryns syndrome, GAPO syndrome, Hall-Riggs syndrome, Mowat-Wilson syndrome, hypertelorism, microtia, facial clefting syndrome, hypoparathyroidism-retardation-dysmorphism syndrome, hypospadias-intellectual disability, Goldblatt type syndrome, Stromme syndrome, Johanson-Blizzard syndrome, Kapur-Toriello syndrome, oculocerebrofacial syndrome, Kaufman type, Keutel syndrome, Lambert syndrome, Laurence-Moon syndrome, intellectual disability-spasticity-ectrodactyly syndrome, prominent glabella-microcephaly-hypogenitalism syndrome, Marden-Walker syndrome, microcephaly-glomerulonephritis-marfanoid habitus syndrome, marfanoid habitus-autosomal recessive intellectual disability syndrome, McDonough syndrome, intellectual disability-dysmorphism-hypogonadism-diabetes mellitus syndrome, intellectual disability, Buenos-Aires type, microcephaly-cardiomyopathy syndrome, Say-Barber-Miller syndrome, microcephaly-cervical spine fusion anomalies syndrome, Jawad syndrome, lethal multiple pterygium syndrome, neurofaciodigitorenal syndrome, oculo-palato-cerebral syndrome, Oliver syndrome, lethal omphalocele-cleft palate syndrome, Peters plus syndrome, Pfeiffer-Palm-Teller syndrome, urban-Rogers-Meyer syndrome, Wiedemann-Rautenstrauch syndrome, holoprosencephaly-postaxial polydactyly syndrome, radioulnar synostosis-developmental delay-hypotonia syndrome, Ulbright-Hodes syndrome, microbrachycephaly-ptosis-cleft lip syndrome, Smith-Lemli-Opitz syndrome, congenital heart defect-round face-developmental delay syndrome, Filippi syndrome, upper limb defect-eye and ear abnormalities syndrome, Weaver syndrome, intellectual disability, Wolff type, CHIME syndrome, X-linked intellectual disability-plagiocephaly syndrome, syndromic X-linked intellectual disability 7, syndromic X-linked intellectual disability Shashi type, syndromic X-linked intellectual disability Lubs type, syndromic X-linked intellectual disability Abidi type, syndromic X-linked intellectual disability Siderius type, creatine transporter deficiency, X-linked intellectual disability, Cabezas type, X-linked intellectual disability-cubitus valgus-dysmorphism syndrome, syndromic X-linked intellectual disability Claes-Jensen type, chromosome Xp11.23-p11.22 duplication syndrome, X-linked colobomatous microphthalmia-microcephaly-intellectual disability-short stature syndrome, SSR4-congenital disorder of glycosylation, X-linked intellectual disability-short stature-overweight syndrome, intellectual disability, X-linked, syndromic 33, syndromic X-linked intellectual disability 34, intellectual disability-balding-patella luxation-acromicria syndrome, syndromic X-linked intellectual disability 5, male hypergonadotropic hypogonadism-intellectual disability-skeletal anomalies syndrome, X-linked intellectual disability with marfanoid habitus, N syndrome, pterygium colli-intellectual disability-digital anomalies syndrome, Lowry-MacLean syndrome, macrocephaly-spastic paraplegia-dysmorphism syndrome, pseudoaminopterin syndrome, acrocardiofacial syndrome, Ayme-Gripp syndrome, Harrod syndrome, fallot complex-intellectual disability-growth delay syndrome, MMEP syndrome, epilepsy-microcephaly-skeletal dysplasia syndrome, Fine-Lubinsky syndrome, intellectual disability-sparse hair-brachydactyly syndrome, colobomatous microphthalmia - obesity - hypogenitalism - intellectual disability syndrome, Pierpont syndrome, congenital cataracts-facial dysmorphism-neuropathy syndrome, Bohring-Opitz syndrome, Wiedemann-Steiner syndrome, cerebrooculonasal syndrome, genitopatellar syndrome, intellectual disability-obesity-prognathism-eye and skin anomalies syndrome, intellectual disability-brachydactyly-Pierre Robin syndrome, AICA-ribosiduria, Goldberg-Shprintzen syndrome, complex cortical dysplasia with other brain malformations 7, Kleefstra syndrome, Koolen-de Vries syndrome, agammaglobulinemia-microcephaly-craniosynostosis-severe dermatitis syndrome, mandibulofacial dysostosis-microcephaly syndrome, camptodactyly syndrome, Guadalajara type 3, chromosome 15q13.3 microdeletion syndrome, chromosome 6pter-p24 deletion syndrome, Zechi-Ceide syndrome, chromosome 19q13.11 deletion syndrome, chromosome 5p13 duplication syndrome, chromosome 17p13.3 duplication syndrome, syndromic multisystem autoimmune disease due to ITCH deficiency, chromosome 15q24 deletion syndrome, chromosome 17q21.31 duplication syndrome, chromosome 19p13.13 deletion syndrome, THOC6-related developmental delay-microcephaly-facial dysmorphism syndrome, DYRK1A-related intellectual disability syndrome, chromosome 8q21.11 deletion syndrome, microcephaly-cerebellar hypoplasia-cardiac conduction defect syndrome, chromosome 16q22 deletion syndrome, Schuurs-Hoeijmakers syndrome, severe intellectual disability-poor language-strabismus-grimacing face-long fingers syndrome, severe intellectual disability-progressive spastic diplegia syndrome, short ulna-dysmorphism-hypotonia-intellectual disability syndrome, microcephaly-intellectual disability-phalangeal and neurological anomalies syndrome, hypotonia, infantile, with psychomotor retardation and characteristic facies, Hartsfield-Bixler-Demyer syndrome, developmental and epileptic encephalopathy, 18, severe feeding difficulties-failure to thrive-microcephaly due to ASXL3 deficiency syndrome, CTCF-related neurodevelopmental disorder, severe intellectual disability-short stature-behavioral abnormalities-facial dysmorphism syndrome, 8q24.3 microdeletion syndrome, microcephaly-thin corpus callosum-intellectual disability syndrome, macrocephaly-developmental delay syndrome, chromosome 5q12 deletion syndrome, intellectual disability-facial dysmorphism syndrome due to SETD5 haploinsufficiency, autism spectrum disorder due to AUTS2 deficiency, developmental and epileptic encephalopathy, 23, ADNP-related multiple congenital anomalies - intellectual disability - autism spectrum disorder, orofaciodigital syndrome type 14, Catel-Manzke syndrome, cerebellar-facial-dental syndrome, autosomal dominant intellectual disability-craniofacial anomalies-cardiac defects syndrome, autosomal recessive spinocerebellar ataxia 20, Houge-Janssens syndrome 1, Houge-Janssens syndrome 2, intellectual disability-microcephaly-strabismus-behavioral abnormalities syndrome, cognitive impairment - coarse facies - heart defects - obesity - pulmonary involvement - short stature - skeletal dysplasia syndrome, hypomyelinating leukodystrophy 10, congenital cataract-microcephaly-nevus flammeus simplex-severe intellectual disability syndrome, macrocephaly-intellectual disability-neurodevelopmental disorder-small thorax syndrome, SLC39A8-CDG, progressive spondyloepimetaphyseal dysplasia-short stature-short fourth metatarsals-intellectual disability syndrome, palatal anomalies-widely spaced teeth-facial dysmorphism-developmental delay syndrome, macrothrombocytopenia-lymphedema-developmental delay-facial dysmorphism-camptodactyly syndrome, spastic paraplegia-severe developmental delay-epilepsy syndrome, cardiac anomalies - developmental delay - facial dysmorphism syndrome, severe intellectual disability-corpus callosum agenesis-facial dysmorphism-cerebellar ataxia syndrome, TELO2-related intellectual disability-neurodevelopmental disorder, transketolase deficiency, severe growth deficiency-strabismus-extensive dermal melanocytosis-intellectual disability syndrome, micrognathia-recurrent infections-behavioral abnormalities-mild intellectual disability syndrome, tall stature-intellectual disability-renal anomalies syndrome, ZTTK syndrome, short stature-brachydactyly-obesity-global developmental delay syndrome, mucopolysaccharidosis-plus syndrome, hypotonia, ataxia, and delayed development syndrome, caudal appendage-deafness syndrome, arachnodactyly-abnormal ossification-intellectual disability syndrome, ataxia-photosensitivity-short stature syndrome, severe microbrachycephaly-intellectual disability-athetoid cerebral palsy syndrome, brachydactyly-mesomelia-intellectual disability-heart defects syndrome, cardiofaciocutaneous syndrome, cataract-intellectual disability-anal atresia-urinary defects syndrome, cataract-deafness-hypogonadism syndrome, Coffin-Siris syndrome, intellectual disability-hypoplastic corpus callosum-preauricular tag syndrome, craniodigital syndrome-intellectual disability syndrome, cryptorchidism-arachnodactyly-intellectual disability syndrome, facial dysmorphism-shawl scrotum-joint laxity syndrome, epiphyseal dysplasia-hearing loss-dysmorphism syndrome, Cornelia de Lange syndrome, cleft palate-short stature-vertebral anomalies syndrome, Hennekam syndrome, Hernández-Aguirre Negrete syndrome, holoprosencephaly, dysmorphism-short stature-deafness-disorder of sex development syndrome, 5q14.3 microdeletion syndrome, Kabuki syndrome, ptosis-syndactyly-learning difficulties syndrome, macrocephaly-short stature-paraplegia syndrome, Warburg micro syndrome, microcephaly-seizures-intellectual disability-heart disease syndrome, microcephaly-cleft palate syndrome, microcephaly-microcornea syndrome, Seemanova type, multiple congenital anomalies due to 14q32.2 maternally expressed gene defect, neuroectodermal-endocrine syndrome, Opitz G/BBB syndrome, Xp22.13p22.2 duplication syndrome, short stature-webbed neck-heart disease syndrome, microtriplication 11q24.1, preaxial polydactyly-colobomata-intellectual disability syndrome, blepharophimosis - intellectual disability syndrome, 3MC syndrome, Baraitser-Winter cerebrofrontofacial syndrome, 11p15.4 microduplication syndrome, X-linked intellectual disability-hypogonadism-ichthyosis-obesity-short stature syndrome, intellectual disability-short stature-hypertelorism syndrome, intellectual disability-polydactyly-uncombable hair syndrome, 20p13 microdeletion syndrome, 7p22.1 microduplication syndrome, intellectual disability-hypotonia-brachycephaly-pyloric stenosis-cryptorchidism syndrome, 15q overgrowth syndrome, van Maldergem syndrome, distal 17p13.1 microdeletion syndrome, deafness-genital anomalies-metacarpal and metatarsal synostosis syndrome, muscular hypertrophy-hepatomegaly-polyhydramnios syndrome, aphonia-deafness-retinal dystrophy-bifid halluces-intellectual disability syndrome, spondylocostal dysostosis-hypospadias-intellectual disability syndrome, telecanthus-hypertelorism-strabismus-pes cavus syndrome, microcephaly-brachydactyly-kyphoscoliosis syndrome, Weaver-Williams syndrome, 20q11.2 microduplication syndrome, 2p13.2 microdeletion syndrome, intellectual disability-seizures-macrocephaly-obesity syndrome, intellectual disability-facial dysmorphism-hand anomalies syndrome, XYLT1-congenital disorder of glycosylation, 3q27.3 microdeletion syndrome, 9q31.1q31.3 microdeletion syndrome, 14q24.1q24.3 microdeletion syndrome, FBLN1-related developmental delay-central nervous system anomaly-syndactyly syndrome, 13q12.3 microdeletion syndrome, cono-spondylar dysplasia, microcephaly-short stature-intellectual disability-facial dysmorphism syndrome, severe intellectual disability-hypotonia-strabismus-coarse face-planovalgus syndrome, 11q22.2q22.3 microdeletion syndrome, 20q11.2 microdeletion syndrome, 19p13.3 microduplication syndrome, neurodevelopmental disorder-craniofacial dysmorphism-cardiac defect-hip dysplasia syndrome, 1p35.2 microdeletion syndrome, megalencephaly-severe kyphoscoliosis-overgrowth syndrome, intellectual disability-muscle weakness-short stature-facial dysmorphism syndrome, X-linked intellectual disability-cerebellar hypoplasia-spondylo-epiphyseal dysplasia syndrome, corpus callosum agenesis-macrocephaly-hypertelorism syndrome, DeSanto-Shinawi syndrome, global developmental delay-visual anomalies-progressive cerebellar atrophy-truncal hypotonia syndrome, Ritscher-Schinzel syndrome, visceral neuropathy-brain anomalies-facial dysmorphism-developmental delay syndrome, brain malformation-congenital heart disease-postaxial polydactyly syndrome, Rubinstein-Taybi syndrome, X-linked intellectual disability-hypogammaglobulinemia-progressive neurological deterioration syndrome, X-linked intellectual disability-epilepsy-progressive joint contractures-dysmorphism syndrome, X-linked intellectual disability, Pai type, X-linked intellectual disability, Stevenson type, X-linked intellectual disability, Stoll type, osteopenia-myopia-hearing loss-intellectual disability-facial dysmorphism syndrome, severe intellectual disability-epilepsy-anal anomalies-distal phalangeal hypoplasia, intellectual disability, autosomal dominant 47, intellectual disability, autosomal dominant 48, skeletal dysplasia-T-cell immunodeficiency-developmental delay syndrome, congenital progressive bone marrow failure-B-cell immunodeficiency-skeletal dysplasia syndrome, developmental and epileptic encephalopathy, 73, pancreatic agenesis-holoprosencephaly syndrome, oculocerebrodental syndrome, PHIP-related behavioral problems-intellectual disability-obesity-dysmorphic features syndrome, KAT6B-related multiple congenital anomalies syndrome, intellectual developmental disorder with gastrointestinal difficulties and high pain threshold, intellectual developmental disorder with dysmorphic facies, seizures, and distal limb anomalies, 16p12.1p12.3 triplication syndrome, 9q33.3q34.11 microdeletion syndrome, congenital labioscrotal agenesis-cerebellar malformation-corneal dystrophy-facial dysmorphism syndrome, early-onset progressive diffuse brain atrophy-microcephaly-muscle weakness-optic atrophy syndrome, early-onset progressive encephalopathy-hearing loss-pons hypoplasia-brain atrophy syndrome, SIN3A-related intellectual disability syndrome, childhood-onset motor and cognitive regression syndrome with extrapyramidal movement disorder, Gabriele de Vries syndrome, Skraban-Deardorff syndrome, neurodevelopmental disorder with progressive microcephaly, spasticity, and brain anomalies, Pilarowski-Bjornsson syndrome, glycosylphosphatidylinositol biosynthesis defect 15, multiple congenital anomalies-hypotonia-seizures syndrome, mesomelic dysplasia-digital anomalies-intellectual disability syndrome, KDM3B-related intellectual disability-facial dysmorphism-short stature syndrome, SLC12A2-related developmental delay-intellectual disability-sensorineural deafness syndrome, intellectual disability-early-onset cataract-microcephaly syndrome, cleft palate-congenital heart defect-intellectual disability syndrome, PRC-2 complex-related overgrowth spectrum, orofacial clefting-cardiac anomalies-facial dysmorphism syndrome, severe congenital myelofibrosis-pancytopenia-intellectual disability-neurologic and ophthalmic abnormalities syndrome, progressive hypotonia-intellectual disability-facial dysmorphism syndrome due to FYVE-defective RBSN, intellectual disability-epilepsy-dental anomalies-facial dysmorphism syndrome, 2q13 microdeletion syndrome, 10p13-p14 deletion syndrome, 3q26q28 deletion syndrome, Pitt-Hopkins or Pitt-Hopkins-like syndrome, PURA-related severe neonatal hypotonia-seizures-encephalopathy syndrome, Martsolf syndrome 1

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

600 retrieved; paginated sample, class counts are floors:

229 likely benign, 198 uncertain significance, 85 pathogenic, 34 likely pathogenic, 23 conflicting classifications of pathogenicity, 10 benign/likely benign, 9 pathogenic/likely pathogenic, 8 benign, 4 not provided

ClinVar	Variant (HGVS)	Gene	Classification	Review
2427540	NC_000002.11:g.(?24443763)(26029226_?)del	ADCY3	Pathogenic	criteria provided, single submitter
1027657	NM_022552.5(DNMT3A):c.427C>T (p.Arg143Ter)	DNMT3A	Pathogenic	criteria provided, multiple submitters, no conflicts
1065568	NM_022552.5(DNMT3A):c.1004A>G (p.Lys335Arg)	DNMT3A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1070654	NM_022552.5(DNMT3A):c.1792C>T (p.Arg598Ter)	DNMT3A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1072186	NM_022552.5(DNMT3A):c.1711dup (p.Ala571fs)	DNMT3A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1173066	NM_022552.5(DNMT3A):c.1757G>T (p.Cys586Phe)	DNMT3A	Pathogenic	criteria provided, single submitter
1183858	NM_022552.5(DNMT3A):c.176dup (p.Val60fs)	DNMT3A	Pathogenic	criteria provided, multiple submitters, no conflicts
1194481	NM_022552.5(DNMT3A):c.2207G>A (p.Arg736His)	DNMT3A	Pathogenic	criteria provided, multiple submitters, no conflicts
1210909	NM_022552.5(DNMT3A):c.2478+1G>A	DNMT3A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1285401	NM_022552.5(DNMT3A):c.890G>A (p.Trp297Ter)	DNMT3A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1320067	NM_022552.5(DNMT3A):c.1555-1G>A	DNMT3A	Pathogenic	criteria provided, single submitter
1330229	NM_022552.5(DNMT3A):c.2322+1G>A	DNMT3A	Pathogenic	criteria provided, single submitter
1332907	NM_022552.5(DNMT3A):c.1647C>A (p.Cys549Ter)	DNMT3A	Pathogenic	criteria provided, multiple submitters, no conflicts
1342607	NM_022552.5(DNMT3A):c.1791del (p.Arg598fs)	DNMT3A	Pathogenic	criteria provided, single submitter
139615	NM_022552.5(DNMT3A):c.889_891del (p.Trp297del)	DNMT3A	Pathogenic	no assertion criteria provided
139616	NM_022552.5(DNMT3A):c.1943T>C (p.Leu648Pro)	DNMT3A	Pathogenic	no assertion criteria provided
139617	NM_022552.5(DNMT3A):c.929T>A (p.Ile310Asn)	DNMT3A	Pathogenic	no assertion criteria provided
139618	NM_022552.5(DNMT3A):c.1643T>A (p.Met548Lys)	DNMT3A	Pathogenic	no assertion criteria provided
139619	NM_022552.5(DNMT3A):c.2705T>C (p.Phe902Ser)	DNMT3A	Pathogenic	no assertion criteria provided
1459355	NC_000002.11:g.(?25458556)(25458714_?)del	DNMT3A	Pathogenic	criteria provided, single submitter
1486678	NM_022552.5(DNMT3A):c.2678G>A (p.Trp893Ter)	DNMT3A	Pathogenic	criteria provided, single submitter
1699425	NM_022552.5(DNMT3A):c.1243C>T (p.Gln415Ter)	DNMT3A	Pathogenic	criteria provided, single submitter
2031023	NM_022552.5(DNMT3A):c.629G>A (p.Trp210Ter)	DNMT3A	Pathogenic	criteria provided, single submitter
2032388	NM_022552.5(DNMT3A):c.1004_1011del (p.Lys335fs)	DNMT3A	Pathogenic	criteria provided, single submitter
2073362	NM_022552.5(DNMT3A):c.1342_1343dup (p.Ala449fs)	DNMT3A	Pathogenic	criteria provided, single submitter
2104480	NM_022552.5(DNMT3A):c.853G>T (p.Glu285Ter)	DNMT3A	Pathogenic	criteria provided, single submitter
2203023	NM_022552.5(DNMT3A):c.2245C>T (p.Arg749Cys)	DNMT3A	Pathogenic	criteria provided, multiple submitters, no conflicts
2423537	NC_000002.11:g.(?25383950)(25523132_?)del	DNMT3A	Pathogenic	criteria provided, single submitter
2427539	NC_000002.11:g.(?25497790)(25498432_?)del	DNMT3A	Pathogenic	criteria provided, single submitter
2501699	NM_022552.5(DNMT3A):c.2597+1G>A	DNMT3A	Pathogenic	no assertion criteria provided

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 10 · Orphanet: 5 · 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
DNMT3A	Definitive	Autosomal dominant	Tatton-Brown-Rahman overgrowth syndrome	10

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
DNMT3A	Orphanet:276621	Sporadic pheochromocytoma/secreting paraganglioma
DNMT3A	Orphanet:404443	Tatton-Brown-Rahman syndrome
DNMT3A	Orphanet:658595	DNMT3A-related microcephalic dwarfism
DNMT3A	Orphanet:86845	Acute myeloid leukaemia with myelodysplasia-related features
PTCHD1	Orphanet:777	X-linked non-syndromic intellectual disability

Cohort genes → proteins

5 cohort genes, 5 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	5

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
DNMT3A	HGNC:2978	ENSG00000119772	Q9Y6K1	DNA (cytosine-5)-methyltransferase 3A	gencc,clinvar
CGREF1	HGNC:16962	ENSG00000138028	Q99674	Cell growth regulator with EF hand domain protein 1	clinvar
ADCY3	HGNC:234	ENSG00000138031	O60266	Adenylate cyclase type 3	clinvar
PTCHD1	HGNC:26392	ENSG00000165186	Q96NR3	Patched domain-containing protein 1	clinvar
EFR3B	HGNC:29155	ENSG00000084710	Q9Y2G0	Protein EFR3 homolog B	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
DNMT3A	DNA (cytosine-5)-methyltransferase 3A	Required for genome-wide de novo methylation and is essential for the establishment of DNA methylation patterns during development.
CGREF1	Cell growth regulator with EF hand domain protein 1	Mediates cell-cell adhesion in a calcium-dependent manner.
ADCY3	Adenylate cyclase type 3	Catalyzes the formation of the signaling molecule cAMP in response to G-protein signaling.
PTCHD1	Patched domain-containing protein 1	Required for the development and function of the thalamic reticular nucleus (TRN), a part of the thalamus that is critical for thalamocortical transmission, generation of sleep rhythms, sensorimotor processing and attention.
EFR3B	Protein EFR3 homolog B	Component of a complex required to localize phosphatidylinositol 4-kinase (PI4K) to the plasma membrane.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 4 · Druggable fraction: 0.2

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
Complement	1	53.6×	0.037
Other/Unknown	4	1.4×	0.269

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
DNMT3A	Complement	yes	2.1.1.37	PWWP_dom, C5_MeTfrase, C5_DNA_meth_AS
CGREF1	Other/Unknown	no		EF_hand_dom, EF-hand-dom_pair, EF_Hand_1_Ca_BS
ADCY3	Other/Unknown	no		A/G_cyclase, A/G_cyclase_CS, Nucleotide_cyclase
PTCHD1	Other/Unknown	no		SSD, PTHD_SSD, Patched_domain-protein
EFR3B	Other/Unknown	no		ARM-like, ARM-type_fold, EFR3-like_ARM

Expression context

Cohort genes with no expression data: 0.

4 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)	5
unknown	0

Top tissues across cohort

Tissue	Cohort genes
sural nerve	2
ganglionic eminence	1
ventricular zone	1
nucleus accumbens	1
right frontal lobe	1
right hemisphere of cerebellum	1
right ovary	1
tibial nerve	1
buccal mucosa cell	1
cauda epididymis	1
corpus epididymis	1
pigmented layer of retina	1
pons	1
superior vestibular nucleus	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
DNMT3A	223	ubiquitous	marker	sural nerve, ganglionic eminence, ventricular zone
CGREF1	191	ubiquitous	marker	right frontal lobe, nucleus accumbens, right hemisphere of cerebellum
ADCY3	281	broad	marker	tibial nerve, right ovary, sural nerve
PTCHD1	167	broad	yes	cauda epididymis, corpus epididymis, buccal mucosa cell
EFR3B	199	ubiquitous	marker	pons, superior vestibular nucleus, pigmented layer of retina

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
DNMT3A	4,771
ADCY3	1,965
EFR3B	924
PTCHD1	822
CGREF1	590

Structural data

PDB: 1 · AlphaFold-only: 4 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
DNMT3A	Q9Y6K1	43

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
PTCHD1	Q96NR3	84.14
EFR3B	Q9Y2G0	82.08
ADCY3	O60266	76.86
CGREF1	Q99674	62.75

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 54. Enrichment computed across 5 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
Adenylate cyclase activating pathway	1	571.0×	0.017	ADCY3
Adenylate cyclase inhibitory pathway	1	380.7×	0.017	ADCY3
PKA activation in glucagon signalling	1	335.9×	0.017	ADCY3
SUMOylation of DNA methylation proteins	1	335.9×	0.017	DNMT3A
PKA activation	1	317.2×	0.017	ADCY3
Activation of GABAB receptors	1	300.5×	0.017	ADCY3
PKA-mediated phosphorylation of CREB	1	285.5×	0.017	ADCY3
GABA B receptor activation	1	271.9×	0.017	ADCY3
Anti-inflammatory response favouring Leishmania parasite infection	1	196.9×	0.017	ADCY3
Leishmania parasite growth and survival	1	196.9×	0.017	ADCY3
Calmodulin induced events	1	190.3×	0.017	ADCY3
CaM pathway	1	190.3×	0.017	ADCY3
Ca-dependent events	1	184.2×	0.017	ADCY3
Aquaporin-mediated transport	1	184.2×	0.017	ADCY3
Glucagon signaling in metabolic regulation	1	173.0×	0.017	ADCY3
G-protein mediated events	1	163.1×	0.017	ADCY3
DAG and IP3 signaling	1	158.6×	0.017	ADCY3
GABA receptor activation	1	158.6×	0.017	ADCY3
Response of endothelial cells to shear stress	1	150.3×	0.017	ADCY3
FCGR3A-mediated IL10 synthesis	1	146.4×	0.017	ADCY3
Opioid Signalling	1	132.8×	0.017	ADCY3
PLC beta mediated events	1	132.8×	0.017	ADCY3
Vasopressin regulates renal water homeostasis via Aquaporins	1	132.8×	0.017	ADCY3
Cellular responses to mechanical stimuli	1	129.8×	0.017	ADCY3
ADORA2B mediated anti-inflammatory cytokines production	1	126.9×	0.017	ADCY3
GPER1 signaling	1	124.1×	0.017	ADCY3
G alpha (z) signalling events	1	116.5×	0.017	ADCY3
Signaling by Hedgehog	1	92.1×	0.020	ADCY3
DNA methylation	1	89.2×	0.020	DNMT3A
Hedgehog ‘off’ state	1	89.2×	0.020	ADCY3

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 5 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
social behavior	2	108.7×	0.007	PTCHD1, EFR3B
olfactory learning	1	1685.2×	0.012	ADCY3
inhibitory chemical synaptic transmission	1	1123.5×	0.012	PTCHD1
positive regulation of cellular response to hypoxia	1	1123.5×	0.012	DNMT3A
cellular response to bisphenol A	1	674.1×	0.015	DNMT3A
autosome genomic imprinting	1	481.5×	0.015	DNMT3A
regulatory ncRNA-mediated heterochromatin formation	1	374.5×	0.015	DNMT3A
cAMP biosynthetic process	1	280.9×	0.015	ADCY3
thalamus development	1	280.9×	0.015	PTCHD1
short-term memory	1	259.3×	0.015	PTCHD1
excitatory chemical synaptic transmission	1	259.3×	0.015	PTCHD1
transposable element silencing by piRNA-mediated DNA methylation	1	224.7×	0.015	DNMT3A
cellular response to forskolin	1	224.7×	0.015	ADCY3
response to vitamin A	1	210.7×	0.015	DNMT3A
negative regulation of gene expression via chromosomal CpG island methylation	1	210.7×	0.015	DNMT3A
cellular response to ethanol	1	210.7×	0.015	DNMT3A
hepatocyte apoptotic process	1	210.7×	0.015	DNMT3A
response to lead ion	1	187.2×	0.015	DNMT3A
oocyte development	1	187.2×	0.015	DNMT3A
acrosome reaction	1	177.4×	0.015	ADCY3
cellular response to glucagon stimulus	1	168.5×	0.015	ADCY3
vascular endothelial cell response to laminar fluid shear stress	1	146.5×	0.016	ADCY3
transmission of nerve impulse	1	129.6×	0.018	EFR3B
response to cocaine	1	116.2×	0.019	DNMT3A
DNA methylation-dependent constitutive heterochromatin formation	1	108.7×	0.019	DNMT3A
renal water homeostasis	1	102.1×	0.020	ADCY3
phosphatidylinositol phosphate biosynthetic process	1	96.3×	0.020	EFR3B
long-term memory	1	84.3×	0.022	PTCHD1
response to ionizing radiation	1	82.2×	0.022	DNMT3A
cellular response to amino acid stimulus	1	61.3×	0.029	DNMT3A

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 5

Druggability breadth: 2 of 5 evidence-associated genes (40%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
DNMT3A	0	0
CGREF1	0	0
ADCY3	0	0
PTCHD1	0	0
EFR3B	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
DNMT3A	120	Binding:118, ADMET:1, Functional:1
ADCY3	17	Binding:15, Functional:2

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
DNMT3A	2.1.1.37	DNA (cytosine-5-)-methyltransferase

Cohort genes with high screening signal

≥100 ChEMBL assays — a studied-ness signal; see Therapeutics for approved-drug status.

Symbol	ChEMBL assays
DNMT3A	120

Pharmacogenomics

Cohort genes with a PharmGKB record: 5; 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	DNMT3A
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	4	CGREF1, ADCY3, PTCHD1, EFR3B

Undrugged target profiles

5 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
DNMT3A	120	—
CGREF1	0	—
ADCY3	17	—
PTCHD1	0	—
EFR3B	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.