autism spectrum disorder due to AUTS2 deficiency

Summary

autism spectrum disorder due to AUTS2 deficiency (MONDO:0014361) is a disease caused by AUTS2 (GenCC Definitive), with 4 cohort genes and 1 clinical trial.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: AUTS2 (GenCC Definitive)
• Cohort genes: 4
• ClinVar variants: 161
• Phenotypes (HPO): 55
• Clinical trials: 1

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)

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

HPO ID	Term	Frequency
HP:0000750	Delayed speech and language development	Very frequent (80-99%)
HP:0001249	Intellectual disability	Very frequent (80-99%)
HP:0001999	Abnormal facial shape	Very frequent (80-99%)
HP:0000160	Narrow mouth	Frequent (30-79%)
HP:0000252	Microcephaly	Frequent (30-79%)
HP:0000286	Epicanthus	Frequent (30-79%)
HP:0000316	Hypertelorism	Frequent (30-79%)
HP:0000322	Short philtrum	Frequent (30-79%)
HP:0000347	Micrognathia	Frequent (30-79%)
HP:0000369	Low-set ears	Frequent (30-79%)
HP:0000431	Wide nasal bridge	Frequent (30-79%)
HP:0000486	Strabismus	Frequent (30-79%)
HP:0000520	Proptosis	Frequent (30-79%)
HP:0000722	Compulsive behaviors	Frequent (30-79%)
HP:0000729	Autistic behavior	Frequent (30-79%)
HP:0000733	Abnormal repetitive mannerisms	Frequent (30-79%)
HP:0001263	Global developmental delay	Frequent (30-79%)
HP:0001290	Generalized hypotonia	Frequent (30-79%)
HP:0001328	Specific learning disability	Frequent (30-79%)
HP:0001488	Bilateral ptosis	Frequent (30-79%)
HP:0001518	Small for gestational age	Frequent (30-79%)
HP:0002553	Highly arched eyebrow	Frequent (30-79%)
HP:0004322	Short stature	Frequent (30-79%)
HP:0008762	Repetitive compulsive behavior	Frequent (30-79%)
HP:0008872	Feeding difficulties in infancy	Frequent (30-79%)
HP:0012745	Short palpebral fissure	Frequent (30-79%)
HP:0025112	Sound sensitivity	Frequent (30-79%)
HP:0000023	Inguinal hernia	Occasional (5-29%)
HP:0000028	Cryptorchidism	Occasional (5-29%)
HP:0000278	Retrognathia	Occasional (5-29%)
HP:0000463	Anteverted nares	Occasional (5-29%)
HP:0000582	Upslanted palpebral fissure	Occasional (5-29%)
HP:0000752	Hyperactivity	Occasional (5-29%)
HP:0000964	Eczematoid dermatitis	Occasional (5-29%)
HP:0001250	Seizure	Occasional (5-29%)
HP:0001257	Spasticity	Occasional (5-29%)
HP:0001276	Hypertonia	Occasional (5-29%)
HP:0001347	Hyperreflexia	Occasional (5-29%)
HP:0001537	Umbilical hernia	Occasional (5-29%)
HP:0001627	Abnormal heart morphology	Occasional (5-29%)
HP:0001631	Atrial septal defect	Occasional (5-29%)
HP:0001760	Abnormal foot morphology	Occasional (5-29%)
HP:0002650	Scoliosis	Occasional (5-29%)
HP:0002803	Congenital contracture	Occasional (5-29%)
HP:0002804	Arthrogryposis multiplex congenita	Occasional (5-29%)
HP:0002808	Kyphosis	Occasional (5-29%)
HP:0004283	Narrow palm	Occasional (5-29%)
HP:0005274	Prominent nasal tip	Occasional (5-29%)
HP:0006184	Decreased palmar creases	Occasional (5-29%)
HP:0007018	Attention deficit hyperactivity disorder	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	autism spectrum disorder due to AUTS2 deficiency
Mondo ID	MONDO:0014361
OMIM	615834
Orphanet	352490
DOID	DOID:0070056
UMLS	C4014435
MedGen	862872
GARD	0017520
Is cancer (heuristic)	no

Also known as: ASD due to AUTS2 deficiency · autism spectrum disorder due to AUTS2 deficiency · AUTS2 syndrome · intellectual developmental disorder, autosomal dominant 26 · intellectual disability type 26 · mental retardation, autosomal dominant 26 · mental retardation, autosomal dominant type 26 · MRD26

Data availability: 161 ClinVar variants · 4 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › nervous system disorder › congenital nervous system disorder › autism spectrum disorder due to AUTS2 deficiency

Related subtypes (216): polymicrogyria, congenital myasthenic syndrome with tubular aggregates, prenatal-onset spinal muscular atrophy with congenital bone fractures, anencephaly, cerebral cavernous malformation, meningocele, progressive external ophthalmoplegia, congenital nystagmus, congenital toxoplasmosis, congenital contractural arachnodactyly, congenital trigeminal anesthesia, familial congenital palsy of trochlear nerve, Myhre syndrome, Aase-Smith syndrome, KBG syndrome, autosomal dominant primary microcephaly, Mobius syndrome, MYH7-related skeletal myopathy, congenital stationary night blindness autosomal dominant 2, Prader-Willi syndrome, congenital myopathy 7A, myosin storage, autosomal dominant, Smith-Magenis syndrome, spina bifida, Freeman-Sheldon syndrome, isolated cerebellar hypoplasia/agenesis, Chediak-Higashi syndrome, Cohen syndrome, multiple pterygium-malignant hyperthermia syndrome, corpus callosum, agenesis of, congenital lactic acidosis, Saguenay-Lac-Saint-Jean type, facial dysmorphism-macrocephaly-myopia-Dandy-Walker malformation syndrome, diastematomyelia, EEM syndrome, Mowat-Wilson syndrome, Johanson-Blizzard syndrome, intellectual disability, Buenos-Aires type, myasthenia, congenital, refractory to acetylcholinesterase inhibitors, congenital myasthenic syndrome 6, Bailey-Bloch congenital myopathy, congenital stationary night blindness 1B, radioulnar synostosis-developmental delay-hypotonia syndrome, Schinzel-Giedion syndrome, schizencephaly, intellectual disability, Wolff type, X-linked intellectual disability-plagiocephaly syndrome, X-linked adrenal hypoplasia congenita, 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, X-linked intellectual disability, Cabezas type, X-linked intellectual disability-cubitus valgus-dysmorphism syndrome, syndromic X-linked intellectual disability Claes-Jensen type, moyamoya angiopathy-short stature-facial dysmorphism-hypergonadotropic hypogonadism syndrome, multiple congenital anomalies-hypotonia-seizures syndrome 2, developmental and epileptic encephalopathy, 36, blepharophimosis - intellectual disability syndrome, MKB type, X-linked intellectual disability-short stature-overweight syndrome, intellectual disability, X-linked, syndromic 33, syndromic X-linked intellectual disability 34, infantile-onset X-linked spinal muscular atrophy, syndromic X-linked intellectual disability 5, holoprosencephaly-hypokinesia-congenital contractures syndrome, X-linked intellectual disability with marfanoid habitus, Wieacker-Wolff syndrome, MERRF syndrome, macrocephaly-spastic paraplegia-dysmorphism syndrome, intellectual disability-sparse hair-brachydactyly syndrome, myofibrillar myopathy 1, isolated hereditary congenital facial paralysis, fibrosis of extraocular muscles, congenital, 2, Pierpont syndrome, congenital cataracts-facial dysmorphism-neuropathy syndrome, Bohring-Opitz syndrome, PHACE syndrome, B4GALT1-congenital disorder of glycosylation, developmental malformations-deafness-dystonia syndrome, sensory ataxic neuropathy, dysarthria, and ophthalmoparesis, AICA-ribosiduria, myofibrillar myopathy 3, fibrosis of extraocular muscles, congenital, 3c, myofibrillar myopathy 4, myofibrillar myopathy 5, cone-rod synaptic disorder, congenital nonprogressive, congenital stationary night blindness autosomal dominant 3, congenital stationary night blindness autosomal dominant 1, intellectual disability, autosomal recessive 12, progressive myoclonic epilepsy type 3, chromosome 15q13.3 microdeletion syndrome, combined pituitary hormone deficiencies, genetic form, congenital stationary night blindness 1D, DYRK1A-related intellectual disability syndrome, Pitt-Hopkins-like syndrome 2, developmental and epileptic encephalopathy, 15, Schuurs-Hoeijmakers syndrome, severe intellectual disability-poor language-strabismus-grimacing face-long fingers syndrome, severe intellectual disability-progressive spastic diplegia syndrome, hypotonia, infantile, with psychomotor retardation and characteristic facies, developmental and epileptic encephalopathy, 18, CTCF-related neurodevelopmental disorder, developmental and epileptic encephalopathy, 23, ADNP-related multiple congenital anomalies - intellectual disability - autism spectrum disorder, Bardet-Biedl syndrome 11, cerebellar-facial-dental syndrome, fibrosis of extraocular muscles, congenital, 5, congenital myasthenic syndrome 15, lethal fetal cerebrorenogenitourinary agenesis/hypoplasia syndrome, autosomal dominant intellectual disability-craniofacial anomalies-cardiac defects syndrome, congenital myasthenic syndrome 18, autosomal recessive spinocerebellar ataxia 20, Houge-Janssens syndrome 1, intellectual disability-microcephaly-strabismus-behavioral abnormalities syndrome, congenital stationary night blindness 1G, hypomyelinating leukodystrophy 10, developmental and epileptic encephalopathy, 50, congenital insensitivity to pain-hypohidrosis syndrome, macrocephaly-intellectual disability-neurodevelopmental disorder-small thorax syndrome, SLC39A8-CDG, 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, intellectual disability, autosomal recessive 53, TELO2-related intellectual disability-neurodevelopmental disorder, micrognathia-recurrent infections-behavioral abnormalities-mild intellectual disability syndrome, autosomal recessive limb-girdle muscular dystrophy type 2Y, myofibrillar myopathy 7, short stature-brachydactyly-obesity-global developmental delay syndrome, autosomal recessive limb-girdle muscular dystrophy type 2R1, severe microbrachycephaly-intellectual disability-athetoid cerebral palsy syndrome, congenital laryngeal palsy, congenital or early infantile CACH syndrome, congenital epulis, severe congenital nemaline myopathy, intermediate nemaline myopathy, typical nemaline myopathy, childhood-onset nemaline myopathy, adult-onset nemaline myopathy, qualitative or quantitative defects of protein involved in O-glycosylation of alpha-dystroglycan, holoprosencephaly, congenital insensitivity to pain with hyperhidrosis, congenital hydrocephalus, familial congenital mirror movements, macrocephaly-short stature-paraplegia syndrome, cephalocele, mitochondrial neurogastrointestinal encephalomyopathy, X-linked intellectual disability-hypogonadism-ichthyosis-obesity-short stature syndrome, 7p22.1 microduplication syndrome, congenital achiasma, congenital retinal arteriovenous communication, 3q27.3 microdeletion syndrome, Prader-Willi-like syndrome, 9q31.1q31.3 microdeletion syndrome, congenital oculomotor nerve palsy, congenital abducens nerve palsy, neurodevelopmental disorder-craniofacial dysmorphism-cardiac defect-hip dysplasia syndrome, congenital insensitivity to pain with severe intellectual disability, X-linked intellectual disability-cerebellar hypoplasia-spondylo-epiphyseal dysplasia syndrome, global developmental delay-visual anomalies-progressive cerebellar atrophy-truncal hypotonia syndrome, lissencephaly spectrum disorders, hyaline body myopathy, 22q11.2 deletion syndrome, craniorachischisis, Leber congenital amaurosis, Ritscher-Schinzel 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, congenital muscular dystrophy, congenital vitreoretinal dysplasia, periventricular nodular heterotopia, postsynaptic congenital myasthenic syndrome, subcortical band heterotopia, congenital fibrosis of extraocular muscles type 1, Al Gazali Khidr Prem Chandran syndrome, distal arthrogryposis Moore weaver type, congenital myotonic dystrophy, myasthenic syndrome, congenital, 7B, presynaptic, autosomal recessive, intellectual disability, autosomal dominant 47, intellectual disability, autosomal dominant 48, spondyloepiphyseal dysplasia, sensorineural hearing loss, impaired intellectual development, and leber congenital amaurosis, myasthenic syndrome, congenital, 23, presynaptic, myasthenic syndrome, congenital, 24, presynaptic, myasthenic syndrome, congenital, 25, presynaptic, developmental and epileptic encephalopathy, 77, night blindness, congenital stationary, type1i, neuropathy, congenital hypomelinating, congenital axonal neuropathy with encephalopathy, developmental and epileptic encephalopathy, 73, PHIP-related behavioral problems-intellectual disability-obesity-dysmorphic features syndrome, isolated exencephaly, myasthenic syndrome, congenital, 22, intellectual developmental disorder with gastrointestinal difficulties and high pain threshold, intellectual developmental disorder with dysmorphic facies, seizures, and distal limb anomalies, 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, SIN3A-related intellectual disability syndrome, childhood-onset motor and cognitive regression syndrome with extrapyramidal movement disorder, X-linked congenital stationary night blindness, neurodevelopmental disorder with progressive microcephaly, spasticity, and brain anomalies, FOXG1 disorder, alpha-actinopathy, TPM3-related myopathy, X-linked recessive mitochondrial myopathy, RYR1-related myopathy, TTN-related myopathy, TPM2-related myopathy, myopathy caused by variation in POMGNT1, central hypoventilation syndrome, congenital, 1, with or without Hirschsprung disease, segmental spinal dysgenesis, myopathy, myofibrillar, 13, with rimmed vacuoles, congenital neuronal ceroid lipofuscinosis 10

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

161 retrieved; paginated sample, class counts are floors:

65 uncertain significance, 33 pathogenic, 23 likely pathogenic, 21 conflicting classifications of pathogenicity, 6 benign/likely benign, 6 pathogenic/likely pathogenic, 5 likely benign, 2 not provided

ClinVar	Variant (HGVS)	Gene	Classification	Review
1033782	NM_015570.4(AUTS2):c.2T>C (p.Met1Thr)	AUTS2	Pathogenic	criteria provided, single submitter
1174542	NM_015570.4(AUTS2):c.1A>T (p.Met1Leu)	AUTS2	Pathogenic	criteria provided, single submitter
1319752	NM_015570.4(AUTS2):c.1018C>T (p.Gln340Ter)	AUTS2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1324010	NM_015570.4(AUTS2):c.479_487delinsC (p.Gln160fs)	AUTS2	Pathogenic	criteria provided, single submitter
1325825	NM_015570.4:c.(690+1_691-1)_(742+1_743-1)del	AUTS2	Pathogenic	criteria provided, single submitter
133343	NC_000007.14:g.(69899499_70118132)_(70134571_70435751)del	AUTS2	Pathogenic	no assertion criteria provided
133344	NC_000007.14:g.(70435782_70698569)_(70766334_70768023)del	AUTS2	Pathogenic	no assertion criteria provided
1334416	NM_015570.4(AUTS2):c.1995_1996del (p.Lys666fs)	AUTS2	Pathogenic	criteria provided, single submitter
1527875	NM_015570.4(AUTS2):c.1913del (p.Pro638fs)	AUTS2	Pathogenic	criteria provided, single submitter
1708260	NM_015570.4(AUTS2):c.2218del (p.His740fs)	AUTS2	Pathogenic	criteria provided, single submitter
1805683	NM_015570.4(AUTS2):c.1135C>T (p.Gln379Ter)	AUTS2	Pathogenic	criteria provided, single submitter
219193	NM_015570.4(AUTS2):c.857_858del (p.Lys286fs)	AUTS2	Pathogenic	no assertion criteria provided
2429962	NM_015570.4(AUTS2):c.940C>T (p.Gln314Ter)	AUTS2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2430359	NM_015570.4(AUTS2):c.390_393dup (p.Gly132fs)	AUTS2	Pathogenic	criteria provided, single submitter
2444256	NM_015570.4(AUTS2):c.454C>T (p.Arg152Ter)	AUTS2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2573135	NM_015570.4(AUTS2):c.742_742+3del	AUTS2	Pathogenic	criteria provided, single submitter
3024247	NM_015570.4(AUTS2):c.1902+1G>A	AUTS2	Pathogenic	criteria provided, single submitter
3242554	NM_015570.4(AUTS2):c.392_393dup (p.Gly132fs)	AUTS2	Pathogenic	criteria provided, single submitter
3362873	Single allele	AUTS2	Pathogenic	criteria provided, single submitter
3594757	NM_015570.4(AUTS2):c.1051C>T (p.Gln351Ter)	AUTS2	Pathogenic	criteria provided, single submitter
372310	NM_015570.4(AUTS2):c.1483C>T (p.Arg495Ter)	AUTS2	Pathogenic	criteria provided, multiple submitters, no conflicts
373078	NM_015570.4(AUTS2):c.1298del (p.Leu433fs)	AUTS2	Pathogenic	criteria provided, multiple submitters, no conflicts
3907113	NC_000007.13:g.(?69063460)(70258493_?)del	AUTS2	Pathogenic	criteria provided, single submitter
391589	NM_015570.4(AUTS2):c.149C>A (p.Ser50Ter)	AUTS2	Pathogenic	criteria provided, multiple submitters, no conflicts
4685554	NM_015570.4(AUTS2):c.1005del (p.Pro336fs)	AUTS2	Pathogenic	criteria provided, single submitter
4819113	NM_015570.4(AUTS2):c.737del (p.Asn246fs)	AUTS2	Pathogenic	criteria provided, single submitter
489014	NM_015570.4(AUTS2):c.946C>T (p.Arg316Ter)	AUTS2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
546063	NM_015570.4(AUTS2):c.1464_1467del (p.Thr487_Tyr488insTer)	AUTS2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
546070	NM_015570.4(AUTS2):c.742+1G>A	AUTS2	Pathogenic	criteria provided, multiple submitters, no conflicts
559629	NM_015570.4(AUTS2):c.357_361dup (p.Leu121fs)	AUTS2	Pathogenic	no assertion criteria provided

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 5 · Orphanet: 17 · 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
AUTS2	Definitive	Autosomal dominant	autism spectrum disorder due to AUTS2 deficiency	5

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
AUTS2	Orphanet:352490	Autism spectrum disorder due to AUTS2 deficiency
AUTS2	Orphanet:641372	B-lymphoblastic leukemia/lymphoma with t(7;9)(q11.2;p13.2)
RYR1	Orphanet:169186	Autosomal recessive centronuclear myopathy
RYR1	Orphanet:169189	Autosomal dominant centronuclear myopathy
RYR1	Orphanet:178145	Moderate multiminicore disease with hand involvement
RYR1	Orphanet:324581	Benign Samaritan congenital myopathy
RYR1	Orphanet:33108	Lethal multiple pterygium syndrome
RYR1	Orphanet:423	Malignant hyperthermia of anesthesia
RYR1	Orphanet:424107	Congenital myopathy with myasthenic-like onset
RYR1	Orphanet:466650	Exercise-induced malignant hyperthermia
RYR1	Orphanet:597	Central core disease
RYR1	Orphanet:700188	Calf-predominant weakness-gastrocnemius medialis atrophy-distal myopathy
RYR1	Orphanet:98905	Congenital multicore myopathy with external ophthalmoplegia
RYR1	Orphanet:99741	King-Denborough syndrome
MYCBP2	Orphanet:528084	Non-specific syndromic intellectual disability
KMT2D	Orphanet:2322	Kabuki syndrome
KMT2D	Orphanet:589856	Choanal atresia-athelia-hypothyroidism-delayed puberty-short stature syndrome

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
AUTS2	HGNC:14262	ENSG00000158321	Q8WXX7	Autism susceptibility gene 2 protein	gencc,clinvar
RYR1	HGNC:10483	ENSG00000196218	P21817	Ryanodine receptor 1	clinvar
MYCBP2	HGNC:23386	ENSG00000005810	O75592	E3 ubiquitin-protein ligase MYCBP2	clinvar
KMT2D	HGNC:7133	ENSG00000167548	O14686	Histone-lysine N-methyltransferase 2D	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
AUTS2	Autism susceptibility gene 2 protein	Component of a Polycomb group (PcG) multiprotein PRC1-like complex, a complex class required to maintain the transcriptionally repressive state of many genes, including Hox genes, throughout development.
RYR1	Ryanodine receptor 1	Cytosolic calcium-activated calcium channel that mediates the release of Ca(2+) from the sarcoplasmic reticulum into the cytosol and thereby plays a key role in triggering muscle contraction following depolarization of T-tubules.
MYCBP2	E3 ubiquitin-protein ligase MYCBP2	Atypical E3 ubiquitin-protein ligase which specifically mediates ubiquitination of threonine and serine residues on target proteins, instead of ubiquitinating lysine residues.
KMT2D	Histone-lysine N-methyltransferase 2D	Histone methyltransferase that catalyzes methyl group transfer from S-adenosyl-L-methionine to the epsilon-amino group of ‘Lys-4’ of histone H3 (H3K4).

Protein-family classification

Druggable: 1 · Difficult: 2 · Unknown: 1 · Druggable fraction: 0.25

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
Ion channel	1	27.9×	0.106
Transcription factor	2	4.1×	0.112
Other/Unknown	1	0.5×	0.962

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
AUTS2	Other/Unknown	no		AUTS2
RYR1	Ion channel	yes		RIH_dom, B30.2/SPRY, Ryanodine_rcpt
MYCBP2	Transcription factor	no	2.3.2.33	Reg_chr_condens, Znf_RING, APC_su10/DOC_dom
KMT2D	Transcription factor	no		SET_dom, Znf_RING, Znf_PHD

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
cortical plate	1
ganglionic eminence	1
tibia	1
gastrocnemius	1
gluteal muscle	1
hindlimb stylopod muscle	1
Brodmann (1909) area 23	1
hair follicle	1
middle temporal gyrus	1
buccal mucosa cell	1
medial globus pallidus	1
sural nerve	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
AUTS2	292	ubiquitous	marker	cortical plate, tibia, ganglionic eminence
RYR1	214	broad	marker	gluteal muscle, gastrocnemius, hindlimb stylopod muscle
MYCBP2	294	ubiquitous	marker	Brodmann (1909) area 23, middle temporal gyrus, hair follicle
KMT2D	272	ubiquitous	marker	buccal mucosa cell, medial globus pallidus, sural nerve

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
KMT2D	3,223
MYCBP2	2,267
RYR1	2,177
AUTS2	1,700

Structural data

PDB: 3 · AlphaFold-only: 1 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
KMT2D	O14686	11
RYR1	P21817	2
MYCBP2	O75592	2

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
AUTS2	Q8WXX7	41.89

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 30. 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
Transcriptional regulation by RUNX1	2	97.6×	0.004	AUTS2, KMT2D
Loss of Function of KMT2D in MLL4 Complex Formation in Kabuki Syndrome	1	761.3×	0.020	KMT2D
Activation of HOX genes during differentiation	1	146.4×	0.038	KMT2D
RUNX1 interacts with co-factors whose precise effect on RUNX1 targets is not known	1	100.2×	0.038	AUTS2
Formation of WDR5-containing histone-modifying complexes	1	88.5×	0.038	KMT2D
Deactivation of the beta-catenin transactivating complex	1	77.7×	0.038	KMT2D
Epigenetic regulation of adipogenesis genes by MLL3 and MLL4 complexes	1	71.8×	0.038	KMT2D
Ion homeostasis	1	68.0×	0.038	RYR1
Epigenetic regulation of gene expression by MLL3 and MLL4 complexes	1	65.6×	0.038	KMT2D
RNA Polymerase II Transcription	2	15.0×	0.038	AUTS2, KMT2D
Gene expression (Transcription)	2	11.9×	0.038	AUTS2, KMT2D
Generic Transcription Pathway	2	10.1×	0.038	AUTS2, KMT2D
PKMTs methylate histone lysines	1	53.6×	0.041	KMT2D
Epigenetic regulation by WDR5-containing histone modifying complexes	1	51.4×	0.041	KMT2D
Stimuli-sensing channels	1	45.3×	0.041	RYR1
Formation of the beta-catenin:TCF transactivating complex	1	40.1×	0.041	KMT2D
RUNX1 regulates genes involved in megakaryocyte differentiation and platelet function	1	40.1×	0.041	KMT2D
TCF dependent signaling in response to WNT	1	39.2×	0.041	KMT2D
Signaling by WNT	1	37.3×	0.041	KMT2D
Cardiac conduction	1	36.2×	0.041	RYR1
Ion channel transport	1	32.0×	0.044	RYR1
Activation of anterior HOX genes in hindbrain development during early embryogenesis	1	30.4×	0.044	KMT2D
MLL4 and MLL3 complexes regulate expression of PPARG target genes in adipogenesis and hepatic steatosis	1	27.6×	0.045	KMT2D
Chromatin organization	1	27.2×	0.045	KMT2D
Muscle contraction	1	25.7×	0.046	RYR1
Chromatin modifying enzymes	1	24.1×	0.046	KMT2D
Epigenetic regulation of gene expression	1	23.8×	0.046	KMT2D
Transport of small molecules	1	8.4×	0.123	RYR1
Developmental Biology	1	4.8×	0.200	KMT2D
Signal Transduction	1	3.4×	0.267	KMT2D

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
beta-catenin-TCF complex assembly	1	4213.0×	0.010	KMT2D
oocyte growth	1	1053.2×	0.011	KMT2D
response to caffeine	1	601.9×	0.011	RYR1
regulation of axon guidance	1	601.9×	0.011	MYCBP2
branchiomotor neuron axon guidance	1	526.6×	0.011	MYCBP2
central nervous system projection neuron axonogenesis	1	468.1×	0.011	MYCBP2
regulation of synaptic assembly at neuromuscular junction	1	421.3×	0.011	MYCBP2
release of sequestered calcium ion into cytosol by sarcoplasmic reticulum	1	421.3×	0.011	RYR1
dendrite extension	1	421.3×	0.011	AUTS2
cellular response to caffeine	1	383.0×	0.011	RYR1
ossification involved in bone maturation	1	351.1×	0.011	RYR1
positive regulation of intracellular estrogen receptor signaling pathway	1	300.9×	0.012	KMT2D
striated muscle contraction	1	210.7×	0.016	RYR1
positive regulation of Rac protein signal transduction	1	162.0×	0.018	AUTS2
regulation of cytoskeleton organization	1	162.0×	0.018	MYCBP2
positive regulation of lamellipodium assembly	1	150.5×	0.018	AUTS2
skeletal muscle fiber development	1	135.9×	0.019	RYR1
neuromuscular process	1	131.7×	0.019	MYCBP2
axon extension	1	123.9×	0.019	AUTS2
skin development	1	110.9×	0.020	RYR1
oogenesis	1	95.8×	0.020	KMT2D
regulation of cytosolic calcium ion concentration	1	95.8×	0.020	RYR1
negative regulation of protein catabolic process	1	91.6×	0.020	MYCBP2
response to estrogen	1	86.0×	0.020	KMT2D
release of sequestered calcium ion into cytosol	1	86.0×	0.020	RYR1
outflow tract morphogenesis	1	76.6×	0.022	RYR1
heterochromatin formation	1	63.8×	0.025	KMT2D
protein homotetramerization	1	59.3×	0.026	RYR1
circadian regulation of gene expression	1	58.5×	0.026	MYCBP2
positive regulation of protein ubiquitination	1	53.3×	0.026	MYCBP2

Therapeutics

Drug target analysis

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

Druggability breadth: 3 of 4 evidence-associated genes (75%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
AUTS2	0	0
RYR1	0	0
MYCBP2	0	0
KMT2D	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
RYR1	16	Binding:13, Functional:3
KMT2D	11	Binding:11
MYCBP2	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
MYCBP2	2.3.2.33	RCR-type E3 ubiquitin transferase

Pharmacogenomics

Cohort genes with a PharmGKB record: 4; with CPIC/DPWG dosing guidelines: 1.

Cohort genes with a CPIC/DPWG dosing guideline

Symbol	CPIC guidelines
RYR1	1

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	RYR1
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	3	AUTS2, MYCBP2, KMT2D

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
AUTS2	0	—
RYR1	16	—
MYCBP2	1	—
KMT2D	11	—

Clinical trials & evidence

Clinical trials

Clinical trials: 1.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT01238250	Not specified	RECRUITING	Online Study of People Who Have Genetic Changes and Features of Autism: Simons Searchlight