Nanophthalmos 4

Summary

Nanophthalmos 4 (MONDO:0014426) is a disease caused by TMEM98 (GenCC Strong), with 3 cohort genes.

At a glance

• Causal gene: TMEM98 (GenCC Strong)
• Cohort genes: 3
• ClinVar variants: 5

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	nanophthalmos 4
Mondo ID	MONDO:0014426
OMIM	615972
UMLS	C4014848
MedGen	863285
GARD	0018629
Is cancer (heuristic)	no

Also known as: nanophthalmia caused by mutation in TMEM98 · nanophthalmos 4 · nanophthalmos type 4 · NNO4 · TMEM98 nanophthalmia

Data availability: 5 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 › nanophthalmia › nanophthalmos 4

Related subtypes (3): nanophthalmos 1, nanophthalmos 2, nanophthalmos 3

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

5 retrieved; paginated sample, class counts are floors:

4 pathogenic, 1 likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
981056	GRCh37/hg19 17q11.2-12(chr17:29989741-32355632)	LRRC37B	Pathogenic	no assertion criteria provided
155721	NM_015544.3(TMEM98):c.577G>C (p.Ala193Pro)	TMEM98	Pathogenic	no assertion criteria provided
224331	NM_015544.3(TMEM98):c.587A>C (p.His196Pro)	TMEM98	Pathogenic	no assertion criteria provided
224332	NM_015544.3(TMEM98):c.236_263+6del	TMEM98	Pathogenic	no assertion criteria provided
4533182	NM_004960.4(FUS):c.1483dup (p.Arg495fs)	FUS	Likely pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 5 · Orphanet: 6 · 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
TMEM98	Strong	Autosomal dominant	nanophthalmos 4	5

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
TMEM98	Orphanet:35612	Nanophthalmos
FUS	Orphanet:275872	Frontotemporal dementia with motor neuron disease
FUS	Orphanet:300605	Juvenile amyotrophic lateral sclerosis
FUS	Orphanet:79105	Myxofibrosarcoma
FUS	Orphanet:803	Amyotrophic lateral sclerosis
FUS	Orphanet:99967	Myxoid/round cell liposarcoma

Cohort genes → proteins

3 cohort genes, 3 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	3

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
TMEM98	HGNC:24529	ENSG00000006042	Q9Y2Y6	Transmembrane protein 98	gencc,clinvar
LRRC37B	HGNC:29070	ENSG00000185158	Q96QE4	Leucine-rich repeat-containing protein 37B	clinvar
FUS	HGNC:4010	ENSG00000089280	P35637	RNA-binding protein FUS	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
TMEM98	Transmembrane protein 98	Functions as a negative regulator of MYRF in oligodendrocyte differentiation and myelination.
FUS	RNA-binding protein FUS	DNA/RNA-binding protein that plays a role in various cellular processes such as transcription regulation, RNA splicing, RNA transport, DNA repair and damage response.

Protein-family classification

Druggable: 0 · Difficult: 1 · Unknown: 2 · 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	2.8×	0.587
Other/Unknown	2	1.2×	0.587

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
TMEM98	Other/Unknown	no		TMEM98
LRRC37B	Other/Unknown	no		Leu-rich_rpt, Leu-rich_rpt_typical-subtyp, LRRC37
FUS	Transcription factor	no		RRM_dom, Znf_RanBP2, Nucleotide-bd_a/b_plait_sf

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)	3
unknown	0

Top tissues across cohort

Tissue	Cohort genes
ileal mucosa	1
pigmented layer of retina	1
retina	1
cerebellar cortex	1
cerebellar hemisphere	1
cerebellum	1
right hemisphere of cerebellum	1
right testis	1
ventricular zone	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
TMEM98	230	ubiquitous	marker	ileal mucosa, pigmented layer of retina, retina
LRRC37B	134	ubiquitous	yes	cerebellar cortex, cerebellar hemisphere, cerebellum
FUS	304	ubiquitous	marker	right testis, ventricular zone, right hemisphere of cerebellum

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
FUS	5,250
TMEM98	557
LRRC37B	221

Structural data

PDB: 1 · AlphaFold-only: 2 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
FUS	P35637	23

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
TMEM98	Q9Y2Y6	71.67
LRRC37B	Q96QE4	53.35

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 4. Enrichment computed across 3 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
mRNA Polyadenylation	1	87.8×	0.022	FUS
Processing of Capped Intron-Containing Pre-mRNA	1	82.2×	0.022	FUS
mRNA Splicing - Major Pathway	1	54.6×	0.022	FUS
Dengue Virus-Host Interactions	1	45.7×	0.022	FUS

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
negative regulation of myelination	1	936.2×	0.005	TMEM98
T-helper 1 cell differentiation	1	766.0×	0.005	TMEM98
negative regulation of protein processing	1	561.7×	0.005	TMEM98
negative regulation of oligodendrocyte differentiation	1	561.7×	0.005	TMEM98
membraneless organelle assembly	1	561.7×	0.005	FUS
negative regulation of protein localization to nucleus	1	421.3×	0.006	TMEM98
amyloid fibril formation	1	300.9×	0.007	FUS
positive regulation of double-strand break repair via homologous recombination	1	191.5×	0.008	FUS
mRNA stabilization	1	183.2×	0.008	FUS
regulation of RNA splicing	1	109.4×	0.013	FUS
protein homooligomerization	1	61.1×	0.021	FUS
RNA splicing	1	44.1×	0.026	FUS
regulation of DNA-templated transcription	1	15.8×	0.067	FUS
regulation of transcription by RNA polymerase II	1	5.8×	0.164	FUS

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 3

Druggability breadth: 1 of 3 evidence-associated genes (33%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
TMEM98	0	0
LRRC37B	0	0
FUS	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
FUS	7	Binding:7

Pharmacogenomics

Cohort genes with a PharmGKB record: 3; 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	3	TMEM98, LRRC37B, FUS

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
TMEM98	0	—
LRRC37B	0	—
FUS	7	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.