Microcephaly, seizures, and developmental delay

Summary

Microcephaly, seizures, and developmental delay (MONDO:0013254) is a disease caused by PNKP (GenCC Strong), with 2 cohort genes.

At a glance

• Causal gene: PNKP (GenCC Strong)
• Cohort genes: 2
• ClinVar variants: 128

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	microcephaly, seizures, and developmental delay
Mondo ID	MONDO:0013254
OMIM	613402
Orphanet	228418
DOID	DOID:0080457
UMLS	C3150667
MedGen	462017
GARD	0010933
Is cancer (heuristic)	no

Also known as: early infantile epileptic encephalopathy-10 · EIEE10 · MCSZ · microcephaly - seizures - developmental delay · microcephaly, seizures, and developmental delay

Data availability: 128 ClinVar variants · 3 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by developmental or physiological process › disorder of development or morphogenesis › microcephaly › microcephaly, seizures, and developmental delay

Related subtypes (9): microcephalic osteodysplastic primordial dwarfism, microcephaly and chorioretinopathy, microcephaly with or without chorioretinopathy, lymphedema, or intellectual disability, Amish lethal microcephaly, isolated congenital microcephaly, isolated microcephaly, microcephaly with intellectual disability, microcephaly with lissencephaly and/or hydranencephaly, microcephaly, progressive, with simplified gyral pattern and cerebellar hypoplasia

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

128 retrieved; paginated sample, class counts are floors:

46 uncertain significance, 45 conflicting classifications of pathogenicity, 11 benign/likely benign, 8 pathogenic, 8 likely pathogenic, 5 pathogenic/likely pathogenic, 4 benign, 1 likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1300178	NM_007254.4(PNKP):c.1299-5_1303del	PNKP	Pathogenic	criteria provided, single submitter
1453676	NM_007254.4(PNKP):c.721G>T (p.Glu241Ter)	PNKP	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
159788	NM_007254.4(PNKP):c.1295_1298+6del	PNKP	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1806352	NM_007254.4(PNKP):c.1286_1287insTAAGC (p.Ser430fs)	PNKP	Pathogenic	criteria provided, single submitter
187766	NM_007254.4(PNKP):c.1123G>T (p.Gly375Trp)	PNKP	Pathogenic	criteria provided, multiple submitters, no conflicts
190219	NM_007254.4(PNKP):c.1221_1223del (p.Thr408del)	PNKP	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
211919	NM_007254.4(PNKP):c.1386+49_1387-33del	PNKP	Pathogenic	criteria provided, multiple submitters, no conflicts
436354	NM_007254.4(PNKP):c.636+1G>T	PNKP	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
4846	NM_007254.4(PNKP):c.976G>A (p.Glu326Lys)	PNKP	Pathogenic	criteria provided, multiple submitters, no conflicts
4847	NM_007254.4(PNKP):c.1253_1269dup (p.Thr424fs)	PNKP	Pathogenic	criteria provided, multiple submitters, no conflicts
4848	NM_007254.4(PNKP):c.526C>T (p.Leu176Phe)	PNKP	Pathogenic	no assertion criteria provided
692103	NM_007254.4(PNKP):c.148C>G (p.Gln50Glu)	PNKP	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
807469	NM_007254.4(PNKP):c.1261_1262insGGGTCGCCATCGACAAC (p.Ile421fs)	PNKP	Pathogenic	criteria provided, single submitter
1691707	NM_016359.5(NUSAP1):c.1209C>A (p.Tyr403Ter)	NUSAP1	Likely pathogenic	criteria provided, single submitter
1497182	NM_007254.4(PNKP):c.865+1G>A	PNKP	Likely pathogenic	criteria provided, multiple submitters, no conflicts
2585035	NM_007254.4(PNKP):c.1314_1317dup (p.Ala440fs)	PNKP	Likely pathogenic	criteria provided, single submitter
3336665	NM_007254.4(PNKP):c.1298+2T>A	PNKP	Likely pathogenic	criteria provided, single submitter
4056433	NM_007254.4(PNKP):c.198G>A (p.Gln66=)	PNKP	Likely pathogenic	criteria provided, single submitter
4845667	NM_007254.4(PNKP):c.1485dup (p.Ser496fs)	PNKP	Likely pathogenic	criteria provided, single submitter
977854	NM_007254.4(PNKP):c.103A>G (p.Arg35Gly)	PNKP	Likely pathogenic	no assertion criteria provided
977906	NM_007254.4(PNKP):c.829dup (p.Thr277fs)	PNKP	Likely pathogenic	no assertion criteria provided
138708	NM_007254.4(PNKP):c.519C>T (p.Asp173=)	PNKP	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
138711	NM_007254.4(PNKP):c.672C>T (p.Arg224=)	PNKP	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
138714	NM_007254.4(PNKP):c.876A>G (p.Gly292=)	PNKP	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
138719	NM_007254.4(PNKP):c.1126+9C>T	PNKP	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
138721	NM_007254.4(PNKP):c.1298+6G>A	PNKP	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
138725	NM_007254.4(PNKP):c.1522G>A (p.Glu508Lys)	PNKP	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
138727	NM_007254.4(PNKP):c.*15C>T	PNKP	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
159790	NM_007254.4(PNKP):c.1482C>A (p.Gly494=)	PNKP	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
159791	NM_007254.4(PNKP):c.151+18T>G	PNKP	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 11 · 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
PNKP	Strong	Autosomal recessive	microcephaly, seizures, and developmental delay	11

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
PNKP	Orphanet:101101	Charcot-Marie-Tooth disease type 2B2
PNKP	Orphanet:1934	Early infantile developmental and epileptic encephalopathy
PNKP	Orphanet:459033	Ataxia-oculomotor apraxia type 4

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
PNKP	HGNC:9154	ENSG00000039650	Q96T60	Bifunctional polynucleotide phosphatase/kinase	gencc,clinvar
NUSAP1	HGNC:18538	ENSG00000137804	Q9BXS6	Nucleolar and spindle-associated protein 1	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
PNKP	Bifunctional polynucleotide phosphatase/kinase	Plays a key role in the repair of DNA damage, functioning as part of both the non-homologous end-joining (NHEJ) and base excision repair (BER) pathways.
NUSAP1	Nucleolar and spindle-associated protein 1	Microtubule-associated protein with the capacity to bundle and stabilize microtubules.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 1 · Druggable fraction: 0.5

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
Phosphatase	1	42.0×	0.047
Other/Unknown	1	0.9×	0.805

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
PNKP	Phosphatase	yes	2.7.1.78	HAD-SF_hydro_IIIA, PNKP, Polynucleotide_phosphatase
NUSAP1	Other/Unknown	no		NuSAP

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
granulocyte	1
right adrenal gland cortex	1
right uterine tube	1
embryo	1
ganglionic eminence	1
ventricular zone	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
PNKP	259	ubiquitous	marker	right uterine tube, granulocyte, right adrenal gland cortex
NUSAP1	138	ubiquitous	marker	ventricular zone, ganglionic eminence, embryo

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
PNKP	2,445
NUSAP1	1,746

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
PNKP	Q96T60	2

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
NUSAP1	Q9BXS6	62.63

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 1. Enrichment computed across 2 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
APEX1-Independent Resolution of AP Sites via the Single Nucleotide Replacement Pathway	1	1631.4×	6e-04	PNKP

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
establishment of mitotic spindle localization	1	1404.3×	0.006	NUSAP1
response to radiation	1	601.9×	0.006	PNKP
base-excision repair, gap-filling	1	561.7×	0.006	PNKP
mitotic chromosome condensation	1	495.6×	0.006	NUSAP1
positive regulation of double-strand break repair via nonhomologous end joining	1	495.6×	0.006	PNKP
DNA-templated DNA replication	1	280.9×	0.006	PNKP
positive regulation of mitotic nuclear division	1	271.8×	0.006	NUSAP1
positive regulation of telomere maintenance	1	255.3×	0.006	PNKP
mitotic sister chromatid segregation	1	240.7×	0.006	NUSAP1
double-strand break repair via nonhomologous end joining	1	210.7×	0.007	PNKP
nucleotide-excision repair	1	191.5×	0.007	PNKP
mitotic cytokinesis	1	129.6×	0.009	NUSAP1
response to oxidative stress	1	65.3×	0.016	PNKP
DNA repair	1	31.9×	0.031	PNKP

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
PNKP	0	0
NUSAP1	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
PNKP	8	Binding:8

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
PNKP	2.7.1.78, 3.1.3.32	polynucleotide 5’-hydroxyl-kinase, polynucleotide 3’-phosphatase

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	1	PNKP
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	NUSAP1

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)
PNKP	8	—
NUSAP1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.