autism, susceptibility to, X-linked 4

disease

On this page

Also known as autism, susceptibility to, X-linked 4, X-linked recessiveautism, susceptibility to, X-linked type 4AUTSX4susceptibility to autism, X-linkedX-linked susceptibility to autism-4

Summary

autism, susceptibility to, X-linked 4 (MONDO:0010440) is a disease caused by PTCHD1 (GenCC Definitive), with 2 cohort genes.

At a glance

Causal gene: PTCHD1 (GenCC Definitive)
Cohort genes: 2
ClinVar variants: 39

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	autism, susceptibility to, X-linked 4
Mondo ID	MONDO:0010440
OMIM	300830
UMLS	C0795888
MedGen	162886
Is cancer (heuristic)	no

Also known as: autism, susceptibility to, X-linked 4 · autism, susceptibility to, X-linked 4, X-linked recessive · autism, susceptibility to, X-linked type 4 · AUTSX4 · susceptibility to autism, X-linked · X-linked susceptibility to autism-4

Data availability: 39 ClinVar variants · 3 GenCC gene-disease records.

Disease family

Classification path: disease susceptibility › inherited disease susceptibility › autism, susceptiblity to › autism, susceptibility to, X-linked 4

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

39 retrieved; paginated sample, class counts are floors:

20 uncertain significance, 7 likely pathogenic, 6 conflicting classifications of pathogenicity, 3 risk factor, 2 pathogenic, 1 likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
2579657	GRCh37/hg19 Xp22.11(chrX:23209046-23383351)	PTCHD1	Pathogenic	no assertion criteria provided
3254644	NM_173495.3(PTCHD1):c.1082_1083dup (p.Glu362fs)	PTCHD1	Pathogenic	criteria provided, single submitter
1251937	NM_173495.3(PTCHD1):c.1434C>G (p.Tyr478Ter)	PTCHD1	Likely pathogenic	criteria provided, single submitter
1707515	NM_173495.3(PTCHD1):c.1557T>G (p.Tyr519Ter)	PTCHD1	Likely pathogenic	criteria provided, single submitter
2501715	NM_173495.3(PTCHD1):c.1434C>A (p.Tyr478Ter)	PTCHD1	Likely pathogenic	criteria provided, single submitter
2506479	NM_173495.3(PTCHD1):c.2097_2098insA (p.Leu700fs)	PTCHD1	Likely pathogenic	criteria provided, single submitter
3376263	NM_173495.3(PTCHD1):c.1164dup (p.Gly389fs)	PTCHD1	Likely pathogenic	criteria provided, single submitter
4071991	NM_173495.3(PTCHD1):c.154_160del (p.Val52fs)	PTCHD1	Likely pathogenic	criteria provided, single submitter
436440	NM_173495.3(PTCHD1):c.893G>A (p.Trp298Ter)	PTCHD1	Likely pathogenic	criteria provided, single submitter
209085	NM_173495.3(PTCHD1):c.2128del (p.Leu710fs)	PTCHD1	risk factor	no assertion criteria provided
209086	NM_173495.3(PTCHD1):c.1796dup (p.Asn599fs)	PTCHD1	risk factor	no assertion criteria provided
209087	NM_173495.3(PTCHD1):c.1444del (p.Leu482fs)	PTCHD1	risk factor	no assertion criteria provided
167103	NM_001368397.1(FRMPD4):c.3937C>A (p.Arg1313=)	FRMPD4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1215751	NM_173495.3(PTCHD1):c.491G>A (p.Arg164Gln)	PTCHD1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
211971	NM_173495.3(PTCHD1):c.517A>G (p.Ile173Val)	PTCHD1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2299041	NM_173495.3(PTCHD1):c.1432T>C (p.Tyr478His)	PTCHD1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
402218	NM_173495.3(PTCHD1):c.542A>C (p.Lys181Thr)	PTCHD1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
988746	NM_173495.3(PTCHD1):c.638A>G (p.Tyr213Cys)	PTCHD1	Conflicting classifications of pathogenicity	no assertion criteria provided
1334078	NM_173495.3(PTCHD1):c.448G>A (p.Val150Met)	PTCHD1	Uncertain significance	criteria provided, single submitter
2442059	NM_173495.3(PTCHD1):c.458T>C (p.Ile153Thr)	PTCHD1	Uncertain significance	criteria provided, multiple submitters, no conflicts
2499571	NM_173495.3(PTCHD1):c.1786C>T (p.Arg596Trp)	PTCHD1	Uncertain significance	criteria provided, multiple submitters, no conflicts
2582400	NM_173495.3(PTCHD1):c.1256C>G (p.Ser419Trp)	PTCHD1	Uncertain significance	criteria provided, single submitter
2664744	NM_173495.3(PTCHD1):c.145GAG[1] (p.Glu50del)	PTCHD1	Uncertain significance	criteria provided, single submitter
2687880	NM_173495.3(PTCHD1):c.2186T>A (p.Leu729His)	PTCHD1	Uncertain significance	criteria provided, single submitter
3236816	NM_173495.3(PTCHD1):c.1772A>G (p.Tyr591Cys)	PTCHD1	Uncertain significance	criteria provided, single submitter
3370290	NM_173495.3(PTCHD1):c.1930del (p.Ala644fs)	PTCHD1	Uncertain significance	criteria provided, single submitter
3383118	NM_173495.3(PTCHD1):c.974A>G (p.Tyr325Cys)	PTCHD1	Uncertain significance	criteria provided, single submitter
3778695	NM_173495.3(PTCHD1):c.1966A>T (p.Thr656Ser)	PTCHD1	Uncertain significance	no assertion criteria provided
4082092	NM_173495.3(PTCHD1):c.2098dup (p.Leu700fs)	PTCHD1	Uncertain significance	criteria provided, single submitter
417957	NM_173495.3(PTCHD1):c.907G>A (p.Gly303Arg)	PTCHD1	Uncertain significance	no assertion criteria provided

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 4 · Orphanet: 2 · 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
PTCHD1	Definitive	X-linked	autism, susceptibility to, X-linked 4	4

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
PTCHD1	Orphanet:777	X-linked non-syndromic intellectual disability
FRMPD4	Orphanet:777	X-linked non-syndromic intellectual disability

Cohort genes → proteins

2 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
PTCHD1	HGNC:26392	ENSG00000165186	Q96NR3	Patched domain-containing protein 1	gencc,clinvar
FRMPD4	HGNC:29007	ENSG00000169933	Q14CM0	FERM and PDZ domain-containing protein 4	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
PTCHD1	Patched domain-containing protein 1	Required for the development and function of the thalamic reticular nucleus (TRN), a part of the thalamus that is critical for thalamocortical transmission, generation of sleep rhythms, sensorimotor processing and attention.
FRMPD4	FERM and PDZ domain-containing protein 4	Positive regulator of dendritic spine morphogenesis and density.

Protein-family classification

Druggable: 0 · Difficult: 1 · 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
Scaffold/PPI	1	8.6×	0.225
Other/Unknown	1	0.9×	0.805

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
PTCHD1	Other/Unknown	no		SSD, PTHD_SSD, Patched_domain-protein
FRMPD4	Scaffold/PPI	no		FERM_domain, WW_dom, PDZ

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)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
buccal mucosa cell	1
cauda epididymis	1
corpus epididymis	1
Brodmann (1909) area 23	1
endothelial cell	1
middle temporal gyrus	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
PTCHD1	167	broad	yes	cauda epididymis, corpus epididymis, buccal mucosa cell
FRMPD4	117	broad	marker	middle temporal gyrus, endothelial cell, Brodmann (1909) area 23

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
FRMPD4	2,222
PTCHD1	822

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
FRMPD4	Q14CM0	5

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
PTCHD1	Q96NR3	84.14

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 0. Enrichment computed across 2 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 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
positive regulation of synapse structural plasticity	1	2808.7×	0.002	FRMPD4
inhibitory chemical synaptic transmission	1	2808.7×	0.002	PTCHD1
thalamus development	1	702.2×	0.003	PTCHD1
short-term memory	1	648.1×	0.003	PTCHD1
excitatory chemical synaptic transmission	1	648.1×	0.003	PTCHD1
long-term memory	1	210.7×	0.008	PTCHD1
cognition	1	142.8×	0.009	PTCHD1
social behavior	1	135.9×	0.009	PTCHD1
smoothened signaling pathway	1	90.6×	0.012	PTCHD1
chemical synaptic transmission	1	38.6×	0.026	PTCHD1

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 2

Druggability breadth: 0 of 2 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
PTCHD1	0	0
FRMPD4	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Pharmacogenomics

Cohort genes with a PharmGKB record: 2; 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	2	PTCHD1, FRMPD4

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
PTCHD1	0	—
FRMPD4	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.

Cohort genes: PTCHD1, FRMPD4