Brain malformations with or without urinary tract defects

Summary

Brain malformations with or without urinary tract defects (MONDO:0100478) is a disease caused by NFIA (GenCC Definitive), with 2 cohort genes.

At a glance

• Causal gene: NFIA (GenCC Definitive)
• Cohort genes: 2
• ClinVar variants: 43

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	brain malformations with or without urinary tract defects
Mondo ID	MONDO:0100478
OMIM	613735
UMLS	C4478940
MedGen	1392440
GARD	0027998
Is cancer (heuristic)	no

Data availability: 43 ClinVar variants · 3 GenCC gene-disease records · 1 cell line.

Disease family

Classification path: disease › human disease › disease by body system or component › nervous system disorder › central nervous system disorder › brain disorder › brain malformations with or without urinary tract defects

Related subtypes (70): leukoencephalopathy, megalencephalic, encephalopathy, acute, infection-induced, diabetic encephalopathy, complex cortical dysplasia with other brain malformations, hydrocephalus, brain compression, cerebral sarcoidosis, hepatic encephalopathy, visual pathway disorder, central nervous system origin vertigo, cerebellar disorder, cerebritis, olfactory nerve disorder, thalamic disorder, pituitary gland disorder, disorder of optic chiasm, basal ganglia disorder, epilepsy, mental disorder, central nervous system cyst, migraine disorder, multiple sclerosis, prion disease, carbon monoxide-induced delayed encephalopathy, cerebral malaria, akinetic mutism, bulbar polio, Reye syndrome, brain edema, encephalomalacia, intracranial hypertension, intracranial hypotension, Wernicke encephalopathy, encephalopathy, recurrent, of childhood, XK aprosencephaly, progressive bulbar palsy, cerebrovascular disorder, glycine encephalopathy, autosomal recessive frontotemporal pachygyria, occipital pachygyria and polymicrogyria, insomnia, narcolepsy-cataplexy syndrome, megalencephaly, meningoencephalocele, cerebral cortical dysplasia, encephaloclastic disorder, bilirubin encephalopathy, autoimmune encephalopathy with parasomnia and obstructive sleep apnea, narcolepsy without cataplexy, hypothalamic hamartomas with gelastic seizures, encephalitis, cerebral lipidosis with dementia, brain neoplasm, colpocephaly, corpus callosum agenesis of blepharophimosis robin type, corpus callosum dysgenesis X-linked recessive, corpus callosum dysgenesis cleft spasm, corpus callosum dysgenesis hypopituitarism, cerebral degeneration, acute bilirubin encephalopathy, chronic bilirubin encephalopathy, atelencephaly, aprosencephaly, brain injury, traumatic encephalopathy, cluster headache syndrome, cerebral cortex disorder, midbrain disorder, encephalopathy due to mitochondrial and peroxisomal fission defect, encephalopathy, acute transient

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

43 retrieved; paginated sample, class counts are floors:

14 likely pathogenic, 11 pathogenic, 11 uncertain significance, 3 pathogenic/likely pathogenic, 2 likely benign, 2 conflicting classifications of pathogenicity

ClinVar	Variant (HGVS)	Gene	Classification	Review
2579168	GRCh38/hg38 1p31.3(chr1:61077177-62865614)x1	ANGPTL3	Pathogenic	criteria provided, single submitter
417967	NG_011787.1:g.(205313_260238)_(334455_354191)del	LOC122056897	Pathogenic	no assertion criteria provided
1184868	NM_001134673.4(NFIA):c.1051C>T (p.Arg351Ter)	NFIA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1699181	NM_001134673.4(NFIA):c.248del (p.Ile83fs)	NFIA	Pathogenic	criteria provided, single submitter
2124621	NM_001134673.4(NFIA):c.739_740del (p.Ser247fs)	NFIA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2690897	NM_001134673.4(NFIA):c.27+1G>C	NFIA	Pathogenic	criteria provided, single submitter
417968	NM_001134673.4(NFIA):c.1094del (p.Pro365fs)	NFIA	Pathogenic	no assertion criteria provided
420999	NM_001134673.4(NFIA):c.70C>T (p.Arg24Ter)	NFIA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
4292603	NM_001134673.4(NFIA):c.645_646insTC (p.Phe217fs)	NFIA	Pathogenic	criteria provided, single submitter
445152	NC_000001.10:g.61497698_61607171del	NFIA	Pathogenic	no assertion criteria provided
4813077	NM_001134673.4(NFIA):c.918_921del (p.Ser307fs)	NFIA	Pathogenic	criteria provided, single submitter
4847666	NC_000001.10:g.(61548491_61553820)_(61554353_61743191)del	NFIA	Pathogenic	criteria provided, single submitter
489177	NM_001134673.4(NFIA):c.250C>T (p.Arg84Ter)	NFIA	Pathogenic	criteria provided, multiple submitters, no conflicts
523874	NM_001134673.4(NFIA):c.220C>T (p.Arg74Ter)	NFIA	Pathogenic	criteria provided, multiple submitters, no conflicts
1325836	NM_001134673.4(NFIA):c.1086dup (p.Ala363fs)	NFIA	Likely pathogenic	criteria provided, single submitter
2412704	NM_001134673.4(NFIA):c.400del (p.Met133_Val134insTer)	NFIA	Likely pathogenic	criteria provided, single submitter
2572617	NM_001134673.4(NFIA):c.925G>T (p.Gly309Ter)	NFIA	Likely pathogenic	criteria provided, single submitter
3065686	NM_001134673.4(NFIA):c.650_651del (p.Phe217fs)	NFIA	Likely pathogenic	criteria provided, single submitter
3338672	NM_001134673.4(NFIA):c.875dup (p.Phe293fs)	NFIA	Likely pathogenic	criteria provided, single submitter
3382221	NM_001134673.4(NFIA):c.963del (p.Thr322fs)	NFIA	Likely pathogenic	criteria provided, single submitter
3382763	NM_001134673.4(NFIA):c.443_444dup (p.Arg149fs)	NFIA	Likely pathogenic	criteria provided, single submitter
3764697	NM_001134673.4(NFIA):c.328C>T (p.Gln110Ter)	NFIA	Likely pathogenic	criteria provided, single submitter
3777193	NM_001134673.4(NFIA):c.859del (p.Ser287fs)	NFIA	Likely pathogenic	criteria provided, single submitter
4278047	NM_001134673.4(NFIA):c.140del (p.Arg47fs)	NFIA	Likely pathogenic	criteria provided, single submitter
4292154	NM_001134673.4(NFIA):c.310_311dup (p.Leu105fs)	NFIA	Likely pathogenic	criteria provided, single submitter
4294508	NM_001134673.4(NFIA):c.375dup (p.Val126fs)	NFIA	Likely pathogenic	criteria provided, single submitter
4531518	NM_001134673.4(NFIA):c.1076-2A>G	NFIA	Likely pathogenic	criteria provided, single submitter
4813076	NM_001134673.4(NFIA):c.346A>G (p.Arg116Gly)	NFIA	Likely pathogenic	criteria provided, single submitter
265253	NM_001134673.4(NFIA):c.361C>T (p.Arg121Cys)	NFIA	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
520757	NM_001134673.4(NFIA):c.112C>T (p.Arg38Ter)	NFIA	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 5 · Orphanet: 1 · 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
NFIA	Definitive	Autosomal dominant	brain malformations with or without urinary tract defects	5

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
NFIA	Orphanet:401986	1p31p32 microdeletion syndrome

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
NFIA	HGNC:7784	ENSG00000162599	Q12857	Nuclear factor 1 A-type	gencc,clinvar
ANGPTL3	HGNC:491	ENSG00000132855	Q9Y5C1	Angiopoietin-related protein 3	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
NFIA	Nuclear factor 1 A-type	Recognizes and binds the palindromic sequence 5’-TTGGCNNNNNGCCAA-3’ present in viral and cellular promoters and in the origin of replication of adenovirus type 2.
ANGPTL3	Angiopoietin-related protein 3	Acts in part as a hepatokine that is involved in regulation of lipid and glucose metabolism.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 2 · 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	2	1.8×	0.312

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
NFIA	Other/Unknown	no		CTF/NFI, MAD_homology1_Dwarfin-type, CTF/NFI_DNA-bd_N
ANGPTL3	Other/Unknown	no		Fibrinogen_a/b/g_C_dom, Fibrinogen_a/b/g_C_1, Fibrinogen-like_C

Expression context

Cohort genes with no expression data: 0.

2 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)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
globus pallidus	1
medial globus pallidus	1
urethra	1
liver	1
nephron tubule	1
right lobe of liver	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
NFIA	281	ubiquitous	marker	medial globus pallidus, globus pallidus, urethra
ANGPTL3	153	tissue_specific	marker	right lobe of liver, liver, nephron tubule

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
NFIA	2,456
ANGPTL3	1,279

Structural data

PDB: 2 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
NFIA	Q12857	5
ANGPTL3	Q9Y5C1	1

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 10. Enrichment computed across 2 evidence-associated genes (2 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 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
NR1H2 & NR1H3 regulate gene expression linked to lipogenesis	1	571.0×	0.010	ANGPTL3
Assembly of active LPL and LIPC lipase complexes	1	300.5×	0.010	ANGPTL3
RNA Polymerase III Transcription Termination	1	248.3×	0.010	NFIA
Plasma lipoprotein remodeling	1	237.9×	0.010	ANGPTL3
NR1H2 and NR1H3-mediated signaling	1	196.9×	0.010	ANGPTL3
RNA Polymerase III Abortive And Retractive Initiation	1	139.3×	0.012	NFIA
Plasma lipoprotein assembly, remodeling, and clearance	1	114.2×	0.012	ANGPTL3
Signaling by Nuclear Receptors	1	51.0×	0.024	ANGPTL3
Transport of small molecules	1	12.6×	0.087	ANGPTL3
Signal Transduction	1	5.1×	0.187	ANGPTL3

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
regulation of chylomicron remodeling	1	4213.0×	0.006	ANGPTL3
glial cell fate specification	1	2106.5×	0.006	NFIA
acylglycerol homeostasis	1	1685.2×	0.006	ANGPTL3
negative regulation of very-low-density lipoprotein particle remodeling	1	1404.3×	0.006	ANGPTL3
ureter development	1	1404.3×	0.006	NFIA
positive regulation of lipid catabolic process	1	936.2×	0.007	ANGPTL3
phospholipid catabolic process	1	601.9×	0.007	ANGPTL3
glycerol metabolic process	1	561.7×	0.007	ANGPTL3
viral genome replication	1	561.7×	0.007	NFIA
exit from mitosis	1	526.6×	0.007	NFIA
limb morphogenesis	1	526.6×	0.007	NFIA
phospholipid homeostasis	1	495.6×	0.007	ANGPTL3
synapse maturation	1	468.1×	0.007	NFIA
glial cell proliferation	1	443.5×	0.007	NFIA
neuron fate specification	1	351.1×	0.007	NFIA
artery morphogenesis	1	337.0×	0.007	ANGPTL3
neural precursor cell proliferation	1	337.0×	0.007	NFIA
lipid storage	1	271.8×	0.008	ANGPTL3
triglyceride homeostasis	1	240.7×	0.009	ANGPTL3
response to hormone	1	216.1×	0.009	ANGPTL3
phospholipid metabolic process	1	172.0×	0.011	ANGPTL3
lipid homeostasis	1	168.5×	0.011	ANGPTL3
retina development in camera-type eye	1	127.7×	0.014	NFIA
cartilage development	1	125.8×	0.014	NFIA
response to wounding	1	110.9×	0.015	NFIA
BMP signaling pathway	1	100.3×	0.015	NFIA
cholesterol metabolic process	1	98.0×	0.015	ANGPTL3
fatty acid metabolic process	1	96.8×	0.015	ANGPTL3
DNA replication	1	82.6×	0.016	NFIA
cell-matrix adhesion	1	81.8×	0.016	ANGPTL3

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 2 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
NFIA	0	0
ANGPTL3	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	NFIA, ANGPTL3

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)
NFIA	0	—
ANGPTL3	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.