Microcephaly 17, primary, autosomal recessive

Summary

Microcephaly 17, primary, autosomal recessive (MONDO:0014908) is a disease caused by CIT (GenCC Strong), with 2 cohort genes.

At a glance

• Causal gene: CIT (GenCC Strong)
• Cohort genes: 2
• ClinVar variants: 55

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	microcephaly 17, primary, autosomal recessive
Mondo ID	MONDO:0014908
OMIM	617090
DOID	DOID:0070288
UMLS	C4310723
MedGen	934690
GARD	0016186
Is cancer (heuristic)	no

Also known as: autosomal recessive primary microcephaly caused by mutation in CIT · autosomal recessive primary microcephaly caused by mutation in cit · CIT autosomal recessive primary microcephaly · cit autosomal recessive primary microcephaly · MCPH17 · microcephaly 17, primary, autosomal recessive · microcephaly 17, primary, autosomal recessive; MCPH17

Data availability: 55 ClinVar variants · 3 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 17, 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 8, 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 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

55 retrieved; paginated sample, class counts are floors:

31 uncertain significance, 10 pathogenic, 6 benign, 3 likely pathogenic, 2 conflicting classifications of pathogenicity, 1 benign/likely benign, 1 pathogenic/likely pathogenic, 1 not provided

ClinVar	Variant (HGVS)	Gene	Classification	Review
1333418	NM_001206999.2(CIT):c.957+1G>T	CIT	Pathogenic	criteria provided, single submitter
252992	NM_001206999.2(CIT):c.1111+1G>A	CIT	Pathogenic	criteria provided, single submitter
254134	NM_001206999.2(CIT):c.317G>T (p.Gly106Val)	CIT	Pathogenic	no assertion criteria provided
254135	NM_001206999.2(CIT):c.376A>C (p.Lys126Gln)	CIT	Pathogenic	no assertion criteria provided
254136	NM_001206999.2(CIT):c.689A>T (p.Asp230Val)	CIT	Pathogenic	no assertion criteria provided
254139	NM_001206999.2(CIT):c.753+3A>T	CIT	Pathogenic	no assertion criteria provided
4537236	NC_000012.11:g.(120288080_120295326)_(120295503_120306863)del	CIT	Pathogenic	criteria provided, single submitter
871735	NM_001206999.2(CIT):c.658C>T (p.Arg220Ter)	CIT	Pathogenic	criteria provided, multiple submitters, no conflicts
983220	NM_001206999.2(CIT):c.4617del (p.Asp1541fs)	CIT	Pathogenic	criteria provided, single submitter
3902695	NM_001206999.2(CIT):c.142C>T (p.Arg48Ter)	LOC126861657	Pathogenic	criteria provided, single submitter
13014	NM_000539.3(RHO):c.1040C>T (p.Pro347Leu)	RHO	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
221283	NM_001206999.2(CIT):c.29_38del (p.Asn10fs)	CIT	Likely pathogenic	criteria provided, single submitter
3234970	NM_001206999.2(CIT):c.1555C>T (p.Arg519Ter)	CIT	Likely pathogenic	criteria provided, single submitter
983219	NM_001206999.2(CIT):c.367T>G (p.Tyr123Asp)	CIT	Likely pathogenic	criteria provided, single submitter
2440088	NM_001206999.2(CIT):c.938A>G (p.Asn313Ser)	CIT	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
636240	NM_001206999.2(CIT):c.3491A>G (p.Asn1164Ser)	CIT	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1030299	NM_001206999.2(CIT):c.3157-5T>G	CIT	Uncertain significance	criteria provided, single submitter
1030300	NM_001206999.2(CIT):c.4691C>A (p.Pro1564Gln)	CIT	Uncertain significance	criteria provided, multiple submitters, no conflicts
1030301	NM_001206999.2(CIT):c.4897C>T (p.Arg1633Cys)	CIT	Uncertain significance	criteria provided, multiple submitters, no conflicts
1030302	NM_001206999.2(CIT):c.4898G>A (p.Arg1633His)	CIT	Uncertain significance	criteria provided, single submitter
1032701	NM_001206999.2(CIT):c.1031G>T (p.Gly344Val)	CIT	Uncertain significance	criteria provided, multiple submitters, no conflicts
1032702	NM_001206999.2(CIT):c.1049A>G (p.Lys350Arg)	CIT	Uncertain significance	criteria provided, single submitter
1032704	NM_001206999.2(CIT):c.644T>C (p.Met215Thr)	CIT	Uncertain significance	criteria provided, single submitter
1064084	NM_001206999.2(CIT):c.3902A>G (p.Asn1301Ser)	CIT	Uncertain significance	criteria provided, multiple submitters, no conflicts
1183275	NM_001206999.2(CIT):c.3271G>A (p.Val1091Ile)	CIT	Uncertain significance	criteria provided, multiple submitters, no conflicts
1207450	NM_001206999.2(CIT):c.3430G>A (p.Ala1144Thr)	CIT	Uncertain significance	criteria provided, multiple submitters, no conflicts
1700779	NM_001206999.2(CIT):c.4393G>A (p.Glu1465Lys)	CIT	Uncertain significance	criteria provided, multiple submitters, no conflicts
1805577	NM_001206999.2(CIT):c.4933C>A (p.Gln1645Lys)	CIT	Uncertain significance	criteria provided, multiple submitters, no conflicts
1805646	NM_001206999.2(CIT):c.731C>T (p.Ala244Val)	CIT	Uncertain significance	criteria provided, multiple submitters, no conflicts
2171345	NM_001206999.2(CIT):c.2086C>T (p.Arg696Cys)	CIT	Uncertain significance	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 4 · Orphanet: 4 · 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
CIT	Strong	Autosomal recessive	microcephaly 17, primary, autosomal recessive	4

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
CIT	Orphanet:2512	Autosomal recessive primary microcephaly
RHO	Orphanet:215	Congenital stationary night blindness
RHO	Orphanet:52427	Retinitis punctata albescens
RHO	Orphanet:791	Retinitis pigmentosa

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
CIT	HGNC:1985	ENSG00000122966	O14578	Citron Rho-interacting kinase	gencc,clinvar
RHO	HGNC:10012	ENSG00000163914	P08100	Rhodopsin	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
CIT	Citron Rho-interacting kinase	Plays a role in cytokinesis.
RHO	Rhodopsin	Photoreceptor required for image-forming vision at low light intensity.

Protein-family classification

Druggable: 2 · 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
Kinase	1	13.9×	0.082
GPCR	1	12.0×	0.082

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
CIT	Kinase	yes		Prot_kinase_dom, AGC-kinase_C, CNH_dom
RHO	GPCR	yes		GPCR_Rhodpsn, Rhodopsin, Opsin

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
lateral nuclear group of thalamus	1
right frontal lobe	1
sural nerve	1
diaphragm	1
neuron projection bundle connecting eye with brain	1
optic choroid	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
CIT	232	ubiquitous	marker	lateral nuclear group of thalamus, right frontal lobe, sural nerve
RHO	38	tissue_specific	marker	optic choroid, neuron projection bundle connecting eye with brain, diaphragm

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
CIT	5,077
RHO	3,578

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
RHO	P08100	4

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
CIT	O14578	69.75

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 11. 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
Opsins	1	634.4×	0.008	RHO
Activation of the phototransduction cascade	1	475.8×	0.008	RHO
RHO GTPases activate CIT	1	300.5×	0.008	CIT
The canonical retinoid cycle in rods (twilight vision)	1	259.6×	0.008	RHO
VxPx cargo-targeting to cilium	1	259.6×	0.008	RHO
Inactivation, recovery and regulation of the phototransduction cascade	1	158.6×	0.012	RHO
RHOB GTPase cycle	1	77.2×	0.019	CIT
RHOC GTPase cycle	1	73.2×	0.019	CIT
RHOA GTPase cycle	1	37.3×	0.033	CIT
RAC1 GTPase cycle	1	30.5×	0.036	CIT
G alpha (i) signalling events	1	19.5×	0.051	RHO

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
thermotaxis	1	4213.0×	0.003	RHO
rod bipolar cell differentiation	1	4213.0×	0.003	RHO
detection of temperature stimulus involved in thermoception	1	2808.7×	0.003	RHO
G protein-coupled opsin signaling pathway	1	1685.2×	0.003	RHO
absorption of visible light	1	1404.3×	0.003	RHO
response to light intensity	1	1053.2×	0.003	RHO
podosome assembly	1	1053.2×	0.003	RHO
generation of neurons	1	766.0×	0.004	CIT
phototransduction, visible light	1	648.1×	0.004	RHO
cellular response to light stimulus	1	526.6×	0.004	RHO
negative regulation of hippo signaling	1	351.1×	0.006	CIT
phototransduction	1	247.8×	0.007	RHO
positive regulation of cytokinesis	1	200.6×	0.008	CIT
photoreceptor cell maintenance	1	179.3×	0.009	RHO
mitotic cytokinesis	1	129.6×	0.011	CIT
neuron apoptotic process	1	92.6×	0.015	CIT
regulation of actin cytoskeleton organization	1	78.8×	0.016	CIT
mitotic cell cycle	1	66.9×	0.018	CIT
microtubule cytoskeleton organization	1	60.6×	0.019	RHO
gene expression	1	39.9×	0.026	RHO
visual perception	1	39.8×	0.026	RHO
G protein-coupled receptor signaling pathway	1	18.1×	0.054	RHO

Therapeutics

Drug target analysis

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

Druggability breadth: 2 of 2 evidence-associated genes (100%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Genes with an approved drug

The molecule shown is one approved compound that hits the gene — not necessarily a drug of choice or one indicated for this disease.

Symbol	Example approved molecule
CIT	MOMELOTINIB

Top cohort targets by molecule count

Symbol	Molecules	Max phase
CIT	41	4
RHO	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
MOMELOTINIB	4	CIT
AFATINIB	4	CIT
FEDRATINIB	4	CIT
SORAFENIB	4	CIT
RUXOLITINIB	4	CIT
BARICITINIB	4	CIT
VANDETANIB	4	CIT
BOSUTINIB	4	CIT
ABEMACICLIB	4	CIT
GILTERITINIB	4	CIT
SUNITINIB	4	CIT
ERLOTINIB	4	CIT
GEFITINIB	4	CIT
VATALANIB	3	CIT
AFURESERTIB	3	CIT
CANERTINIB	3	CIT
FASUDIL	3	CIT
ALVOCIDIB	3	CIT
DOVITINIB	3	CIT
MOTESANIB	3	CIT
LESTAURTINIB	3	CIT
RUBOXISTAURIN	3	CIT
DORAMAPIMOD	2	CIT
FORETINIB	2	CIT
SU-014813	2	CIT
DEFOSBARASERTIB	2	CIT
BMS-690514	2	CIT
R-406	2	CIT
PILAVAPADIN	2	CIT
BI-2536	2	CIT

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
CIT	145	Binding:145
RHO	1	Binding:1

Cohort genes with high screening signal

≥100 ChEMBL assays — a studied-ness signal; see Therapeutics for approved-drug status.

Symbol	ChEMBL assays
CIT	145

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

30 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.

Compound	Max phase	Cohort target (bioactivity)
MOMELOTINIB	4	CIT
AFATINIB	4	CIT
FEDRATINIB	4	CIT
SORAFENIB	4	CIT
RUXOLITINIB	4	CIT
BARICITINIB	4	CIT
VANDETANIB	4	CIT
BOSUTINIB	4	CIT
ABEMACICLIB	4	CIT
GILTERITINIB	4	CIT
SUNITINIB	4	CIT
ERLOTINIB	4	CIT
GEFITINIB	4	CIT
VATALANIB	3	CIT
AFURESERTIB	3	CIT
CANERTINIB	3	CIT
FASUDIL	3	CIT
ALVOCIDIB	3	CIT
DOVITINIB	3	CIT
MOTESANIB	3	CIT
LESTAURTINIB	3	CIT
RUBOXISTAURIN	3	CIT
DORAMAPIMOD	2	CIT
FORETINIB	2	CIT
SU-014813	2	CIT
DEFOSBARASERTIB	2	CIT
BMS-690514	2	CIT
R-406	2	CIT
PILAVAPADIN	2	CIT
BI-2536	2	CIT

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	CIT
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	1	RHO
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)
RHO	1	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.