Shprintzen-Goldberg syndrome

Summary

Shprintzen-Goldberg syndrome (MONDO:0008426) is a disease caused by SKI (GenCC Definitive), with 4 cohort genes and 2 clinical trials.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: SKI (GenCC Definitive)
• Cohort genes: 4
• ClinVar variants: 935
• Phenotypes (HPO): 53
• Clinical trials: 2

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		60	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

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

HPO ID	Term	Frequency
HP:0000268	Dolichocephaly	Very frequent (80-99%)
HP:0000278	Retrognathia	Very frequent (80-99%)
HP:0000316	Hypertelorism	Very frequent (80-99%)
HP:0000347	Micrognathia	Very frequent (80-99%)
HP:0000358	Posteriorly rotated ears	Very frequent (80-99%)
HP:0000369	Low-set ears	Very frequent (80-99%)
HP:0000494	Downslanted palpebral fissures	Very frequent (80-99%)
HP:0000506	Telecanthus	Very frequent (80-99%)
HP:0000520	Proptosis	Very frequent (80-99%)
HP:0001166	Arachnodactyly	Very frequent (80-99%)
HP:0001249	Intellectual disability	Very frequent (80-99%)
HP:0001252	Hypotonia	Very frequent (80-99%)
HP:0001763	Pes planus	Very frequent (80-99%)
HP:0002705	High, narrow palate	Very frequent (80-99%)
HP:0001382	Joint hypermobility	Frequent (30-79%)
HP:0000023	Inguinal hernia	Frequent (30-79%)
HP:0000327	Hypoplasia of the maxilla	Frequent (30-79%)
HP:0000348	High forehead	Frequent (30-79%)
HP:0000486	Strabismus	Frequent (30-79%)
HP:0000508	Ptosis	Frequent (30-79%)
HP:0000767	Pectus excavatum	Frequent (30-79%)
HP:0000768	Pectus carinatum	Frequent (30-79%)
HP:0001334	Communicating hydrocephalus	Frequent (30-79%)
HP:0001363	Craniosynostosis	Frequent (30-79%)
HP:0001537	Umbilical hernia	Frequent (30-79%)
HP:0001634	Mitral valve prolapse	Frequent (30-79%)
HP:0001646	Abnormal aortic valve morphology	Frequent (30-79%)
HP:0001653	Mitral regurgitation	Frequent (30-79%)
HP:0002007	Frontal bossing	Frequent (30-79%)
HP:0002650	Scoliosis	Frequent (30-79%)
HP:0100490	Camptodactyly of finger	Frequent (30-79%)
HP:0000028	Cryptorchidism	Occasional (5-29%)
HP:0000252	Microcephaly	Occasional (5-29%)
HP:0000405	Conductive hearing impairment	Occasional (5-29%)
HP:0000411	Protruding ear	Occasional (5-29%)
HP:0000463	Anteverted nares	Occasional (5-29%)
HP:0000545	Myopia	Occasional (5-29%)
HP:0000774	Narrow chest	Occasional (5-29%)
HP:0000921	Missing ribs	Occasional (5-29%)
HP:0000938	Osteopenia	Occasional (5-29%)
HP:0000944	Abnormal metaphysis morphology	Occasional (5-29%)
HP:0000974	Hyperextensible skin	Occasional (5-29%)
HP:0001387	Joint stiffness	Occasional (5-29%)
HP:0001508	Failure to thrive	Occasional (5-29%)
HP:0002020	Gastroesophageal reflux	Occasional (5-29%)
HP:0002104	Apnea	Occasional (5-29%)
HP:0002119	Ventriculomegaly	Occasional (5-29%)
HP:0002308	Chiari malformation	Occasional (5-29%)
HP:0002857	Genu valgum	Occasional (5-29%)
HP:0003042	Elbow dislocation	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	Shprintzen-Goldberg syndrome
Mondo ID	MONDO:0008426
OMIM	182212
Orphanet	2462
NCIT	C124840
SNOMED CT	719069008
UMLS	C1321551
MedGen	231160
GARD	0004861
NORD	1908
Is cancer (heuristic)	no

Also known as: Marfanoid craniosynostosis syndrome · Marfanoid disorder with craniosynostosis type 1 · Marfanoid-craniosynostosis syndrome · SGS · Shprintzen Goldberg Syndrome · Shprintzen-Goldberg craniosynostosis syndrome · Shprintzen-Goldberg marfanoid syndrome · Shprintzen-Goldberg syndrome

Data availability: 935 ClinVar variants · 8 GenCC gene-disease records · 3 cell lines.

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 › Shprintzen-Goldberg 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, 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, Tatton-Brown-Rahman overgrowth syndrome, 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:

262 likely benign, 245 uncertain significance, 51 conflicting classifications of pathogenicity, 28 benign/likely benign, 6 benign, 4 likely pathogenic, 2 pathogenic/likely pathogenic, 2 pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1196933	NM_003036.4(SKI):c.349G>A (p.Gly117Ser)	SKI	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2202692	NM_003036.4(SKI):c.82T>A (p.Ser28Thr)	SKI	Pathogenic	criteria provided, single submitter
224868	NM_003036.4(SKI):c.349G>C (p.Gly117Arg)	SKI	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
224869	NM_003036.4(SKI):c.62T>G (p.Leu21Arg)	SKI	Pathogenic	criteria provided, single submitter
1679387	NM_003036.4(SKI):c.106G>C (p.Ala36Pro)	SKI	Likely pathogenic	criteria provided, single submitter
1695374	NM_003036.4(SKI):c.350G>A (p.Gly117Asp)	SKI	Likely pathogenic	criteria provided, single submitter
1709127	NM_003036.4(SKI):c.103C>G (p.Pro35Ala)	SKI	Likely pathogenic	criteria provided, single submitter
3686637	NM_003036.4(SKI):c.104C>T (p.Pro35Leu)	SKI	Likely pathogenic	criteria provided, single submitter
1035650	NM_003036.4(SKI):c.611C>T (p.Ala204Val)	SKI	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1035726	NM_003036.4(SKI):c.985C>T (p.Pro329Ser)	SKI	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1043983	NM_003036.4(SKI):c.242C>A (p.Pro81Gln)	SKI	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1220046	NM_003036.4(SKI):c.1711G>A (p.Val571Met)	SKI	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1306121	NM_003036.4(SKI):c.170C>T (p.Ala57Val)	SKI	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1309209	NM_003036.4(SKI):c.1339G>A (p.Ala447Thr)	SKI	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1313938	NM_003036.4(SKI):c.1654G>A (p.Gly552Ser)	SKI	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1314447	NM_003036.4(SKI):c.188C>T (p.Pro63Leu)	SKI	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1354096	NM_003036.4(SKI):c.581C>A (p.Ala194Asp)	SKI	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1417909	NM_003036.4(SKI):c.190G>A (p.Val64Met)	SKI	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1438306	NM_003036.4(SKI):c.1382C>T (p.Thr461Ile)	SKI	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1764370	NM_003036.4(SKI):c.86T>G (p.Met29Arg)	SKI	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1774563	NM_003036.4(SKI):c.1528G>T (p.Ala510Ser)	SKI	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1779029	NM_003036.4(SKI):c.1057T>C (p.Ser353Pro)	SKI	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1782528	NM_003036.4(SKI):c.1913A>G (p.Lys638Arg)	SKI	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1783820	NM_003036.4(SKI):c.1981G>A (p.Ala661Thr)	SKI	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
193248	NM_003036.4(SKI):c.798C>T (p.Ala266=)	SKI	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
193249	NM_003036.4(SKI):c.216C>T (p.Pro72=)	SKI	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
198155	NM_003036.4(SKI):c.1890C>T (p.Ala630=)	SKI	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
213667	NM_003036.4(SKI):c.1162G>A (p.Ala388Thr)	SKI	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
213671	NM_003036.4(SKI):c.1212-8C>T	SKI	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
213675	NM_003036.4(SKI):c.1556G>A (p.Arg519His)	SKI	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 31 · Orphanet: 16 · 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
SKI	Definitive	Autosomal dominant	Shprintzen-Goldberg syndrome	7
FBN1	Limited	Unknown	Shprintzen-Goldberg syndrome	24

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
SKI	Orphanet:1606	1p36 deletion syndrome
SKI	Orphanet:2462	Shprintzen-Goldberg syndrome
FBN1	Orphanet:1885	Isolated ectopia lentis
FBN1	Orphanet:2084	Glaucoma-ectopia lentis-microspherophakia-stiff joints-short stature syndrome
FBN1	Orphanet:2462	Shprintzen-Goldberg syndrome
FBN1	Orphanet:2623	Geleophysic dysplasia
FBN1	Orphanet:2833	Stiff skin syndrome
FBN1	Orphanet:284963	Marfan syndrome type 1
FBN1	Orphanet:284979	Neonatal Marfan syndrome
FBN1	Orphanet:300382	Progeroid and marfanoid aspect-lipodystrophy syndrome
FBN1	Orphanet:3449	Weill-Marchesani syndrome
FBN1	Orphanet:91387	Familial thoracic aortic aneurysm and aortic dissection
FBN1	Orphanet:969	Acromicric dysplasia
GABRD	Orphanet:1606	1p36 deletion syndrome
GABRD	Orphanet:307	Juvenile myoclonic epilepsy
GABRD	Orphanet:36387	Genetic epilepsy with febrile seizure plus

Cohort genes → proteins

4 cohort genes, 4 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	4

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
SKI	HGNC:10896	ENSG00000157933	P12755	Ski oncogene	gencc,clinvar
FBN1	HGNC:3603	ENSG00000166147	P35555	Fibrillin-1	gencc
CPTP	HGNC:28116	ENSG00000224051	Q5TA50	Ceramide-1-phosphate transfer protein	clinvar
GABRD	HGNC:4084	ENSG00000187730	O14764	Gamma-aminobutyric acid receptor subunit delta	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
SKI	Ski oncogene	May play a role in terminal differentiation of skeletal muscle cells but not in the determination of cells to the myogenic lineage.
FBN1	Fibrillin-1	Structural component of the 10-12 nm diameter microfibrils of the extracellular matrix, which conveys both structural and regulatory properties to load-bearing connective tissues.
CPTP	Ceramide-1-phosphate transfer protein	Mediates the intracellular transfer of ceramide-1-phosphate (C1P) between organelle membranes and the cell membrane.
GABRD	Gamma-aminobutyric acid receptor subunit delta	Delta subunit of the heteropentameric ligand-gated chloride channel gated by gamma-aminobutyric acid (GABA), a major inhibitory neurotransmitter in the brain.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 4 · 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	4	1.8×	0.097

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
SKI	Other/Unknown	no		SKI/SNO/DAC, DNA-bd_dom_put_sf, SAND-like_dom_sf
FBN1	Other/Unknown	no		EGF-type_Asp/Asn_hydroxyl_site, EGF, EGF-like_Ca-bd_dom
CPTP	Other/Unknown	no		Glycolipid_transfer_prot_dom, GLTP_sf
GABRD	Other/Unknown	no		GABAA/Glycine_rcpt, Neurotrans-gated_channel_TM, Neur_channel

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)	4
unknown	0

Top tissues across cohort

Tissue	Cohort genes
cerebellar hemisphere	2
right hemisphere of cerebellum	2
nipple	1
decidua	1
skin of hip	1
synovial joint	1
apex of heart	1
heart left ventricle	1
lower esophagus mucosa	1
cerebellar cortex	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
SKI	268	ubiquitous	marker	nipple, right hemisphere of cerebellum, cerebellar hemisphere
FBN1	275	ubiquitous	marker	synovial joint, skin of hip, decidua
CPTP	278	ubiquitous	marker	apex of heart, lower esophagus mucosa, heart left ventricle
GABRD	176	broad	marker	right hemisphere of cerebellum, cerebellar hemisphere, cerebellar cortex

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
FBN1	3,640
GABRD	2,084
SKI	1,415
CPTP	512

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
FBN1	P35555	11
GABRD	O14764	7
CPTP	Q5TA50	6
SKI	P12755	4

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 17. Enrichment computed across 4 evidence-associated genes (3 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 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Glycosphingolipid transport	1	475.8×	0.024	CPTP
Transcriptional activity of SMAD2/SMAD3:SMAD4 heterotrimer	1	122.8×	0.024	SKI
Downregulation of SMAD2/3:SMAD4 transcriptional activity	1	122.8×	0.024	SKI
Signaling by BMP	1	119.0×	0.024	SKI
Elastic fibre formation	1	112.0×	0.024	FBN1
TGF-beta receptor signaling activates SMADs	1	108.8×	0.024	FBN1
Molecules associated with elastic fibres	1	102.9×	0.024	FBN1
Signaling by TGF-beta Receptor Complex	1	66.8×	0.032	SKI
Integrin cell surface interactions	1	44.8×	0.040	FBN1
Degradation of the extracellular matrix	1	39.2×	0.040	FBN1
Signaling by TGFB family members	1	38.5×	0.040	SKI
Post-translational protein phosphorylation	1	33.4×	0.042	FBN1
Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs)	1	28.8×	0.045	FBN1
RNA Polymerase II Transcription	1	7.5×	0.155	SKI
Gene expression (Transcription)	1	6.0×	0.180	SKI
Generic Transcription Pathway	1	5.0×	0.197	SKI
Signal Transduction	1	3.4×	0.267	SKI

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 4 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
camera-type eye development	2	179.3×	0.003	SKI, FBN1
ceramide 1-phosphate transport	1	4213.0×	0.007	CPTP
nose morphogenesis	1	1404.3×	0.009	SKI
post-embryonic eye morphogenesis	1	1404.3×	0.009	FBN1
obsolete sequestering of BMP in extracellular matrix	1	1053.2×	0.009	FBN1
obsolete sequestering of TGFbeta in extracellular matrix	1	1053.2×	0.009	FBN1
negative regulation of osteoclast development	1	842.6×	0.010	FBN1
negative regulation of Schwann cell proliferation	1	601.9×	0.012	SKI
myotube differentiation	1	526.6×	0.012	SKI
ceramide transport	1	383.0×	0.012	CPTP
embryonic eye morphogenesis	1	383.0×	0.012	FBN1
negative regulation of activin receptor signaling pathway	1	351.1×	0.012	SKI
lens morphogenesis in camera-type eye	1	324.1×	0.012	SKI
cellular response to insulin-like growth factor stimulus	1	324.1×	0.012	FBN1
positive regulation of DNA binding	1	300.9×	0.012	SKI
intermembrane lipid transfer	1	300.9×	0.012	CPTP
negative regulation of NLRP3 inflammasome complex assembly	1	247.8×	0.014	CPTP
myelination in peripheral nervous system	1	221.7×	0.014	SKI
olfactory bulb development	1	191.5×	0.014	SKI
camera-type eye morphogenesis	1	191.5×	0.014	SKI
anterior/posterior axis specification	1	183.2×	0.014	SKI
cell adhesion mediated by integrin	1	168.5×	0.014	FBN1
bone morphogenesis	1	150.5×	0.014	SKI
negative regulation of SMAD protein signal transduction	1	150.5×	0.014	SKI
cardiac muscle cell proliferation	1	145.3×	0.014	SKI
gamma-aminobutyric acid signaling pathway	1	135.9×	0.014	GABRD
negative regulation of osteoclast differentiation	1	135.9×	0.014	FBN1
skeletal muscle fiber development	1	135.9×	0.014	SKI
metanephros development	1	127.7×	0.014	FBN1
negative regulation of interleukin-1 beta production	1	127.7×	0.014	CPTP

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 4 evidence-associated genes (25%) 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
GABRD	ENZALUTAMIDE

Top cohort targets by molecule count

Symbol	Molecules	Max phase
GABRD	16	4
SKI	0	0
FBN1	0	0
CPTP	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
ENZALUTAMIDE	4	GABRD
DIAZEPAM	4	GABRD
LIOTHYRONINE	4	GABRD
GANAXOLONE	4	GABRD
BREXANOLONE	4	GABRD
APALUTAMIDE	4	GABRD
FLUMAZENIL	4	GABRD
CLONAZEPAM	4	GABRD
ZURANOLONE	4	GABRD
DELORAZEPAM	2	GABRD
FLAVONE	2	GABRD
PROGABIDE	2	GABRD
ABECARNIL	2	GABRD
BAICALEIN	2	GABRD
MUSCIMOL	1	GABRD
GAMMA-AMINOBUTYRIC ACID	1	GABRD

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
GABRD	203	Binding:184, Functional:15, Toxicity:3, ADMET:1

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
GABRD	203

Pharmacogenomics

Cohort genes with a PharmGKB record: 4; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

16 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)
ENZALUTAMIDE	4	GABRD
DIAZEPAM	4	GABRD
LIOTHYRONINE	4	GABRD
GANAXOLONE	4	GABRD
BREXANOLONE	4	GABRD
APALUTAMIDE	4	GABRD
FLUMAZENIL	4	GABRD
CLONAZEPAM	4	GABRD
ZURANOLONE	4	GABRD
DELORAZEPAM	2	GABRD
FLAVONE	2	GABRD
PROGABIDE	2	GABRD
ABECARNIL	2	GABRD
BAICALEIN	2	GABRD
MUSCIMOL	1	GABRD
GAMMA-AMINOBUTYRIC ACID	1	GABRD

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	GABRD
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	3	SKI, FBN1, CPTP

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
SKI	0	—
FBN1	0	—
CPTP	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 2.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	2

Top trials by phase / activity

NCT	Phase	Status	Title
NCT03440697	Not specified	ACTIVE_NOT_RECRUITING	Pathogenetic Basis of Aortopathy and Aortic Valve Disease
NCT01322165	Not specified	COMPLETED	National Registry of Genetically Triggered Thoracic Aortic Aneurysms and Cardiovascular Conditions