Microcephaly 8, primary, autosomal recessive

Summary

Microcephaly 8, primary, autosomal recessive (MONDO:0013849) is a disease caused by CEP135 (GenCC Strong), with 1 cohort gene.

At a glance

• Causal gene: CEP135 (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 33

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	microcephaly 8, primary, autosomal recessive
Mondo ID	MONDO:0013849
OMIM	614673
DOID	DOID:0070282
UMLS	C3553414
MedGen	766328
GARD	0015833
Is cancer (heuristic)	no

Also known as: autosomal recessive primary microcephaly caused by mutation in CEP135 · CEP135 autosomal recessive primary microcephaly · MCPH8 · microcephaly 8, primary, autosomal recessive

Data availability: 33 ClinVar variants · 2 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 › microcephaly 8, primary, autosomal recessive

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 9, primary, autosomal recessive, microcephalic primordial dwarfism due to ZNF335 deficiency, 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

33 retrieved; paginated sample, class counts are floors:

10 pathogenic, 6 uncertain significance, 6 likely pathogenic, 5 pathogenic/likely pathogenic, 4 conflicting classifications of pathogenicity, 1 benign/likely benign, 1 likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1012268	NM_025009.5(CEP135):c.2863C>T (p.Arg955Ter)	CEP135	Pathogenic	no assertion criteria provided
1012269	NM_025009.5(CEP135):c.1376_1379del (p.Lys459fs)	CEP135	Pathogenic	criteria provided, multiple submitters, no conflicts
1338334	NM_025009.5(CEP135):c.3247C>T (p.Arg1083Ter)	CEP135	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1526125	NM_025009.5(CEP135):c.3118_3121del (p.Asn1040fs)	CEP135	Pathogenic	criteria provided, single submitter
1705518	NM_025009.5(CEP135):c.3129_3132del (p.Lys1043fs)	CEP135	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2782546	NM_025009.5(CEP135):c.2990C>A (p.Ser997Ter)	CEP135	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
31661	NM_025009.5(CEP135):c.970del (p.Gln324fs)	CEP135	Pathogenic	no assertion criteria provided
417785	NM_025009.5(CEP135):c.1473+1G>A	CEP135	Pathogenic	no assertion criteria provided
4279703	NM_025009.5(CEP135):c.2501dup (p.Asn834fs)	CEP135	Pathogenic	criteria provided, single submitter
433185	NM_025009.5(CEP135):c.2930_2931del (p.Leu977fs)	CEP135	Pathogenic	criteria provided, single submitter
4752169	NM_025009.5(CEP135):c.1252C>T (p.Arg418Ter)	CEP135	Pathogenic	criteria provided, multiple submitters, no conflicts
4813732	NM_025009.5(CEP135):c.1405C>T (p.Gln469Ter)	CEP135	Pathogenic	criteria provided, single submitter
518356	NM_025009.5(CEP135):c.874C>T (p.Arg292Ter)	CEP135	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
977828	NM_025009.5(CEP135):c.3211A>T (p.Lys1071Ter)	CEP135	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
982087	NM_025009.5(CEP135):c.2722C>T (p.Arg908Ter)	CEP135	Pathogenic	criteria provided, multiple submitters, no conflicts
1324049	NM_025009.5(CEP135):c.3102del (p.Glu1034fs)	CEP135	Likely pathogenic	criteria provided, single submitter
2438985	NM_025009.5(CEP135):c.1980_1984del (p.His661fs)	CEP135	Likely pathogenic	criteria provided, single submitter
3336667	NM_025009.5(CEP135):c.473-1G>C	CEP135	Likely pathogenic	criteria provided, multiple submitters, no conflicts
3764674	NM_025009.5(CEP135):c.1226_1228delinsT (p.Lys409fs)	CEP135	Likely pathogenic	criteria provided, single submitter
3779507	NM_025009.5(CEP135):c.3325C>T (p.Arg1109Ter)	CEP135	Likely pathogenic	criteria provided, single submitter
977859	NM_025009.5(CEP135):c.3215+2T>C	CEP135	Likely pathogenic	no assertion criteria provided
210678	NM_025009.5(CEP135):c.2534T>C (p.Val845Ala)	CEP135	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2979174	NM_025009.5(CEP135):c.1474-2A>G	CEP135	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
3368673	NM_025009.5(CEP135):c.1408C>T (p.Arg470Ter)	CEP135	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
694015	NM_025009.5(CEP135):c.993A>T (p.Arg331Ser)	CEP135	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1028863	NM_025009.5(CEP135):c.3346C>T (p.Arg1116Ter)	CEP135	Uncertain significance	criteria provided, single submitter
1032208	NM_025009.5(CEP135):c.231A>C (p.Arg77Ser)	CEP135	Uncertain significance	criteria provided, single submitter
1032209	NM_025009.5(CEP135):c.575A>T (p.Asp192Val)	CEP135	Uncertain significance	criteria provided, multiple submitters, no conflicts
2439903	NM_025009.5(CEP135):c.1824A>C (p.Lys608Asn)	CEP135	Uncertain significance	criteria provided, single submitter
694013	NM_025009.5(CEP135):c.2458A>G (p.Asn820Asp)	CEP135	Uncertain significance	no assertion criteria provided

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 3 · 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
CEP135	Strong	Autosomal recessive	microcephaly 8, primary, autosomal recessive	3

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
CEP135	Orphanet:2512	Autosomal recessive primary microcephaly

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
CEP135	HGNC:29086	ENSG00000174799	Q66GS9	Centrosomal protein of 135 kDa	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
CEP135	Centrosomal protein of 135 kDa	Centrosomal microtubule-binding protein involved in centriole biogenesis.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 1 · 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	1	1.8×	0.558

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
CEP135	Other/Unknown	no		Centriole_BasalBody_StrucProt

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
amniotic fluid	1
buccal mucosa cell	1
sperm	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
CEP135	238	ubiquitous	marker	amniotic fluid, buccal mucosa cell, sperm

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
CEP135	2,226

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
CEP135	Q66GS9	2

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 7. 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
Loss of Nlp from mitotic centrosomes	1	158.6×	0.009	CEP135
Loss of proteins required for interphase microtubule organization from the centrosome	1	158.6×	0.009	CEP135
AURKA Activation by TPX2	1	152.3×	0.009	CEP135
Recruitment of mitotic centrosome proteins and complexes	1	135.9×	0.009	CEP135
Regulation of PLK1 Activity at G2/M Transition	1	126.9×	0.009	CEP135
Recruitment of NuMA to mitotic centrosomes	1	116.5×	0.009	CEP135
Anchoring of the basal body to the plasma membrane	1	113.1×	0.009	CEP135

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 establishment of protein localization	1	2808.7×	0.001	CEP135
positive regulation of non-motile cilium assembly	1	1872.4×	0.001	CEP135
centriole-centriole cohesion	1	1296.3×	0.001	CEP135
centriole replication	1	732.7×	0.001	CEP135

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
CEP135	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	CEP135

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)
CEP135	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.