Maternal phenylketonuria

Summary

Maternal phenylketonuria (MONDO:0016366) is a disease with 1 cohort gene and 1 clinical trial.

At a glance

• Prevalence: Unknown (Europe) [Orphanet-validated]
• Cohort genes: 1
• Phenotypes (HPO): 32
• Clinical trials: 1

Clinical features

Epidemiology

Prevalence records

1 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Annual incidence	1-5 / 10 000	10	Europe	Validated

Signs & symptoms

Clinical features (HPO)

32 HPO clinical features (Orphanet curated; top 32 by frequency):

HPO ID	Term	Frequency
HP:0001627	Abnormal heart morphology	Very frequent (80-99%)
HP:0000252	Microcephaly	Frequent (30-79%)
HP:0001249	Intellectual disability	Frequent (30-79%)
HP:0001263	Global developmental delay	Frequent (30-79%)
HP:0001511	Intrauterine growth retardation	Frequent (30-79%)
HP:0001680	Coarctation of aorta	Frequent (30-79%)
HP:0001999	Abnormal facial shape	Frequent (30-79%)
HP:0004383	Hypoplastic left heart	Frequent (30-79%)
HP:0000218	High palate	Occasional (5-29%)
HP:0000343	Long philtrum	Occasional (5-29%)
HP:0000347	Micrognathia	Occasional (5-29%)
HP:0000431	Wide nasal bridge	Occasional (5-29%)
HP:0000463	Anteverted nares	Occasional (5-29%)
HP:0000752	Hyperactivity	Occasional (5-29%)
HP:0001250	Seizure	Occasional (5-29%)
HP:0001629	Ventricular septal defect	Occasional (5-29%)
HP:0001636	Tetralogy of Fallot	Occasional (5-29%)
HP:0001719	Double outlet right ventricle	Occasional (5-29%)
HP:0002079	Hypoplasia of the corpus callosum	Occasional (5-29%)
HP:0000286	Epicanthus	Very rare (<1-4%)
HP:0000340	Sloping forehead	Very rare (<1-4%)
HP:0000486	Strabismus	Very rare (<1-4%)
HP:0000601	Hypotelorism	Very rare (<1-4%)
HP:0001156	Brachydactyly	Very rare (<1-4%)
HP:0001488	Bilateral ptosis	Very rare (<1-4%)
HP:0002032	Esophageal atresia	Very rare (<1-4%)
HP:0002836	Bladder exstrophy	Very rare (<1-4%)
HP:0004411	Deviated nasal septum	Very rare (<1-4%)
HP:0008589	Hypoplastic helices	Very rare (<1-4%)
HP:0009611	Bifid distal phalanx of the thumb	Very rare (<1-4%)
HP:0012210	Abnormal renal morphology	Very rare (<1-4%)
HP:0030084	Clinodactyly	Very rare (<1-4%)

Identifiers

Disease identifiers

Field	Value
Canonical name	maternal phenylketonuria
Mondo ID	MONDO:0016366
MeSH	D017042
Orphanet	2209
ICD-11	1509230254
UMLS	C0085547
MedGen	88435
GARD	0003413
Is cancer (heuristic)	no

Also known as: hyperphenylalaninemic embryopathy · maternal hyperphenylalaninemia · maternal PKU · phenylketonuric embryopathy

Data availability: 1 GenCC gene-disease record.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › autosomal genetic disease › autosomal recessive disease › phenylketonuria › maternal phenylketonuria

Related subtypes (4): tetrahydrobiopterin-responsive hyperphenylalaninemia/phenylketonuria, mild phenylketonuria, classic phenylketonuria, mild hyperphenylalaninemia

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

No tiered GWAS variants or ClinVar records for this disease.

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 9 · Orphanet: 3 · 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
PAH	Definitive	Autosomal recessive	phenylketonuria	9

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
PAH	Orphanet:2209	Maternal phenylketonuria syndrome
PAH	Orphanet:293284	Tetrahydrobiopterin-responsive phenylketonuria
PAH	Orphanet:708895	Tetrahydrobiopterin-unresponsive phenylketonuria

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
PAH	HGNC:8582	ENSG00000171759	P00439	Phenylalanine-4-hydroxylase	gencc

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
PAH	Phenylalanine-4-hydroxylase	Catalyzes the hydroxylation of L-phenylalanine to L-tyrosine.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 0 · Druggable fraction: 1.0

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
Enzyme (other)	1	12.0×	0.083

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
PAH	Enzyme (other)	yes	1.14.16.1	ArAA_hydroxylase, ACT_dom, Phe-4-hydroxylase_tetra

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
gall bladder	1
liver	1
right lobe of liver	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
PAH	175	broad	marker	right lobe of liver, liver, gall bladder

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
PAH	1,953

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
PAH	P00439	20

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 2. 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
Phenylketonuria	1	11420.0×	2e-04	PAH
Phenylalanine metabolism	1	1903.3×	5e-04	PAH

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
L-tyrosine biosynthetic process	1	16852.0×	1e-04	PAH
amino acid biosynthetic process	1	16852.0×	1e-04	PAH
catecholamine biosynthetic process	1	5617.3×	2e-04	PAH
L-phenylalanine catabolic process	1	2106.5×	5e-04	PAH

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 1 evidence-associated genes (100%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
PAH	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
PAH	4	Binding:4

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
PAH	1.14.16.1	phenylalanine 4-monooxygenase

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	1	PAH
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	0

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)
PAH	4	—

Clinical trials & evidence

Clinical trials

Clinical trials: 1.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT04224142	Not specified	COMPLETED	Evaluation of PKU Sphere in Maternal PKU