Pneumococcal meningitis

Summary

Pneumococcal meningitis (MONDO:0006913) is a disease with 8 cohort genes (8 GWAS associations across 4 studies) and 4 clinical trials. Top therapeutic interventions include phenytoin and daptomycin.

At a glance

• Cohort genes: 8
• GWAS associations: 8
• Clinical trials: 4

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	pneumococcal meningitis
Mondo ID	MONDO:0006913
EFO	EFO:1001114
MeSH	D008586
Orphanet	55655
ICD-10-CM	G00.1
NCIT	C157958
SNOMED CT	51169003
UMLS	C0025295
MedGen	44354
GARD	0018849
MedDRA	10027253, 10035645
Is cancer (heuristic)	no

Also known as: Streptococcus pneumoniae caused infectious meningitis · Streptococcus pneumoniae infectious meningitis

Data availability: 8 GWAS associations (4 studies).

Disease family

Classification path: disease › human disease › disease by body system or component › nervous system disorder › central nervous system disorder › encephalomyelitis › meningitis › infectious meningitis › bacterial meningitis › streptococcal meningitis › pneumococcal meningitis

Genetics & variants

GWAS landscape

8 GWAS associations across 4 studies. Top hits map to 3 distinct genes (as reported by GWAS).

Top associations by p-value

rsID	p-value	Gene	Risk allele	Odds ratio
chr6:148788006	4e-09		?	9.2
rs10870273	1e-08	STK32C	?	4.28
chr13:98891272	4e-08		?	6.3
rs2850542	8e-08	MRO - ME2	?	1.54
rs3870369	4e-07	RNA5SP224 - RNA5SP225	T
rs13057743	6e-07	TBC1D22A	?	1.35
rs210967	9e-07	ROS1	?	1.3
GPHN	9e-06		?

Top studies (by case count)

Study	Lead author	Year	Cases	Controls	Title
GCST009086	Lees JA	2019	732	4,836	Joint sequencing of human and pathogen genomes reveals the genetics of pneumococcal meningitis.
GCST009087	Lees JA	2019	353	3,278	Joint sequencing of human and pathogen genomes reveals the genetics of pneumococcal meningitis.
GCST009082	Lees JA	2019	0	0	Joint sequencing of human and pathogen genomes reveals the genetics of pneumococcal meningitis.
GCST009084	Lees JA	2019	0	0	Joint sequencing of human and pathogen genomes reveals the genetics of pneumococcal meningitis.

Variant details and genetic-evidence tiers

Tier distribution (top 50 variants)

Tier	Variants
Tier 1: coding	0
Tier 2: splice/UTR	0
Tier 3: regulatory	0
Tier 4: intronic/intergenic	8

MAF distribution

Bucket	Variants
common (>=0.05)	5
low_freq (0.01-0.05)	0
rare (<0.01)	0
unknown	3

Functional consequences

Consequence	Count
intron_variant	4
unknown	3
intergenic_variant	1

Top variants

rsID	Chr	Pos	Alleles	MAF	Consequence	Gene	p-value	Tier
chr6:148788006							4e-09	Tier 4: intronic/intergenic
rs10870273	10	132232632	A>G,T	0.05	intron_variant	STK32C	1e-08	Tier 4: intronic/intergenic
chr13:98891272							4e-08	Tier 4: intronic/intergenic
rs2850542	18	50877190	G>A,T	0.05	intergenic_variant	MRO - ME2	8e-08	Tier 4: intronic/intergenic
rs3870369	6	153261855	T>A,G	0.05	intron_variant	RNA5SP224 - RNA5SP225	4e-07	Tier 4: intronic/intergenic
rs13057743	22	47110264	G>A	0.05	intron_variant	TBC1D22A	6e-07	Tier 4: intronic/intergenic
rs210967	6	117303386	C>A,G,T	0.05	intron_variant	ROS1	9e-07	Tier 4: intronic/intergenic
GPHN							9e-06	Tier 4: intronic/intergenic

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 0 · Orphanet: 6 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
ROS1	Orphanet:251579	Giant cell glioblastoma
ROS1	Orphanet:70567	Cholangiocarcinoma
GPHN	Orphanet:308400	Sulfite oxidase deficiency due to molybdenum cofactor deficiency type C
GPHN	Orphanet:3197	Hereditary hyperekplexia
SASH1	Orphanet:231040	Familial generalized lentiginosis
SASH1	Orphanet:447961	Pigmentation defects-palmoplantar keratoderma-skin carcinoma syndrome

Cohort genes → proteins

8 cohort genes, 8 distinct canonical proteins.

Evidence partition

Subset	Genes
gwas_only	8

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
ROS1	HGNC:10261	ENSG00000047936	P08922	Proto-oncogene tyrosine-protein kinase ROS	gwas
TBC1D22A	HGNC:1309	ENSG00000054611	Q8WUA7	TBC1 domain family member 22A	gwas
RGS17	HGNC:14088	ENSG00000091844	Q9UGC6	Regulator of G-protein signaling 17	gwas
GPHN	HGNC:15465	ENSG00000171723	Q9NQX3	Gephyrin	gwas
SASH1	HGNC:19182	ENSG00000111961	O94885	SAM and SH3 domain-containing protein 1	gwas
STK32C	HGNC:21332	ENSG00000165752	Q86UX6	Serine/threonine-protein kinase 32C	gwas
FARP1	HGNC:3591	ENSG00000152767	Q9Y4F1	FERM, ARHGEF and pleckstrin domain-containing protein 1	gwas
ME2	HGNC:6984	ENSG00000082212	P23368	NAD-dependent malic enzyme, mitochondrial	gwas

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
ROS1	Proto-oncogene tyrosine-protein kinase ROS	Receptor tyrosine kinase (RTK) that plays a role in epithelial cell differentiation and regionalization of the proximal epididymal epithelium.
TBC1D22A	TBC1 domain family member 22A	May act as a GTPase-activating protein for Rab family protein(s).
RGS17	Regulator of G-protein signaling 17	Regulates G protein-coupled receptor signaling cascades, including signaling via muscarinic acetylcholine receptor CHRM2 and dopamine receptor DRD2.
GPHN	Gephyrin	Microtubule-associated protein involved in membrane protein-cytoskeleton interactions.
SASH1	SAM and SH3 domain-containing protein 1	Is a positive regulator of NF-kappa-B signaling downstream of TLR4 activation.
FARP1	FERM, ARHGEF and pleckstrin domain-containing protein 1	Functions as a guanine nucleotide exchange factor for RAC1.
ME2	NAD-dependent malic enzyme, mitochondrial	NAD-dependent mitochondrial malic enzyme that catalyzes the oxidative decarboxylation of malate to pyruvate.

Protein-family classification

Druggable: 3 · Difficult: 2 · Unknown: 3 · Druggable fraction: 0.38

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	2	6.9×	0.157
Scaffold/PPI	1	2.2×	0.805
Enzyme (other)	1	1.5×	0.805
Transcription factor	1	1.0×	0.805
Other/Unknown	3	0.7×	0.919

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
ROS1	Kinase	yes	2.7.10.1	LDLR_classB_rpt, Prot_kinase_dom, Ser-Thr/Tyr_kinase_cat_dom
TBC1D22A	Other/Unknown	no		Rab-GAP-TBC_dom, Rab-GAP_TBC_sf
RGS17	Other/Unknown	no		RGS, RGS_sf, RGS_subdomain_2
GPHN	Other/Unknown	no		MoaB/Mog_dom, MoeA_linker/N, MoeA_C_domain_IV
SASH1	Transcription factor	no		SH3_domain, SAM, SAM/pointed_sf
STK32C	Kinase	yes		Prot_kinase_dom, Ser/Thr_kinase_AS, Kinase-like_dom_sf
FARP1	Scaffold/PPI	no		DH_dom, FERM_domain, Ez/rad/moesin-like
ME2	Enzyme (other)	yes	1.1.1.38	Malic_OxRdtase, Malic_N_dom, Malic_NAD-bd

Expression context

Cohort genes with no expression data: 0.

8 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)	8
unknown	0

Top tissues across cohort

Tissue	Cohort genes
corpus epididymis	1
upper lobe of left lung	1
upper lobe of lung	1
amniotic fluid	1
cervix squamous epithelium	1
pancreatic ductal cell	1
buccal mucosa cell	1
cortical plate	1
tendon of biceps brachii	1
cerebellar cortex	1
cerebellar hemisphere	1
right hemisphere of cerebellum	1
lateral globus pallidus	1
skin of hip	1
synovial joint	1
anterior cingulate cortex	1
left testis	1
right testis	1
adrenal tissue	1
renal medulla	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
ROS1	79	tissue_specific	marker	upper lobe of left lung, upper lobe of lung, corpus epididymis
TBC1D22A	276	ubiquitous	marker	pancreatic ductal cell, cervix squamous epithelium, amniotic fluid
RGS17	227	ubiquitous	marker	cortical plate, buccal mucosa cell, tendon of biceps brachii
GPHN	270	ubiquitous	marker	cerebellar cortex, cerebellar hemisphere, right hemisphere of cerebellum
SASH1	293	ubiquitous	marker	synovial joint, lateral globus pallidus, skin of hip
STK32C	198	ubiquitous	marker	right testis, left testis, anterior cingulate cortex
FARP1	283	ubiquitous	marker	renal medulla, stromal cell of endometrium, adrenal tissue
ME2	293	ubiquitous	marker	choroid plexus epithelium, jejunal mucosa, cardiac muscle of right atrium

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
GPHN	2,500
ROS1	2,210
ME2	1,894
TBC1D22A	1,733
RGS17	1,504
FARP1	1,298
STK32C	942
SASH1	879

Structural data

PDB: 7 · AlphaFold-only: 1 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
ME2	P23368	18
ROS1	P08922	5
RGS17	Q9UGC6	2
SASH1	O94885	2
TBC1D22A	Q8WUA7	1
GPHN	Q9NQX3	1
FARP1	Q9Y4F1	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
STK32C	Q86UX6	79.95

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 13. Enrichment computed across 8 evidence-associated genes (4 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 4 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Molybdenum cofactor biosynthesis	1	407.9×	0.032	GPHN
Pyruvate metabolism	1	102.0×	0.055	ME2
RHOF GTPase cycle	1	64.9×	0.055	FARP1
G alpha (z) signalling events	1	58.3×	0.055	RGS17
Mitochondrial protein degradation	1	28.6×	0.088	ME2
Aerobic respiration and respiratory electron transport	1	22.1×	0.088	ME2
RHOA GTPase cycle	1	18.7×	0.088	FARP1
CDC42 GTPase cycle	1	18.1×	0.088	FARP1
RAC1 GTPase cycle	1	15.3×	0.088	FARP1
G alpha (q) signalling events	1	14.3×	0.088	RGS17
G alpha (i) signalling events	1	9.7×	0.117	RGS17
Metabolism of proteins	1	3.1×	0.302	ME2
Metabolism	1	2.9×	0.302	ME2

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 7 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
columnar/cuboidal epithelial cell development	1	2407.4×	0.003	ROS1
glycine receptor clustering	1	2407.4×	0.003	GPHN
regulation of protein K63-linked ubiquitination	1	2407.4×	0.003	SASH1
regulation of protein autoubiquitination	1	2407.4×	0.003	SASH1
synapse assembly	2	66.0×	0.003	GPHN, FARP1
establishment of synaptic specificity at neuromuscular junction	1	1203.7×	0.005	GPHN
regulation of NADP metabolic process	1	1203.7×	0.005	ME2
retrograde trans-synaptic signaling by trans-synaptic protein complex	1	802.5×	0.006	FARP1
gamma-aminobutyric acid receptor clustering	1	481.5×	0.009	GPHN
regulation of epithelial cell migration	1	401.2×	0.010	SASH1
Mo-molybdopterin cofactor biosynthetic process	1	343.9×	0.010	GPHN
malate metabolic process	1	267.5×	0.010	ME2
postsynaptic actin cytoskeleton organization	1	267.5×	0.010	FARP1
positive regulation of skeletal muscle acetylcholine-gated channel clustering	1	267.5×	0.010	FARP1
response to metal ion	1	218.9×	0.011	GPHN
positive regulation of lipopolysaccharide-mediated signaling pathway	1	218.9×	0.011	SASH1
enzyme-linked receptor protein signaling pathway	1	185.2×	0.012	FARP1
positive regulation of JUN kinase activity	1	185.2×	0.012	SASH1
regulation of TOR signaling	1	133.8×	0.015	ROS1
neurotransmitter receptor localization to postsynaptic specialization membrane	1	114.6×	0.017	GPHN
positive regulation of p38MAPK cascade	1	89.2×	0.021	SASH1
regulation of ERK1 and ERK2 cascade	1	83.0×	0.021	ROS1
Rac protein signal transduction	1	80.2×	0.021	FARP1
regulation of presynapse assembly	1	77.7×	0.021	FARP1
response to amphetamine	1	70.8×	0.022	RGS17
establishment of protein localization	1	61.7×	0.023	GPHN
dendrite morphogenesis	1	61.7×	0.023	FARP1
negative regulation of signal transduction	1	53.5×	0.026	RGS17
positive regulation of non-canonical NF-kappaB signal transduction	1	36.5×	0.036	SASH1
positive regulation of endothelial cell migration	1	35.9×	0.036	SASH1

Therapeutics

Drugs indicated for this disease

No approved or late-stage (phase ≥3) drug is indicated for this disease; the following are in earlier-phase trials only.

Earlier-phase candidates (phase 2, investigational — efficacy not yet established): Daptomycin.

Drug target analysis

Approved (phase 4): 1 · Phase ≥3: 2 · Phased (≥1): 3 · Undrugged: 5

Druggability breadth: 4 of 8 evidence-associated genes (50%) 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
ROS1	LORLATINIB

Top cohort targets by molecule count

Symbol	Molecules	Max phase
ROS1	41	4
RGS17	2	2
STK32C	1	3
TBC1D22A	0	0
GPHN	0	0
SASH1	0	0
FARP1	0	0
ME2	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
LORLATINIB	4	ROS1
BRIGATINIB	4	ROS1
REPOTRECTINIB	4	ROS1
CRIZOTINIB	4	ROS1
FEDRATINIB	4	ROS1
AXITINIB	4	ROS1
ALECTINIB	4	ROS1
INFIGRATINIB PHOSPHATE	4	ROS1
INFIGRATINIB	4	ROS1
ENTRECTINIB	4	ROS1
CERITINIB	4	ROS1
GILTERITINIB	4	ROS1
LAROTRECTINIB	4	ROS1
PAZOPANIB	4	ROS1
NINTEDANIB	4	ROS1
MITOXANTRONE	4	ROS1
MIDOSTAURIN	4	ROS1
ENTOSPLETINIB	3	ROS1
ALISERTIB	3	ROS1
LESTAURTINIB	3	ROS1, STK32C
RUBOXISTAURIN	3	ROS1
FORETINIB	2	ROS1
NEFLAMAPIMOD	2	ROS1
REBASTINIB	2	ROS1
CENISERTIB	2	ROS1
ILORASERTIB	2	ROS1
OSI-632	2	ROS1
DALMELITINIB	2	ROS1
SELITRECTINIB	2	ROS1
R-406	2	ROS1

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 2.

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

Symbol	Assays	Type breakdown
ROS1	461	Binding:459, Functional:2
STK32C	148	Binding:148
RGS17	20	Binding:20
ME2	2	Binding:2

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
ROS1	2.7.10.1	receptor protein-tyrosine kinase
ME2	1.1.1.38	malate dehydrogenase (oxaloacetate-decarboxylating)

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
ROS1	461
STK32C	148

Pharmacogenomics

Cohort genes with a PharmGKB record: 8; 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)
LORLATINIB	4	ROS1
BRIGATINIB	4	ROS1
REPOTRECTINIB	4	ROS1
CRIZOTINIB	4	ROS1
FEDRATINIB	4	ROS1
AXITINIB	4	ROS1
ALECTINIB	4	ROS1
INFIGRATINIB PHOSPHATE	4	ROS1
INFIGRATINIB	4	ROS1
ENTRECTINIB	4	ROS1
CERITINIB	4	ROS1
GILTERITINIB	4	ROS1
LAROTRECTINIB	4	ROS1
PAZOPANIB	4	ROS1
NINTEDANIB	4	ROS1
MITOXANTRONE	4	ROS1
MIDOSTAURIN	4	ROS1
ENTOSPLETINIB	3	ROS1
ALISERTIB	3	ROS1
LESTAURTINIB	3	ROS1, STK32C
RUBOXISTAURIN	3	ROS1
FORETINIB	2	ROS1
NEFLAMAPIMOD	2	ROS1
REBASTINIB	2	ROS1
CENISERTIB	2	ROS1
ILORASERTIB	2	ROS1
OSI-632	2	ROS1
DALMELITINIB	2	ROS1
SELITRECTINIB	2	ROS1
R-406	2	ROS1

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	ROS1
B	Phased (≥1) drug, not yet approved	2	RGS17, STK32C
C	Druggable family + PDB, no drug	1	ME2
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	4	TBC1D22A, GPHN, SASH1, FARP1

Undrugged target profiles

5 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
TBC1D22A	0	—
GPHN	0	—
SASH1	0	—
FARP1	0	—
ME2	2	—

Clinical trials & evidence

Clinical trials

Clinical trials: 4.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	2
PHASE4	1
PHASE2	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT01478035	PHASE4	TERMINATED	Study on the Efficacy of Phenytoin in the Prophylaxis of Seizures of Patients With Pneumococcal Meningitis at Least 50 Yrs Old.
NCT03480191	PHASE2	COMPLETED	Adjunction of Daptomycin for the Treatment of Pneumococcal Meningitis
NCT00162578	Not specified	COMPLETED	Vancomycin Concentration in Cerebrospinal Fluid During Pneumococcal Meningitis
NCT00227214	Not specified	COMPLETED	Study Evaluating Pneumococcal Meningitis in the Paediatric Population in Spain Four Years After the Marketing of Prevenar.

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
PHENYTOIN	4	2
DAPTOMYCIN	4	1
CHEMBL1649722	0	1
CHEMBL4286784	0	1
CHEMBL4744444	0	1