Intellectual developmental disorder with microcephaly and with or without ocular malformations or hypogonadotropic hypogonadism

Summary

Intellectual developmental disorder with microcephaly and with or without ocular malformations or hypogonadotropic hypogonadism (MONDO:0014376) is a disease caused by SOX11 (GenCC Definitive), with 1 cohort gene.

At a glance

• Causal gene: SOX11 (GenCC Definitive)
• Cohort genes: 1
• ClinVar variants: 121

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	intellectual developmental disorder with microcephaly and with or without ocular malformations or hypogonadotropic hypogonadism
Mondo ID	MONDO:0014376
OMIM	615866
DOID	DOID:0070057
UMLS	C4014528
MedGen	862965
GARD	0016023
Is cancer (heuristic)	no

Also known as: autosomal dominant intellectual disability 27 · Coffin-Siris syndrome 9 · CSS9 · intellectual disability, autosomal dominant 27 · intellectual disability, autosomal dominant type 27 · mental retardation, autosomal dominant 27 · mental retardation, autosomal dominant type 27 · MRD27

Data availability: 121 ClinVar variants · 4 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › autosomal genetic disease › autosomal dominant disease › intellectual developmental disorder with microcephaly and with or without ocular malformations or hypogonadotropic hypogonadism

Related subtypes (191): autosomal dominant polycystic liver disease, cerebral arteriopathy, autosomal dominant, with subcortical infarcts and leukoencephalopathy, type 1, tuberous sclerosis, Treacher-Collins syndrome, hereditary breast ovarian cancer syndrome, autosomal dominant polycystic kidney disease, Lynch syndrome, branchio-oto-renal syndrome, autosomal dominant Aarskog syndrome, acroosteolysis dominant type, ADULT syndrome, autosomal dominant Alport syndrome, amelogenesis imperfecta type 1B, Townes-Brocks syndrome, nevoid basal cell carcinoma syndrome, blepharophimosis, ptosis, and epicanthus inversus syndrome, autosomal dominant brachyolmia, branchiooculofacial syndrome, pheochromocytoma/paraganglioma syndrome 4, cataract-aberrant oral frenula-growth delay syndrome, cherubism, autosomal dominant chondrodysplasia punctata, autosomal dominant popliteal pterygium syndrome, blepharocheilodontic syndrome, cochleosaccular degeneration-cataract syndrome, renal coloboma syndrome, Beare-Stevenson cutis gyrata syndrome, autosomal dominant vibratory urticaria, neurohypophyseal diabetes insipidus, autosomal dominant Kenny-Caffey syndrome, Rapp-Hodgkin syndrome, Ehlers-Danlos syndrome, classic type, autosomal dominant Ehlers-Danlos syndrome, vascular type, multiple endocrine neoplasia type 1, Coffin-Siris syndrome 1, isolated congenital adermatoglyphia, Flynn-Aird syndrome, Frasier syndrome, hand-foot-genital syndrome, Holt-Oram syndrome, hyperkeratosis-hyperpigmentation syndrome, autosomal dominant ichthyosis vulgaris, hyper-IgE recurrent infection syndrome 1, autosomal dominant, autosomal dominant keratitis, autosomal dominant keratitis-ichthyosis-hearing loss syndrome, LADD syndrome, trichorhinophalangeal syndrome type II, Noonan syndrome with multiple lentigines, microcephaly with or without chorioretinopathy, lymphedema, or intellectual disability, Marfan syndrome, melanoma, cutaneous malignant, susceptibility to, 2, autosomal dominant primary microcephaly, autosomal dominant progressive external ophthalmoplegia, monilethrix, Muir-Torre syndrome, autosomal dominant myoglobinuria, autosomal dominant centronuclear myopathy, nail-patella syndrome, multiple endocrine neoplasia type 2B, autosomal dominant omodysplasia, pheochromocytoma/paraganglioma syndrome 1, Pelger-Huet anomaly, multiple endocrine neoplasia type 2A, piebaldism, autosomal dominant medullary cystic kidney disease with or without hyperuricemia, generalized juvenile polyposis/juvenile polyposis coli, juvenile polyposis/hereditary hemorrhagic telangiectasia syndrome, Peutz-Jeghers syndrome, contractures, pterygia, and spondylocarpotarsal fusion syndrome 1A, autosomal dominant distal renal tubular acidosis, retinoschisis, autosomal dominant, autosomal dominant Robinow syndrome, scapuloperoneal spinal muscular atrophy, autosomal dominant, autosomal dominant sideroblastic anemia, spondyloepiphyseal dysplasia tarda, autosomal dominant, proximal symphalangism, calcaneonavicular coalition, thanatophoric dysplasia type 1, trichorhinophalangeal syndrome type I, Muckle-Wells syndrome, autosomal dominant hypophosphatemic rickets, von Hippel-Lindau disease, Denys-Drash syndrome, autosomal dominant severe congenital neutropenia, Costello syndrome, EEC syndrome, multiple cutaneous and mucosal venous malformations, diffuse nonepidermolytic palmoplantar keratoderma, Timothy syndrome, pheochromocytoma/paraganglioma syndrome 2, spondyloepimetaphyseal dysplasia with multiple dislocations, Brooke-Spiegler syndrome, macrocephaly-autism syndrome, pheochromocytoma/paraganglioma syndrome 3, Duane-radial ray syndrome, PCWH syndrome, heart-hand syndrome, Slovenian type, congenital stationary night blindness autosomal dominant 3, mandibulofacial dysostosis-microcephaly syndrome, multiple endocrine neoplasia type 4, juvenile cataract-microcornea-renal glucosuria syndrome, Crouzon syndrome-acanthosis nigricans syndrome, Birk-Barel syndrome, thrombophilia due to protein S deficiency, autosomal dominant, dyskeratosis congenita, autosomal dominant 2, dyskeratosis congenita, autosomal dominant 3, colorectal cancer, hereditary nonpolyposis, type 6, colorectal cancer, hereditary nonpolyposis, type 7, brain small vessel disease 2A, autosomal dominant, intellectual disability, autosomal dominant 14, intellectual disability, autosomal dominant 15, intellectual disability, autosomal dominant 16, hypopigmentation-punctate palmoplantar keratoderma syndrome, intellectual disability-facial dysmorphism syndrome due to SETD5 haploinsufficiency, postaxial polydactyly-anterior pituitary anomalies-facial dysmorphism syndrome, intellectual disability, autosomal dominant 29, intellectual disability, autosomal dominant 30, Houge-Janssens syndrome 2, severe achondroplasia-developmental delay-acanthosis nigricans syndrome, dyskeratosis congenita, autosomal dominant 6, epidermolysis bullosa simplex 6, generalized, with scarring and hair loss, autosomal dominant complex spastic paraplegia, early-onset autosomal dominant Alzheimer disease, muscular dystrophy, limb-girdle, autosomal dominant, Feingold syndrome, Carney complex, neuronopathy, distal hereditary motor, autosomal dominant, autosomal dominant coarctation of aorta, autosomal dominant spondylocostal dysostosis, autosomal dominant hypohidrotic ectodermal dysplasia, Cowden disease, autosomal dominant distal myopathy, autosomal dominant rhegmatogenous retinal detachment, palmoplantar keratoderma-spastic paralysis syndrome, Alagille syndrome due to a JAG1 point mutation, PTEN hamartoma tumor syndrome, gastric adenocarcinoma and proximal polyposis of the stomach, autosomal dominant proximal renal tubular acidosis, autosomal dominant spastic ataxia, Waardenburg syndrome, hereditary retinoblastoma, autosomal dominant hypocalcemia, Li-Fraumeni syndrome, Loeys-Dietz syndrome, hereditary hemorrhagic telangiectasia, hereditary inclusion body myopathy-joint contractures-ophthalmoplegia syndrome, microcephalic osteodysplastic dysplasia, Saul-Wilson type, autosomal dominant intermediate Charcot-Marie-Tooth disease, autosomal dominant cutis laxa, autosomal dominant nonsyndromic hearing loss, autosomal dominant optic atrophy, autosomal dominant Emery-Dreifuss muscular dystrophy, autosomal dominant cerebellar ataxia, autosomal dominant osteopetrosis, autosomal dominant epidermolytic ichthyosis, ventricular arrhythmias due to cardiac ryanodine receptor calcium release deficiency syndrome, distal arthrogryposis type 2B1, neurofibromatosis, autosomal dominant cataract, arthrogryposis, distal, type 2B2, arthrogryposis, distal, type 2B3, Charcot-Marie-Tooth disease, demyelinating, type 1G, Delpire-McNeill syndrome, LAMA5-related multisystemic syndrome, autosomal dominant oculocutaneous albinism, Charcot-Marie-tooth disease, axonal, type 2DD, Pilarowski-Bjornsson syndrome, intellectual disability, autosomal dominant, fatty acyl-CoA reductase 1 upregulation, GUCY2D-related dominant retinopathy, RPE65-related dominant retinopathy, autosomal dominant titinopathy, NOG-related symphalangism spectrum disorder, ALPL-related autosomal dominant hypophosphatasia, MYH10-related neurodevelopmental disorder with congenital anomalies, spastic paraplegia 30A, autosomal dominant, TMEM127-related tumor predisposition, MAX-related tumor predisposition, BMPR1A-related juvenile polyposis syndrome, RP1-related dominant retinopathy, Birt-Hogg-Dube syndrome, inclusion body myopathy and brain white matter abnormalities, KINSSHIP syndrome, autosomal dominant nebulin-related myopathy, IMPG1-related dominant retinopathy, PROM1-related dominant retinopathy, PURA-related severe neonatal hypotonia-seizures-encephalopathy syndrome, ALG8-related autosomal dominant polycystic kidney and/or liver disease, NOTCH1-related AOS spectrum disorder, FLNB-associated autosomal dominant filamin related bone disorder, familial antiphospholipid 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

121 retrieved; paginated sample, class counts are floors:

54 uncertain significance, 36 likely pathogenic, 12 pathogenic, 11 conflicting classifications of pathogenicity, 8 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1067260	NM_003108.4(SOX11):c.152G>A (p.Arg51Gln)	SOX11	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1067424	NM_003108.4(SOX11):c.168C>G (p.Phe56Leu)	SOX11	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1344679	NM_003108.4(SOX11):c.191G>A (p.Arg64His)	SOX11	Pathogenic	criteria provided, single submitter
139530	NM_003108.4(SOX11):c.178T>C (p.Ser60Pro)	SOX11	Pathogenic	no assertion criteria provided
1686222	NM_003108.4(SOX11):c.170T>C (p.Met57Thr)	SOX11	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1804060	NM_003108.4(SOX11):c.250G>C (p.Gly84Arg)	SOX11	Pathogenic	criteria provided, single submitter
2443007	NM_003108.4(SOX11):c.87C>A (p.Cys29Ter)	SOX11	Pathogenic	criteria provided, single submitter
2443009	NM_003108.4(SOX11):c.155C>T (p.Pro52Leu)	SOX11	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2443014	NM_003108.4(SOX11):c.176G>A (p.Trp59Ter)	SOX11	Pathogenic	criteria provided, single submitter
2443020	NM_003108.4(SOX11):c.317G>C (p.Arg106Pro)	SOX11	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2443029	NM_003108.4(SOX11):c.150G>C (p.Lys50Asn)	SOX11	Pathogenic	criteria provided, single submitter
2443030	NM_003108.4(SOX11):c.148A>C (p.Lys50Gln)	SOX11	Pathogenic	criteria provided, single submitter
3235714	NM_003108.4(SOX11):c.1178C>A (p.Ser393Ter)	SOX11	Pathogenic	criteria provided, single submitter
374396	NM_003108.4(SOX11):c.1286G>A (p.Trp429Ter)	SOX11	Pathogenic	no assertion criteria provided
3906864	NM_003108.4(SOX11):c.168C>A (p.Phe56Leu)	SOX11	Pathogenic	no assertion criteria provided
4082371	NM_003108.4(SOX11):c.305C>A (p.Ala102Glu)	SOX11	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
420675	NM_003108.4(SOX11):c.299G>C (p.Arg100Pro)	SOX11	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
520936	NM_003108.4(SOX11):c.791C>A (p.Ser264Ter)	SOX11	Pathogenic	criteria provided, multiple submitters, no conflicts
807694	NM_003108.4(SOX11):c.353A>C (p.Tyr118Ser)	SOX11	Pathogenic	criteria provided, single submitter
870388	NM_003108.4(SOX11):c.305C>T (p.Ala102Val)	SOX11	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1029671	NM_003108.4(SOX11):c.700G>T (p.Glu234Ter)	SOX11	Likely pathogenic	criteria provided, multiple submitters, no conflicts
1320206	NM_003108.4(SOX11):c.886G>T (p.Glu296Ter)	SOX11	Likely pathogenic	criteria provided, single submitter
1332805	NM_003108.4(SOX11):c.239C>T (p.Ser80Phe)	SOX11	Likely pathogenic	criteria provided, single submitter
1338785	NM_003108.4(SOX11):c.650_651insGA (p.Lys218fs)	SOX11	Likely pathogenic	criteria provided, single submitter
1685451	NM_003108.4(SOX11):c.167T>G (p.Phe56Cys)	SOX11	Likely pathogenic	criteria provided, single submitter
1705386	NM_003108.4(SOX11):c.190C>T (p.Arg64Cys)	SOX11	Likely pathogenic	criteria provided, multiple submitters, no conflicts
1802586	NM_003108.4(SOX11):c.159G>T (p.Met53Ile)	SOX11	Likely pathogenic	criteria provided, single submitter
1804059	NM_003108.4(SOX11):c.146T>G (p.Ile49Ser)	SOX11	Likely pathogenic	criteria provided, single submitter
2430907	NM_003108.4(SOX11):c.191G>C (p.Arg64Pro)	SOX11	Likely pathogenic	criteria provided, multiple submitters, no conflicts
2443008	NM_003108.4(SOX11):c.152G>T (p.Arg51Leu)	SOX11	Likely pathogenic	criteria provided, single submitter

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
SOX11	Definitive	Autosomal dominant	intellectual developmental disorder with microcephaly and with or without ocular malformations or hypogonadotropic hypogonadism	5

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
SOX11	Orphanet:1465	Coffin-Siris 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
SOX11	HGNC:11191	ENSG00000176887	P35716	Transcription factor SOX-11	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
SOX11	Transcription factor SOX-11	Transcription factor that acts as a transcriptional activator.

Protein-family classification

Druggable: 0 · Difficult: 1 · Unknown: 0 · Druggable fraction: 0.0

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Transcription factor	1	8.3×	0.121

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
SOX11	Transcription factor	no		HMG_box_dom, SOX-12/11/4, HMG_box_dom_sf

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
cortical plate	1
embryo	1
ganglionic eminence	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
SOX11	93	broad	marker	ganglionic eminence, cortical plate, embryo

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
SOX11	2,090

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
SOX11	P35716	4

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 0. Enrichment computed across 1 evidence-associated genes (0 with Reactome annotation).

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
negative regulation of transcription regulatory region DNA binding	1	16852.0×	0.002	SOX11
closure of optic fissure	1	8426.0×	0.002	SOX11
positive regulation of lens epithelial cell proliferation	1	8426.0×	0.002	SOX11
negative regulation of lymphocyte proliferation	1	3370.4×	0.002	SOX11
soft palate development	1	3370.4×	0.002	SOX11
noradrenergic neuron differentiation	1	2407.4×	0.002	SOX11
positive regulation of hormone secretion	1	1685.2×	0.002	SOX11
hard palate development	1	1685.2×	0.002	SOX11
negative regulation of glial cell proliferation	1	1685.2×	0.002	SOX11
neuroepithelial cell differentiation	1	1532.0×	0.002	SOX11
lens morphogenesis in camera-type eye	1	1296.3×	0.002	SOX11
cornea development in camera-type eye	1	1296.3×	0.002	SOX11
positive regulation of hippo signaling	1	1053.2×	0.002	SOX11
lung morphogenesis	1	1053.2×	0.002	SOX11
eyelid development in camera-type eye	1	1053.2×	0.002	SOX11
positive regulation of ossification	1	936.2×	0.002	SOX11
sympathetic nervous system development	1	936.2×	0.002	SOX11
embryonic digestive tract morphogenesis	1	936.2×	0.002	SOX11
glial cell proliferation	1	887.0×	0.002	SOX11
regulation of transforming growth factor beta receptor signaling pathway	1	802.5×	0.002	SOX11
camera-type eye morphogenesis	1	766.0×	0.002	SOX11
oligodendrocyte development	1	601.9×	0.003	SOX11
positive regulation of neurogenesis	1	581.1×	0.003	SOX11
positive regulation of stem cell proliferation	1	526.6×	0.003	SOX11
spinal cord development	1	510.7×	0.003	SOX11
positive regulation of BMP signaling pathway	1	455.5×	0.003	SOX11
ventricular septum morphogenesis	1	432.1×	0.003	SOX11
embryonic skeletal system morphogenesis	1	391.9×	0.004	SOX11
skeletal muscle cell differentiation	1	343.9×	0.004	SOX11
outflow tract morphogenesis	1	306.4×	0.004	SOX11

Therapeutics

Drug target analysis

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

Druggability breadth: 0 of 1 evidence-associated genes (0%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
SOX11	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Pharmacogenomics

Cohort genes with a PharmGKB record: 1; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

0 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	SOX11

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)
SOX11	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.