microcephalic primordial dwarfism due to ZNF335 deficiency

Summary

microcephalic primordial dwarfism due to ZNF335 deficiency (MONDO:0014043) is a disease caused by ZNF335 (GenCC Strong), with 1 cohort gene.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: ZNF335 (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 73
• Phenotypes (HPO): 9

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		10	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

9 HPO clinical features (Orphanet curated; top 9 by frequency):

HPO ID	Term	Frequency
HP:0000252	Microcephaly	Very frequent (80-99%)
HP:0001317	Abnormal cerebellum morphology	Very frequent (80-99%)
HP:0002060	Abnormal cerebral morphology	Very frequent (80-99%)
HP:0002119	Ventriculomegaly	Very frequent (80-99%)
HP:0002472	Small cerebral cortex	Very frequent (80-99%)
HP:0002538	Abnormality of the cerebral cortex	Very frequent (80-99%)
HP:0009879	Simplified gyral pattern	Very frequent (80-99%)
HP:0012444	Brain atrophy	Very frequent (80-99%)
HP:0012757	Abnormal neuron morphology	Very frequent (80-99%)

Identifiers

Disease identifiers

Field	Value
Canonical name	microcephalic primordial dwarfism due to ZNF335 deficiency
Mondo ID	MONDO:0014043
OMIM	615095
Orphanet	329228
DOID	DOID:0070294
SNOMED CT	724141003
UMLS	C3554499
MedGen	767413
GARD	0017498
Is cancer (heuristic)	no

Also known as: MCPH10 · microcephalic primordial dwarfism, Walsh type · microcephaly 10, primary, autosomal recessive

Data availability: 73 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 › autosomal genetic disease › autosomal recessive disease › autosomal recessive primary microcephaly › microcephalic primordial dwarfism due to ZNF335 deficiency

Related subtypes (28): microcephaly 1, primary, autosomal recessive, microcephaly with simplified gyral pattern, microcephaly 2, primary, autosomal recessive, with or without cortical malformations, microcephaly 4, primary, autosomal recessive, microcephaly 3, primary, autosomal recessive, microcephaly 5, primary, autosomal recessive, microcephaly 7, primary, autosomal recessive, microcephaly 8, primary, autosomal recessive, microcephaly 9, primary, autosomal recessive, microcephaly 11, primary, autosomal recessive, microcephaly 13, primary, autosomal recessive, microcephaly 12, primary, autosomal recessive, microcephaly 14, primary, autosomal recessive, microcephaly 15, primary, autosomal recessive, microcephaly 16, primary, autosomal recessive, microcephaly 17, primary, autosomal recessive, microcephaly 28, primary, autosomal recessive, microcephaly 29, primary, autosomal recessive, microcephaly 24, primary, autosomal recessive, microcephaly 25, primary, autosomal recessive, microcephaly 19, primary, autosomal recessive, microcephaly 20, primary, autosomal recessive, microcephaly 21, primary, autosomal recessive, microcephaly 22, primary, autosomal recessive, microcephaly 23, primary, autosomal recessive, microcephaly with or without short stature, microcephaly 30, primary, autosomal recessive, microcephaly 31, primary, autosomal recessive

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

73 retrieved; paginated sample, class counts are floors:

21 uncertain significance, 16 benign, 15 benign/likely benign, 8 conflicting classifications of pathogenicity, 5 pathogenic, 5 likely pathogenic, 2 pathogenic/likely pathogenic, 1 likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1686312	NM_022095.4(ZNF335):c.3014_3015insG (p.Ser1007fs)	ZNF335	Pathogenic	criteria provided, single submitter
3393087	NM_022095.4(ZNF335):c.1978C>T (p.Arg660Ter)	ZNF335	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
375392	NM_022095.4(ZNF335):c.3787G>T (p.Glu1263Ter)	ZNF335	Pathogenic	criteria provided, single submitter
375393	NM_022095.4(ZNF335):c.2744_2747del (p.Ser915fs)	ZNF335	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
40116	NM_022095.4(ZNF335):c.3332G>A (p.Arg1111His)	ZNF335	Pathogenic	no assertion criteria provided
4685505	NM_022095.4(ZNF335):c.3576_3577del (p.Gln1192fs)	ZNF335	Pathogenic	criteria provided, single submitter
619006	NM_022095.4(ZNF335):c.1399T>C (p.Cys467Arg)	ZNF335	Pathogenic	no assertion criteria provided
212646	NM_022095.4(ZNF335):c.2515_2518dup (p.Thr840fs)	ZNF335	Likely pathogenic	criteria provided, single submitter
3255579	NM_022095.4(ZNF335):c.1460A>G (p.His487Arg)	ZNF335	Likely pathogenic	criteria provided, single submitter
3780812	NM_022095.4(ZNF335):c.315del (p.Val107fs)	ZNF335	Likely pathogenic	criteria provided, single submitter
3780813	NM_022095.4(ZNF335):c.3487+1G>C	ZNF335	Likely pathogenic	criteria provided, single submitter
619007	NM_022095.4(ZNF335):c.1505A>G (p.Tyr502Cys)	ZNF335	Likely pathogenic	criteria provided, single submitter
1678808	NM_022095.4(ZNF335):c.857G>A (p.Arg286Gln)	ZNF335	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2167571	NM_022095.4(ZNF335):c.1696G>A (p.Val566Met)	ZNF335	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
377237	NM_022095.4(ZNF335):c.808C>T (p.Arg270Cys)	ZNF335	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
520770	NM_022095.4(ZNF335):c.3092G>A (p.Arg1031Gln)	ZNF335	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
561147	NM_022095.4(ZNF335):c.715GTG[3] (p.Val242del)	ZNF335	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
624196	NM_022095.4(ZNF335):c.1441C>G (p.Arg481Gly)	ZNF335	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
800946	NM_022095.4(ZNF335):c.3158C>T (p.Pro1053Leu)	ZNF335	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
998091	NM_022095.4(ZNF335):c.3346G>A (p.Gly1116Arg)	ZNF335	Conflicting classifications of pathogenicity	no assertion criteria provided
1029842	NM_022095.4(ZNF335):c.2891G>A (p.Cys964Tyr)	ZNF335	Uncertain significance	criteria provided, multiple submitters, no conflicts
1301769	NM_022095.4(ZNF335):c.1508G>A (p.Arg503His)	ZNF335	Uncertain significance	criteria provided, multiple submitters, no conflicts
1342535	NM_022095.4(ZNF335):c.1665G>C (p.Pro555=)	ZNF335	Uncertain significance	criteria provided, single submitter
1806088	NM_022095.4(ZNF335):c.2047T>C (p.Cys683Arg)	ZNF335	Uncertain significance	criteria provided, single submitter
1806360	NM_022095.4(ZNF335):c.2062C>T (p.Arg688Trp)	ZNF335	Uncertain significance	criteria provided, single submitter
212644	NM_022095.4(ZNF335):c.2168TCT[1] (p.Phe724del)	ZNF335	Uncertain significance	criteria provided, multiple submitters, no conflicts
2319333	NM_022095.4(ZNF335):c.1319G>A (p.Arg440Gln)	ZNF335	Uncertain significance	criteria provided, multiple submitters, no conflicts
2429737	NM_022095.4(ZNF335):c.3206A>G (p.His1069Arg)	ZNF335	Uncertain significance	criteria provided, multiple submitters, no conflicts
2438681	NM_022095.4(ZNF335):c.3274C>T (p.Arg1092Trp)	ZNF335	Uncertain significance	criteria provided, single submitter
2438682	NM_022095.4(ZNF335):c.3887_3888del (p.His1296fs)	ZNF335	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 4 · 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
ZNF335	Strong	Autosomal recessive	microcephalic primordial dwarfism due to ZNF335 deficiency	4

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
ZNF335	Orphanet:329228	Microcephalic primordial dwarfism due to ZNF335 deficiency

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
ZNF335	HGNC:15807	ENSG00000198026	Q9H4Z2	Zinc finger protein 335	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
ZNF335	Zinc finger protein 335	Component or associated component of some histone methyltransferase complexes may regulate transcription through recruitment of those complexes on gene promoters.

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)
ZNF335	Transcription factor	no		Znf_C2H2_type, Znf_C2H2_sf, Zinc_finger/UBP_domain

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
cerebellar hemisphere	1
granulocyte	1
right hemisphere of cerebellum	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
ZNF335	199	ubiquitous	marker	granulocyte, right hemisphere of cerebellum, cerebellar hemisphere

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
ZNF335	1,156

Structural data

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

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
ZNF335	Q9H4Z2	52.13

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 1. 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
Activation of anterior HOX genes in hindbrain development during early embryogenesis	1	91.4×	0.011	ZNF335

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
positive regulation of lymphocyte proliferation	1	1872.4×	0.003	ZNF335
cerebral cortex neuron differentiation	1	1203.7×	0.003	ZNF335
brain morphogenesis	1	732.7×	0.003	ZNF335
positive regulation of neuroblast proliferation	1	581.1×	0.003	ZNF335
positive regulation of neurogenesis	1	581.1×	0.003	ZNF335
epigenetic regulation of gene expression	1	383.0×	0.004	ZNF335
neuron projection morphogenesis	1	276.3×	0.005	ZNF335
brain development	1	79.5×	0.015	ZNF335
in utero embryonic development	1	72.0×	0.015	ZNF335
positive regulation of transcription by RNA polymerase II	1	14.9×	0.067	ZNF335

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
ZNF335	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	ZNF335

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)
ZNF335	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.