X-linked lissencephaly with abnormal genitalia

Summary

X-linked lissencephaly with abnormal genitalia (MONDO:0010268) is a disease caused by ARX (GenCC Strong), with 1 cohort gene.

At a glance

• Prevalence: Unknown (Worldwide) [Orphanet-validated]
• Causal gene: ARX (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 56
• Phenotypes (HPO): 21

Clinical features

Epidemiology

Prevalence records

1 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		30	Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

21 HPO clinical features (Orphanet curated; top 21 by frequency):

HPO ID	Term	Frequency
HP:0000028	Cryptorchidism	Very frequent (80-99%)
HP:0000062	Ambiguous genitalia	Very frequent (80-99%)
HP:0000252	Microcephaly	Very frequent (80-99%)
HP:0001249	Intellectual disability	Very frequent (80-99%)
HP:0001250	Seizure	Very frequent (80-99%)
HP:0001263	Global developmental delay	Very frequent (80-99%)
HP:0001274	Agenesis of corpus callosum	Very frequent (80-99%)
HP:0001302	Pachygyria	Very frequent (80-99%)
HP:0008736	Hypoplasia of penis	Very frequent (80-99%)
HP:0000966	Hypohidrosis	Frequent (30-79%)
HP:0001252	Hypotonia	Frequent (30-79%)
HP:0001522	Death in infancy	Frequent (30-79%)
HP:0002024	Malabsorption	Frequent (30-79%)
HP:0002119	Ventriculomegaly	Frequent (30-79%)
HP:0000347	Micrognathia	Occasional (5-29%)
HP:0001257	Spasticity	Occasional (5-29%)
HP:0001629	Ventricular septal defect	Occasional (5-29%)
HP:0001643	Patent ductus arteriosus	Occasional (5-29%)
HP:0001738	Exocrine pancreatic insufficiency	Occasional (5-29%)
HP:0002251	Aganglionic megacolon	Occasional (5-29%)
HP:0011220	Prominent forehead	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	X-linked lissencephaly with abnormal genitalia
Mondo ID	MONDO:0010268
MeSH	C564563
OMIM	300215
Orphanet	452
DOID	DOID:0112238
SNOMED CT	717632002
UMLS	C1846171
MedGen	375832
GARD	0012491
Is cancer (heuristic)	no

Also known as: hydranencephaly with abnormal genitalia · lissencephaly, X-linked 2 · lissencephaly, X-linked, 2 · lissencephaly, X-linked, type 2 · LISX2 · X-linked lissencephaly - agenesis of the corpus callosum - genital anomalies · X-linked lissencephaly with abnormal genitalia · X-linked lissencephaly with ambiguous genitalia · X-linked lissencephaly-agenesis of the corpus callosum-genital anomalies syndrome · X-linked lissencephaly-corpus callosum agenesis-genital anomalies syndrome · XLAG (X-linked lissencephaly with abnormal genitalia) syndrome · XLAG syndrome

Data availability: 56 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 › X-linked disease › X-linked lissencephaly with abnormal genitalia

Related subtypes (49): X-linked Opitz G/BBB syndrome, X-linked immunoneurologic disorder, X-linked adrenal hypoplasia congenita, X-linked severe congenital neutropenia, X-linked distal spinal muscular atrophy type 3, epilepsy, X-linked 1, with variable learning disabilities and behavior disorders, Aland island eye disease, X-linked erythropoietic protoporphyria, X-linked central congenital hypothyroidism with late-onset testicular enlargement, X-linked colobomatous microphthalmia-microcephaly-intellectual disability-short stature syndrome, X-linked acrogigantism due to Xq26 microduplication, Wiskott-Aldrich syndrome, X-linked Alport syndrome, X-linked mandibulofacial dysostosis, X-linked chondrodysplasia punctata, choroideremia, cone dystrophy, X-linked, with tapetal-like sheen, diabetes insipidus, nephrogenic, X-linked, Dyggve-Melchior-Clausen syndrome, X-linked, dyskeratosis congenita, X-linked, X-linked hypohidrotic ectodermal dysplasia, X-linked Ehlers-Danlos syndrome, epidermodysplasia verruciformis, X-linked, exudative vitreoretinopathy 2, X-linked, Aarskog-Scott syndrome, X-linked, hemophilia A, X-linked hydrocephalus with stenosis of the aqueduct of Sylvius, hyper-IgM syndrome type 1, X-linked lymphoproliferative syndrome, macular dystrophy, X-linked, X-linked Emery-Dreifuss muscular dystrophy, X-linked myotubular myopathy, X-linked lethal multiple pterygium syndrome, X-linked retinoschisis, spondyloepiphyseal dysplasia tarda, X-linked, X-linked cerebellar ataxia, adrenoleukodystrophy, Charcot-Marie-Tooth disease type X, X-linked dominant disease, X-linked recessive disease, X-linked hypophosphatemic rickets, X-linked sideroblastic anemia 1, X-linked deafness, X-linked cone-rod dystrophy, X-linked congenital stationary night blindness, X-linked congenital hemolytic anemia, X-linked complex neurodevelopmental disorder, X-linked intellectual disability, leukemia, acute, X-linked

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

56 retrieved; paginated sample, class counts are floors:

33 pathogenic, 9 likely pathogenic, 6 uncertain significance, 5 pathogenic/likely pathogenic, 2 conflicting classifications of pathogenicity, 1 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
11188	NM_139058.3(ARX):c.1058C>T (p.Pro353Leu)	ARX	Pathogenic	criteria provided, multiple submitters, no conflicts
11192	NM_139058.3(ARX):c.995G>A (p.Arg332His)	ARX	Pathogenic	criteria provided, multiple submitters, no conflicts
11193	NM_139058.3(ARX):c.1117C>T (p.Gln373Ter)	ARX	Pathogenic	no assertion criteria provided
11194	NM_139058.3(ARX):c.1187dup (p.Gly397fs)	ARX	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
11195	NG_008281.1:g.(?4983)(8028_10643)del	ARX	Pathogenic	no assertion criteria provided
11197	NM_139058.3(ARX):c.1028T>A (p.Leu343Gln)	ARX	Pathogenic	no assertion criteria provided
11205	NM_139058.3(ARX):c.232G>T (p.Glu78Ter)	ARX	Pathogenic	no assertion criteria provided
1494703	NM_139058.3(ARX):c.994C>G (p.Arg332Gly)	ARX	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
157744	NM_139058.3(ARX):c.1372del (p.Ala458fs)	ARX	Pathogenic	criteria provided, single submitter
157746	NM_139058.3(ARX):c.1414C>T (p.Arg472Ter)	ARX	Pathogenic	criteria provided, single submitter
157748	NM_139058.3(ARX):c.1465del (p.Ala489fs)	ARX	Pathogenic	criteria provided, single submitter
157756	NM_139058.3(ARX):c.335_368del (p.Ala112fs)	ARX	Pathogenic	criteria provided, single submitter
157759	NM_139058.3(ARX):c.617del (p.Gly206fs)	ARX	Pathogenic	criteria provided, single submitter
157765	NM_139058.3(ARX):c.995G>T (p.Arg332Leu)	ARX	Pathogenic	criteria provided, single submitter
210316	NM_139058.3(ARX):c.1096del (p.Asp366fs)	ARX	Pathogenic	criteria provided, single submitter
210317	NM_139058.3(ARX):c.1120-82_1469dup	ARX	Pathogenic	criteria provided, single submitter
210318	NM_139058.3(ARX):c.1164_1165insCAAAG (p.Ala389fs)	ARX	Pathogenic	criteria provided, single submitter
210319	NM_139058.3(ARX):c.1337dup (p.Pro447fs)	ARX	Pathogenic	criteria provided, single submitter
210320	NM_139058.3(ARX):c.1449-82_1469dup	ARX	Pathogenic	criteria provided, single submitter
210321	NM_139058.3(ARX):c.1471dup (p.Leu491fs)	ARX	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
210326	NM_139058.2(ARX):c.304_305ins21 (p.?)	ARX	Pathogenic	criteria provided, single submitter
210327	NM_139058.3(ARX):c.306GGC[18] (p.Ala108_Ala115dup)	ARX	Pathogenic	criteria provided, multiple submitters, no conflicts
210330	NM_139058.3(ARX):c.409dup (p.Glu137fs)	ARX	Pathogenic	criteria provided, single submitter
210335	NM_139058.3(ARX):c.562_563delinsTA (p.Ala188Ter)	ARX	Pathogenic	criteria provided, single submitter
287023	NM_139058.3(ARX):c.790del (p.Arg264fs)	ARX	Pathogenic	criteria provided, single submitter
3066286	NM_139058.3(ARX):c.557dup (p.Pro187fs)	ARX	Pathogenic	criteria provided, single submitter
3370505	NM_139058.3(ARX):c.425_456del (p.Ala142fs)	ARX	Pathogenic	criteria provided, single submitter
3382594	NM_139058.3(ARX):c.880G>T (p.Glu294Ter)	ARX	Pathogenic	criteria provided, multiple submitters, no conflicts
4056441	NM_139058.3(ARX):c.1030G>T (p.Glu344Ter)	ARX	Pathogenic	criteria provided, single submitter
434396	NM_139058.3(ARX):c.1141del (p.Ala381fs)	ARX	Pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 16 · Orphanet: 8 · 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
ARX	Definitive	X-linked	X-linked complex neurodevelopmental disorder	16

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
ARX	Orphanet:1934	Early infantile developmental and epileptic encephalopathy
ARX	Orphanet:2508	Corpus callosum agenesis-abnormal genitalia syndrome
ARX	Orphanet:3175	X-linked spasticity-intellectual disability-epilepsy syndrome
ARX	Orphanet:364063	Infantile epileptic-dyskinetic encephalopathy
ARX	Orphanet:452	X-linked lissencephaly with abnormal genitalia
ARX	Orphanet:697160	Infantile epileptic spasms syndrome
ARX	Orphanet:777	X-linked non-syndromic intellectual disability
ARX	Orphanet:94083	Partington 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
ARX	HGNC:18060	ENSG00000004848	Q96QS3	Homeobox protein ARX	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
ARX	Homeobox protein ARX	Transcription factor.

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)
ARX	Transcription factor	no		HD, OAR_dom, Homeodomain-like_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
left ovary	1
ovary	1
right ovary	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
ARX	162	broad	marker	left ovary, ovary, right ovary

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
ARX	758

Structural data

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

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
ARX	Q96QS3	56.51

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
embryonic olfactory bulb interneuron precursor migration	1	8426.0×	0.001	ARX
cerebral cortex tangential migration	1	4213.0×	0.001	ARX
epithelial cell fate commitment	1	4213.0×	0.001	ARX
globus pallidus development	1	3370.4×	0.001	ARX
lipid digestion	1	3370.4×	0.001	ARX
cerebral cortex GABAergic interneuron migration	1	2808.7×	0.001	ARX
positive regulation of organ growth	1	1404.3×	0.002	ARX
cell proliferation in forebrain	1	1296.3×	0.002	ARX
regulation of epithelial cell proliferation	1	936.2×	0.002	ARX
neuron fate commitment	1	802.5×	0.002	ARX
organ growth	1	732.7×	0.002	ARX
neuron development	1	255.3×	0.006	ARX
axon guidance	1	90.6×	0.014	ARX
positive regulation of gene expression	1	38.7×	0.031	ARX
negative regulation of transcription by RNA polymerase II	1	17.7×	0.064	ARX
positive regulation of transcription by RNA polymerase II	1	14.9×	0.071	ARX
regulation of transcription by RNA polymerase II	1	11.7×	0.086	ARX

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
ARX	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	ARX

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)
ARX	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.