Pitt-Hopkins-like syndrome 2

Summary

Pitt-Hopkins-like syndrome 2 (MONDO:0013690) is a disease caused by NRXN1 (GenCC Strong), with 4 cohort genes.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: NRXN1 (GenCC Strong)
• Cohort genes: 4
• ClinVar variants: 2,003

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		11	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Identifiers

Disease identifiers

Field	Value
Canonical name	Pitt-Hopkins-like syndrome 2
Mondo ID	MONDO:0013690
OMIM	614325
Orphanet	600663
DOID	DOID:0111332
UMLS	C3280479
MedGen	482109
GARD	0024939
Is cancer (heuristic)	no

Also known as: NRXN1 Pitt-Hopkins-like syndrome · NRXN1-related severe neurodevelopmental disorder-motor stereotypies-chronic constipation-sleep-wake cycle disturbance · Pitt-Hopkins-like syndrome 2 · Pitt-Hopkins-like syndrome caused by mutation in NRXN1 · Pitt-Hopkins-like syndrome type 2 · PTHSL2

Data availability: 2,003 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 › Pitt-Hopkins-like syndrome 2

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, 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, autism spectrum disorder due to AUTS2 deficiency, 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

600 retrieved; paginated sample, class counts are floors:

290 uncertain significance, 238 likely benign, 32 conflicting classifications of pathogenicity, 12 benign/likely benign, 10 pathogenic, 7 likely pathogenic, 7 benign, 3 pathogenic/likely pathogenic, 1 not provided

ClinVar	Variant (HGVS)	Gene	Classification	Review
1048082	NM_001330078.2(NRXN1):c.772+1128_772+1129del	NRXN1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1074562	NC_000002.11:g.(?51148997)(51259192_?)del	NRXN1	Pathogenic	criteria provided, single submitter
1187252	NM_001330078.2(NRXN1):c.3430C>T (p.Arg1144Ter)	NRXN1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1383533	NM_001330078.2(NRXN1):c.4021_4022del (p.Thr1341fs)	NRXN1	Pathogenic	criteria provided, single submitter
1387846	NC_000002.11:g.(?51148987)(51255411_?)del	NRXN1	Pathogenic	criteria provided, single submitter
1390346	NM_001330078.2(NRXN1):c.772+1129_772+1132del	NRXN1	Pathogenic	criteria provided, single submitter
1399605	NM_001330078.2(NRXN1):c.2386G>T (p.Glu796Ter)	NRXN1	Pathogenic	criteria provided, single submitter
1451359	NM_001330078.2(NRXN1):c.601G>T (p.Glu201Ter)	NRXN1	Pathogenic	criteria provided, single submitter
1451464	NM_001330078.2(NRXN1):c.2792del (p.Phe931fs)	NRXN1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1452805	NC_000002.11:g.(?51253489)(51255411_?)del	NRXN1	Pathogenic	criteria provided, single submitter
1452876	NM_001330078.2(NRXN1):c.2281dup (p.Arg761fs)	NRXN1	Pathogenic	criteria provided, single submitter
1455324	NC_000002.11:g.(?50463907)(50464128_?)del	NRXN1	Pathogenic	criteria provided, single submitter
1460378	NC_000002.11:g.(?50692560)(50780183_?)del	NRXN1	Pathogenic	criteria provided, single submitter
1098641	NC_000002.12:g.50531675_50577825del	NRXN1	Likely pathogenic	criteria provided, single submitter
1323375	NM_001330078.2(NRXN1):c.2239C>T (p.Arg747Ter)	NRXN1	Likely pathogenic	criteria provided, multiple submitters, no conflicts
1324820	NM_001330078.2(NRXN1):c.3625del (p.Asp1209fs)	NRXN1	Likely pathogenic	criteria provided, single submitter
1324821	NM_001330078.2(NRXN1):c.3835C>T (p.Gln1279Ter)	NRXN1	Likely pathogenic	criteria provided, single submitter
1348504	NM_001330078.2(NRXN1):c.1759+2T>C	NRXN1	Likely pathogenic	criteria provided, single submitter
1503359	NC_000002.11:g.(?50847140)(51153113_?)dup	NRXN1	Likely pathogenic	criteria provided, single submitter
1503370	NC_000002.11:g.(?50750595)(50765696_?)del	NRXN1	Likely pathogenic	criteria provided, single submitter
1000802	NM_001330078.2(NRXN1):c.3082A>G (p.Ile1028Val)	NRXN1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1179352	NM_001330078.2(NRXN1):c.1158+20C>T	NRXN1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1196704	NM_001330078.2(NRXN1):c.4472C>T (p.Ala1491Val)	NRXN1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1216940	NM_001330078.2(NRXN1):c.4125C>G (p.Ser1375Arg)	NRXN1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1217974	NM_001330078.2(NRXN1):c.622C>G (p.Pro208Ala)	NRXN1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1264229	NM_001330078.2(NRXN1):c.771A>G (p.Gln257=)	NRXN1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
129818	NM_001330078.2(NRXN1):c.1158+26A>T	NRXN1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
129819	NM_001330078.2(NRXN1):c.3219C>T (p.Asn1073=)	NRXN1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
129824	NM_001330078.2(NRXN1):c.4254A>G (p.Pro1418=)	NRXN1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
129826	NM_001330078.2(NRXN1):c.777C>T (p.Asp259=)	NRXN1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 7 · Orphanet: 4 · 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
NRXN1	Strong	Autosomal recessive	Pitt-Hopkins-like syndrome 2	7

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
NRXN1	Orphanet:600663	NRXN1-related severe neurodevelopmental disorder-motor stereotypies-chronic constipation-sleep-wake cycle disturbance
FBXO11	Orphanet:528084	Non-specific syndromic intellectual disability
FSHR	Orphanet:243	46,XX gonadal dysgenesis
FSHR	Orphanet:64739	Ovarian hyperstimulation 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
NRXN1	HGNC:8008	ENSG00000179915	P58400	Neurexin-1-beta	gencc,clinvar
FBXO11	HGNC:13590	ENSG00000138081	Q86XK2	F-box only protein 11	clinvar
GTF2A1L	HGNC:30727	ENSG00000242441	Q9UNN4	TFIIA-alpha and beta-like factor	clinvar
FSHR	HGNC:3969	ENSG00000170820	P23945	Follicle-stimulating hormone receptor	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
NRXN1	Neurexin-1-beta	Neuronal cell surface protein involved in cell recognition and cell adhesion by forming intracellular junctions through binding to neuroligins.
FBXO11	F-box only protein 11	Substrate recognition component of a SCF (SKP1-CUL1-F-box protein) E3 ubiquitin-protein ligase complex which mediates the ubiquitination and subsequent proteasomal degradation of target proteins, such as DTL/CDT2, BCL6, SNAI1 and PRDM1/BLI…
GTF2A1L	TFIIA-alpha and beta-like factor	May function as a testis specific transcription factor.
FSHR	Follicle-stimulating hormone receptor	G protein-coupled receptor for follitropin, the follicle-stimulating hormone.

Protein-family classification

Druggable: 1 · Difficult: 1 · Unknown: 2 · 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
GPCR	1	6.0×	0.471
Transcription factor	1	2.1×	0.605
Other/Unknown	2	0.9×	0.769

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
NRXN1	Other/Unknown	no		Laminin_G, Neurexin-like, ConA-like_dom_sf
FBXO11	Transcription factor	no		F-box_dom, Znf_UBR, PbH1
GTF2A1L	Other/Unknown	no		TFIIA_asu/bsu, TFIIA_b-brl
FSHR	GPCR	yes		GPCR_Rhodpsn, LRRNT, Gphrmn_rcpt_fam

Expression context

Cohort genes with no expression data: 0.

3 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	2
middle temporal gyrus	1
sural nerve	1
ganglionic eminence	1
ventricular zone	1
left testis	1
primordial germ cell in gonad	1
right testis	1
apex of heart	1
lower esophagus mucosa	1
male germ line stem cell (sensu Vertebrata) in testis	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
NRXN1	222	broad	marker	sural nerve, cortical plate, middle temporal gyrus
FBXO11	287	ubiquitous	marker	cortical plate, ganglionic eminence, ventricular zone
GTF2A1L	156	tissue_specific	yes	left testis, primordial germ cell in gonad, right testis
FSHR	98	tissue_specific	marker	male germ line stem cell (sensu Vertebrata) in testis, lower esophagus mucosa, apex of heart

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
FBXO11	2,000
FSHR	1,667
GTF2A1L	626
NRXN1	120

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
FSHR	P23945	5
NRXN1	P58400	3
FBXO11	Q86XK2	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
GTF2A1L	Q9UNN4	53.77

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 6. 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
Hormone ligand-binding receptors	1	317.2×	0.019	FSHR
Neurexins and neuroligins	1	65.6×	0.039	NRXN1
Non-integrin membrane-ECM interactions	1	51.4×	0.039	NRXN1
G alpha (s) signalling events	1	24.4×	0.061	FSHR
Neddylation	1	15.8×	0.074	FBXO11
Antigen processing: Ubiquitination & Proteasome degradation	1	12.4×	0.079	FBXO11

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
obsolete positive regulation of cAMP-mediated signaling	1	4213.0×	0.005	NRXN1
regulation of acetylcholine metabolic process	1	4213.0×	0.005	FSHR
protein-containing complex assembly involved in synapse maturation	1	4213.0×	0.005	NRXN1
positive regulation of presynaptic active zone assembly	1	4213.0×	0.005	NRXN1
primary ovarian follicle growth	1	2106.5×	0.005	FSHR
regulation of platelet-derived growth factor receptor signaling pathway	1	2106.5×	0.005	FSHR
guanylate kinase-associated protein clustering	1	2106.5×	0.005	NRXN1
follicle-stimulating hormone signaling pathway	1	1404.3×	0.005	FSHR
neuroligin clustering involved in postsynaptic membrane assembly	1	1404.3×	0.005	NRXN1
positive regulation of neuromuscular synaptic transmission	1	1404.3×	0.005	NRXN1
obsolete regulation of protein kinase A signaling	1	1053.2×	0.005	FSHR
regulation of hormone metabolic process	1	842.6×	0.005	FSHR
negative regulation of filopodium assembly	1	842.6×	0.005	NRXN1
gamma-aminobutyric acid receptor clustering	1	842.6×	0.005	NRXN1
NMDA glutamate receptor clustering	1	842.6×	0.005	NRXN1
gephyrin clustering involved in postsynaptic density assembly	1	842.6×	0.005	NRXN1
AMPA selective glutamate receptor signaling pathway	1	842.6×	0.005	NRXN1
neuron projection development	2	61.1×	0.005	NRXN1, FSHR
positive regulation of ERK1 and ERK2 cascade	2	42.6×	0.005	NRXN1, FSHR
positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction	2	39.2×	0.005	NRXN1, FSHR
Sertoli cell proliferation	1	702.2×	0.006	FSHR
postsynaptic density protein 95 clustering	1	702.2×	0.006	NRXN1
intracellular water homeostasis	1	601.9×	0.006	FSHR
neuronal signal transduction	1	601.9×	0.006	NRXN1
postsynaptic membrane assembly	1	601.9×	0.006	NRXN1
NMDA selective glutamate receptor signaling pathway	1	601.9×	0.006	NRXN1
positive regulation of phospholipase C-activating G protein-coupled receptor signaling pathway	1	601.9×	0.006	NRXN1
cerebellar granule cell differentiation	1	526.6×	0.006	NRXN1
vocal learning	1	526.6×	0.006	NRXN1
receptor localization to synapse	1	526.6×	0.006	NRXN1

Therapeutics

Drug target analysis

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

Druggability breadth: 2 of 4 evidence-associated genes (50%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
NRXN1	0	0
FBXO11	0	0
GTF2A1L	0	0
FSHR	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
FSHR	43	Functional:26, Binding:17
FBXO11	2	Binding:2

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

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	FSHR
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	3	NRXN1, FBXO11, GTF2A1L

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)
NRXN1	0	—
FBXO11	2	—
GTF2A1L	0	—
FSHR	43	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.