autism, susceptibility to, X-linked 2

disease

On this page

Also known as autism susceptibility, X-linked 2, isolated cases, X-linkedautism, susceptibility to, X-linked type 2AUTSX2intellectual developmental disorder, X-linked, Isolated cases, X-linkedmental retardation, X-linked

Summary

autism, susceptibility to, X-linked 2 (MONDO:0010341) is a disease caused by NLGN4X (GenCC Strong), with 1 cohort gene and 3 clinical trials. Top therapeutic interventions include metformin.

At a glance

Causal gene: NLGN4X (GenCC Strong)
Cohort genes: 1
ClinVar variants: 32
Clinical trials: 3

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	autism, susceptibility to, X-linked 2
Mondo ID	MONDO:0010341
MeSH	D038901
OMIM	300495
UMLS	C1845539
MedGen	336964
Is cancer (heuristic)	no

Also known as: autism susceptibility, X-linked 2, isolated cases, X-linked · autism, susceptibility to, X-linked 2 · autism, susceptibility to, X-linked type 2 · AUTSX2 · intellectual developmental disorder, X-linked, Isolated cases, X-linked · mental retardation, X-linked

Data availability: 32 ClinVar variants · 4 GenCC gene-disease records.

Disease family

Classification path: disease susceptibility › inherited disease susceptibility › autism, susceptiblity to › autism, susceptibility to, X-linked 2

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

32 retrieved; paginated sample, class counts are floors:

23 uncertain significance, 2 pathogenic; risk factor, 2 benign/likely benign, 2 pathogenic, 1 risk factor, 1 conflicting classifications of pathogenicity, 1 likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
11051	NM_181332.3(NLGN4X):c.1254_1255del (p.Glu418fs)	NLGN4X	Pathogenic; risk factor	no assertion criteria provided
11052	NC_000023.11:g.5250357_6007153del	NLGN4X	Pathogenic; risk factor	no assertion criteria provided
374392	NM_181332.3(NLGN4X):c.301C>T (p.Arg101Ter)	NLGN4X	Pathogenic	criteria provided, single submitter
4531342	NM_181332.3(NLGN4X):c.779_782dup (p.Leu262fs)	NLGN4X	Pathogenic	criteria provided, single submitter
2500874	NM_181332.3(NLGN4X):c.626-1G>A	NLGN4X	Likely pathogenic	criteria provided, single submitter
11050	NM_181332.3(NLGN4X):c.1185dup (p.Asp396Ter)	NLGN4X	risk factor	no assertion criteria provided
211681	NM_181332.3(NLGN4X):c.2360C>T (p.Thr787Met)	NLGN4X	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1030724	NM_181332.3(NLGN4X):c.872A>G (p.Tyr291Cys)	NLGN4X	Uncertain significance	criteria provided, single submitter
1184260	NM_181332.3(NLGN4X):c.2294G>A (p.Arg765His)	NLGN4X	Uncertain significance	criteria provided, single submitter
1299169	NM_181332.3(NLGN4X):c.187C>A (p.Pro63Thr)	NLGN4X	Uncertain significance	criteria provided, multiple submitters, no conflicts
1330232	NM_181332.3(NLGN4X):c.2084C>T (p.Ala695Val)	NLGN4X	Uncertain significance	criteria provided, single submitter
2218987	NM_181332.3(NLGN4X):c.1897T>C (p.Trp633Arg)	NLGN4X	Uncertain significance	criteria provided, multiple submitters, no conflicts
2434374	NM_181332.3(NLGN4X):c.1309C>T (p.Arg437Trp)	NLGN4X	Uncertain significance	criteria provided, single submitter
2434376	NM_181332.3(NLGN4X):c.1614A>C (p.Gln538His)	NLGN4X	Uncertain significance	criteria provided, single submitter
2613092	NM_181332.3(NLGN4X):c.847G>T (p.Ala283Ser)	NLGN4X	Uncertain significance	criteria provided, multiple submitters, no conflicts
284715	NM_181332.3(NLGN4X):c.2259G>C (p.Arg753Ser)	NLGN4X	Uncertain significance	criteria provided, multiple submitters, no conflicts
3200431	NM_181332.3(NLGN4X):c.1486G>A (p.Val496Ile)	NLGN4X	Uncertain significance	criteria provided, multiple submitters, no conflicts
3242010	NM_181332.3(NLGN4X):c.910G>A (p.Val304Ile)	NLGN4X	Uncertain significance	criteria provided, single submitter
3255022	NM_181332.3(NLGN4X):c.1387T>C (p.Tyr463His)	NLGN4X	Uncertain significance	criteria provided, single submitter
3362421	NM_181332.3(NLGN4X):c.811+15C>T	NLGN4X	Uncertain significance	criteria provided, single submitter
3364958	NM_181332.3(NLGN4X):c.1354_1365del (p.Pro452_Ala455del)	NLGN4X	Uncertain significance	criteria provided, multiple submitters, no conflicts
3377315	NM_181332.3(NLGN4X):c.1178A>G (p.Asn393Ser)	NLGN4X	Uncertain significance	criteria provided, single submitter
3382643	NM_181332.3(NLGN4X):c.980T>A (p.Ile327Asn)	NLGN4X	Uncertain significance	criteria provided, single submitter
3891837	NM_181332.3(NLGN4X):c.1888G>A (p.Ala630Thr)	NLGN4X	Uncertain significance	criteria provided, single submitter
3895480	NM_181332.3(NLGN4X):c.1583del (p.Thr528fs)	NLGN4X	Uncertain significance	criteria provided, single submitter
4526642	NM_181332.3(NLGN4X):c.1138G>A (p.Val380Met)	NLGN4X	Uncertain significance	criteria provided, single submitter
4813272	NM_181332.3(NLGN4X):c.1182C>T (p.Asp394=)	NLGN4X	Uncertain significance	criteria provided, single submitter
561066	NM_181332.3(NLGN4X):c.2428G>A (p.Gly810Arg)	NLGN4X	Uncertain significance	criteria provided, multiple submitters, no conflicts
829851	NM_181332.3(NLGN4X):c.1661T>C (p.Phe554Ser)	NLGN4X	Uncertain significance	no assertion criteria provided
976154	NM_181332.3(NLGN4X):c.2080G>A (p.Ala694Thr)	NLGN4X	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 4 · Orphanet: 0 · 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
NLGN4X	Strong	X-linked	autism, susceptibility to, X-linked 2	4

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
NLGN4X	HGNC:14287	ENSG00000146938	Q8N0W4	Neuroligin-4, X-linked	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
NLGN4X	Neuroligin-4, X-linked	Cell surface protein involved in cell-cell-interactions via its interactions with neurexin family members.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 1 · 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	1	1.8×	0.558

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
NLGN4X	Other/Unknown	no		Nlgn, CarbesteraseB, Carboxylesterase_B_CS

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
Brodmann (1909) area 23	1
dorsal root ganglion	1
middle temporal gyrus	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
NLGN4X	223	broad	marker	middle temporal gyrus, Brodmann (1909) area 23, dorsal root ganglion

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
NLGN4X	1,823

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
NLGN4X	Q8N0W4	3

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 1. Enrichment computed across 1 evidence-associated genes (1 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 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Neurexins and neuroligins	1	196.9×	0.005	NLGN4X

GO biological processes by enrichment

GO term	Cohort genes	Fold	FDR	Sample cohort genes
brainstem development	1	2106.5×	0.003	NLGN4X
presynaptic membrane assembly	1	1685.2×	0.003	NLGN4X
negative regulation of excitatory postsynaptic potential	1	1296.3×	0.003	NLGN4X
presynapse assembly	1	1203.7×	0.003	NLGN4X
neuron cell-cell adhesion	1	991.3×	0.003	NLGN4X
vocalization behavior	1	887.0×	0.003	NLGN4X
organ growth	1	732.7×	0.003	NLGN4X
regulation of synapse assembly	1	702.2×	0.003	NLGN4X
cell-cell junction organization	1	624.1×	0.003	NLGN4X
adult behavior	1	468.1×	0.004	NLGN4X
cerebellum development	1	358.6×	0.004	NLGN4X
learning	1	280.9×	0.004	NLGN4X
synapse organization	1	280.9×	0.004	NLGN4X
social behavior	1	271.8×	0.004	NLGN4X
synapse assembly	1	230.8×	0.005	NLGN4X
modulation of chemical synaptic transmission	1	183.2×	0.006	NLGN4X
neuron differentiation	1	100.3×	0.010	NLGN4X

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
NLGN4X	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	NLGN4X

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)
NLGN4X	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 3.

Phase distribution (across all retrieved trials)

Phase	Trials
PHASE2/PHASE3	1
PHASE2	1
Not specified	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT03479476	PHASE2/PHASE3	COMPLETED	A Trial of Metformin in Individuals With Fragile X Syndrome
NCT03862950	PHASE2	COMPLETED	A Trial of Metformin in Individuals With Fragile X Syndrome (Met)
NCT06740162	Not specified	RECRUITING	Physical Activity and Community EmPOWERment Project

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
METFORMIN	4	2

Cohort genes: NLGN4X
Drugs: Metformin