Joubert syndrome with renal defect

Summary

Joubert syndrome with renal defect (MONDO:0012308) is a disease caused by NPHP1 (GenCC Definitive), with 4 cohort genes.

At a glance

• Prevalence: Unknown (Worldwide)
• Causal gene: NPHP1 (GenCC Definitive)
• Cohort genes: 4
• ClinVar variants: 266
• Phenotypes (HPO): 36

Clinical features

Signs & symptoms

Clinical features (HPO)

36 HPO clinical features (Orphanet curated; top 36 by frequency):

HPO ID	Term	Frequency
HP:0000112	Nephropathy	Very frequent (80-99%)
HP:0000657	Oculomotor apraxia	Very frequent (80-99%)
HP:0001249	Intellectual disability	Very frequent (80-99%)
HP:0001251	Ataxia	Very frequent (80-99%)
HP:0001252	Hypotonia	Very frequent (80-99%)
HP:0001263	Global developmental delay	Very frequent (80-99%)
HP:0001320	Cerebellar vermis hypoplasia	Very frequent (80-99%)
HP:0002104	Apnea	Very frequent (80-99%)
HP:0002419	Molar tooth sign on MRI	Very frequent (80-99%)
HP:0002793	Abnormal pattern of respiration	Very frequent (80-99%)
HP:0000276	Long face	Frequent (30-79%)
HP:0000358	Posteriorly rotated ears	Frequent (30-79%)
HP:0000639	Nystagmus	Frequent (30-79%)
HP:0001288	Gait disturbance	Frequent (30-79%)
HP:0004422	Biparietal narrowing	Frequent (30-79%)
HP:0011968	Feeding difficulties	Frequent (30-79%)
HP:0000083	Renal insufficiency	Occasional (5-29%)
HP:0000175	Cleft palate	Occasional (5-29%)
HP:0000202	Orofacial cleft	Occasional (5-29%)
HP:0000238	Hydrocephalus	Occasional (5-29%)
HP:0000426	Prominent nasal bridge	Occasional (5-29%)
HP:0000463	Anteverted nares	Occasional (5-29%)
HP:0000486	Strabismus	Occasional (5-29%)
HP:0000508	Ptosis	Occasional (5-29%)
HP:0000612	Iris coloboma	Occasional (5-29%)
HP:0000864	Abnormality of the hypothalamus-pituitary axis	Occasional (5-29%)
HP:0001161	Hand polydactyly	Occasional (5-29%)
HP:0001250	Seizure	Occasional (5-29%)
HP:0001274	Agenesis of corpus callosum	Occasional (5-29%)
HP:0001337	Tremor	Occasional (5-29%)
HP:0002084	Encephalocele	Occasional (5-29%)
HP:0002126	Polymicrogyria	Occasional (5-29%)
HP:0002251	Aganglionic megacolon	Occasional (5-29%)
HP:0002553	Highly arched eyebrow	Occasional (5-29%)
HP:0002650	Scoliosis	Occasional (5-29%)
HP:0030680	Abnormal cardiovascular system morphology	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	Joubert syndrome with renal defect
Mondo ID	MONDO:0012308
MeSH	C536296
OMIM	609583
Orphanet	220497
DOID	DOID:0110999
ICD-11	1419767028
NCIT	C74997
SNOMED CT	716999001
UMLS	C1846790
MedGen	335526
GARD	0010169
Is cancer (heuristic)	no

Also known as: JBTS4 · Joubert syndrome 4 · Joubert syndrome type 4 · Joubert syndrome with renal anomalies · JS-R

Data availability: 266 ClinVar variants · 5 GenCC gene-disease records · 1 cell line.

Disease family

Classification path: disease › human disease › disease by body system or component › syndromic disease › Joubert syndrome › Joubert syndrome with renal defect

Related subtypes (38): Joubert syndrome 1, Joubert syndrome 10, Joubert syndrome 2, Joubert syndrome 3, Joubert syndrome 5, Joubert syndrome 6, Joubert syndrome 7, Joubert syndrome 9, Joubert syndrome 8, Joubert syndrome 13, Joubert syndrome 14, Joubert syndrome 15, Joubert syndrome 16, Joubert syndrome 17, Joubert syndrome 18, Joubert syndrome 20, Joubert syndrome 21, Joubert syndrome 22, Joubert syndrome 23, Joubert syndrome 24, Joubert syndrome 25, Joubert syndrome 26, Joubert syndrome 27, Joubert syndrome 28, Joubert syndrome 38, Joubert syndrome 39, Joubert syndrome 40, Joubert syndrome 37, Joubert syndrome 35, Joubert syndrome 36, Joubert syndrome 30, Joubert syndrome 32, Joubert syndrome 31, Joubert syndrome 33, Joubert syndrome 19, Joubert syndrome 29, Joubert syndrome 11, Joubert syndrome 34

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

266 retrieved; paginated sample, class counts are floors:

132 uncertain significance, 46 likely pathogenic, 32 conflicting classifications of pathogenicity, 19 pathogenic, 16 pathogenic/likely pathogenic, 13 likely benign, 5 benign/likely benign, 3 benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
217684	2q13 deletion		Pathogenic	criteria provided, single submitter
237627	NM_000272.5(NPHP1):c.(?-45)(*443_?)del	LOC126806306	Pathogenic	criteria provided, multiple submitters, no conflicts
4755442	Single allele	MALL	Pathogenic	criteria provided, single submitter
1030710	NM_001128178.3(NPHP1):c.1588C>T (p.Arg530Ter)	NPHP1	Pathogenic	criteria provided, multiple submitters, no conflicts
1070446	NM_001128178.3(NPHP1):c.483del (p.Asp162fs)	NPHP1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1075465	NM_001128178.3(NPHP1):c.1379dup (p.Thr461fs)	NPHP1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1076772	NM_001128178.3(NPHP1):c.1270-1G>A	NPHP1	Pathogenic	criteria provided, multiple submitters, no conflicts
1179110	GRCh37/hg19 2q13(chr2:110880925-110962590)	NPHP1	Pathogenic	no assertion criteria provided
1179212	GRCh37/hg19 2q13(chr2:110880893-110962659)	NPHP1	Pathogenic	no assertion criteria provided
1444725	NM_001128178.3(NPHP1):c.1130del (p.Lys377fs)	NPHP1	Pathogenic	criteria provided, multiple submitters, no conflicts
2171349	NM_001128178.3(NPHP1):c.771+58C>T	NPHP1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2203131	NM_001128178.3(NPHP1):c.84_87del (p.Ser29fs)	NPHP1	Pathogenic	criteria provided, multiple submitters, no conflicts
2677261	NM_001128178.3(NPHP1):c.625-2A>G	NPHP1	Pathogenic	criteria provided, single submitter
2677262	NM_001128178.3(NPHP1):c.882C>A (p.Tyr294Ter)	NPHP1	Pathogenic	criteria provided, single submitter
2677264	NM_001128178.3(NPHP1):c.1897_1906del (p.Thr633fs)	NPHP1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2677267	NM_001128178.3(NPHP1):c.1270-2A>G	NPHP1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2677270	NM_001128178.3(NPHP1):c.69+1del	NPHP1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2677274	NM_001128178.3(NPHP1):c.127C>T (p.Gln43Ter)	NPHP1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2677279	NM_001128178.3(NPHP1):c.771+124C>T	NPHP1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2734257	NM_001128178.3(NPHP1):c.735del (p.His247fs)	NPHP1	Pathogenic	criteria provided, multiple submitters, no conflicts
283524	NM_001128178.3(NPHP1):c.555dup (p.Pro186fs)	NPHP1	Pathogenic	criteria provided, multiple submitters, no conflicts
286936	NM_001128178.3(NPHP1):c.329+1G>A	NPHP1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3239950	NM_001128178.3(NPHP1):c.182del (p.Asn61fs)	NPHP1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3239952	NM_001128178.3(NPHP1):c.385_386del (p.Ser129fs)	NPHP1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3382874	NM_001128178.3(NPHP1):c.349G>T (p.Glu117Ter)	NPHP1	Pathogenic	criteria provided, single submitter
3507	NM_001128178.3(NPHP1):c.1716+1G>T	NPHP1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3510	NM_001128178.3(NPHP1):c.859G>A (p.Gly287Arg)	NPHP1	Pathogenic	criteria provided, multiple submitters, no conflicts
579607	NM_001128178.3(NPHP1):c.871C>T (p.Arg291Ter)	NPHP1	Pathogenic	criteria provided, multiple submitters, no conflicts
595311	NM_001128178.3(NPHP1):c.415G>T (p.Glu139Ter)	NPHP1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
595558	NM_001128178.3(NPHP1):c.1551del (p.Ile517fs)	NPHP1	Pathogenic	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 24 · Orphanet: 11 · 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
NPHP1	Definitive	Autosomal recessive	Joubert syndrome with renal defect	9
TMEM237	Definitive	Autosomal recessive	Joubert syndrome 14	9
RPGRIP1L	Strong	Autosomal recessive	Joubert syndrome 7	6

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
NPHP1	Orphanet:110	Bardet-Biedl syndrome
NPHP1	Orphanet:220497	Joubert syndrome with renal defect
NPHP1	Orphanet:3156	Senior-Loken syndrome
NPHP1	Orphanet:93592	Juvenile nephronophthisis
TMEM237	Orphanet:220497	Joubert syndrome with renal defect
TMEM237	Orphanet:2318	Joubert syndrome with oculorenal defect
TMEM237	Orphanet:475	Isolated Joubert syndrome
TMEM237	Orphanet:564	Meckel syndrome
RPGRIP1L	Orphanet:1454	Joubert syndrome with hepatic defect
RPGRIP1L	Orphanet:220497	Joubert syndrome with renal defect
RPGRIP1L	Orphanet:564	Meckel syndrome

Cohort genes → proteins

4 cohort genes, 4 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	4

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
NPHP1	HGNC:7905	ENSG00000144061	O15259	Nephrocystin-1	gencc,clinvar
TMEM237	HGNC:14432	ENSG00000155755	Q96Q45	Transmembrane protein 237	gencc
RPGRIP1L	HGNC:29168	ENSG00000103494	Q68CZ1	Protein fantom	gencc
MALL	HGNC:6818	ENSG00000144063	Q13021	MAL-like protein	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
NPHP1	Nephrocystin-1	Together with BCAR1 it may play a role in the control of epithelial cell polarity.
TMEM237	Transmembrane protein 237	Component of the transition zone in primary cilia.
RPGRIP1L	Protein fantom	Negatively regulates signaling through the G-protein coupled thromboxane A2 receptor (TBXA2R).

Protein-family classification

Druggable: 0 · Difficult: 1 · Unknown: 3 · 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
Scaffold/PPI	1	4.3×	0.404
Other/Unknown	3	1.3×	0.404

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
NPHP1	Scaffold/PPI	no		SH3_domain, NPHP1_SH3, SH3-like_dom_sf
TMEM237	Other/Unknown	no		TMEM237
RPGRIP1L	Other/Unknown	no		C2_dom, C2-C2_1, RPGRIP1_fam
MALL	Other/Unknown	no		Marvel, MAL, MARVEL-CKLF_proteins

Expression context

Cohort genes with no expression data: 0.

4 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)	4
unknown	0

Top tissues across cohort

Tissue	Cohort genes
bronchial epithelial cell	2
olfactory segment of nasal mucosa	1
right uterine tube	1
adrenal tissue	1
calcaneal tendon	1
ventricular zone	1
male germ line stem cell (sensu Vertebrata) in testis	1
primordial germ cell in gonad	1
duodenum	1
esophagus mucosa	1
lower esophagus mucosa	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
NPHP1	193	ubiquitous	marker	right uterine tube, bronchial epithelial cell, olfactory segment of nasal mucosa
TMEM237	250	ubiquitous	marker	calcaneal tendon, adrenal tissue, ventricular zone
RPGRIP1L	207	ubiquitous	marker	bronchial epithelial cell, primordial germ cell in gonad, male germ line stem cell (sensu Vertebrata) in testis
MALL	141	ubiquitous	marker	lower esophagus mucosa, duodenum, esophagus mucosa

Protein interactions among cohort

Intra-cohort edges: 4.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
NPHP1	2,302
TMEM237	2,169
RPGRIP1L	2,027
MALL	986

Intra-cohort edges

A	B	Sources
MALL	NPHP1	string_interaction
NPHP1	RPGRIP1L	intact, string_interaction
NPHP1	TMEM237	intact, string_interaction
RPGRIP1L	TMEM237	string_interaction

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
NPHP1	O15259	2
RPGRIP1L	Q68CZ1	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
MALL	Q13021	90.13
TMEM237	Q96Q45	63.79

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 2. Enrichment computed across 4 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
Anchoring of the basal body to the plasma membrane	2	113.1×	2e-04	NPHP1, RPGRIP1L
Hedgehog ‘off’ state	1	89.2×	0.011	RPGRIP1L

GO biological processes 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.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
protein localization involved in establishment of planar polarity	1	1404.3×	0.010	NPHP1
visual behavior	1	702.2×	0.010	NPHP1
neural tube patterning	1	702.2×	0.010	RPGRIP1L
nose development	1	601.9×	0.010	RPGRIP1L
pericardium development	1	468.1×	0.010	RPGRIP1L
retinal rod cell development	1	421.3×	0.010	RPGRIP1L
spermatid differentiation	1	421.3×	0.010	NPHP1
positive regulation of bicellular tight junction assembly	1	421.3×	0.010	NPHP1
lateral ventricle development	1	324.1×	0.011	RPGRIP1L
negative regulation of G protein-coupled receptor signaling pathway	1	300.9×	0.011	RPGRIP1L
establishment of planar polarity	1	263.3×	0.011	RPGRIP1L
regulation of Wnt signaling pathway	1	221.7×	0.012	TMEM237
corpus callosum development	1	210.7×	0.012	RPGRIP1L
olfactory bulb development	1	191.5×	0.012	RPGRIP1L
regulation of smoothened signaling pathway	1	156.0×	0.014	RPGRIP1L
embryonic hindlimb morphogenesis	1	145.3×	0.014	RPGRIP1L
embryonic forelimb morphogenesis	1	123.9×	0.016	RPGRIP1L
cochlea development	1	117.0×	0.016	RPGRIP1L
establishment or maintenance of cell polarity	1	100.3×	0.017	RPGRIP1L
cell projection organization	1	93.6×	0.017	NPHP1
cerebellum development	1	89.6×	0.017	RPGRIP1L
non-motile cilium assembly	1	72.6×	0.021	RPGRIP1L
determination of left/right symmetry	1	63.8×	0.021	RPGRIP1L
retina development in camera-type eye	1	63.8×	0.021	NPHP1
myelination	1	62.9×	0.021	MALL
liver development	1	55.4×	0.023	RPGRIP1L
cholesterol homeostasis	1	39.0×	0.031	MALL
kidney development	1	35.1×	0.033	RPGRIP1L
cell-cell adhesion	1	25.4×	0.044	NPHP1
actin cytoskeleton organization	1	19.8×	0.055	NPHP1

Therapeutics

Drug target analysis

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

Druggability breadth: 0 of 4 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
NPHP1	0	0
TMEM237	0	0
RPGRIP1L	0	0
MALL	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Pharmacogenomics

Cohort genes with a PharmGKB record: 4; 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	4	NPHP1, TMEM237, RPGRIP1L, MALL

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
NPHP1	0	—
TMEM237	0	—
RPGRIP1L	0	—
MALL	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.