Retinitis pigmentosa 59

Summary

Retinitis pigmentosa 59 (MONDO:0013468) is a disease caused by DHDDS (GenCC Definitive), with 3 cohort genes.

At a glance

• Causal gene: DHDDS (GenCC Definitive)
• Cohort genes: 3
• ClinVar variants: 516

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	retinitis pigmentosa 59
Mondo ID	MONDO:0013468
OMIM	613861
DOID	DOID:0110352
UMLS	C3151227
MedGen	462577
GARD	0015724
Is cancer (heuristic)	no

Also known as: congenital disorder of glycosylation, type 1bb · DHDDS retinitis pigmentosa · retinitis pigmentosa 59 · retinitis pigmentosa caused by mutation in DHDDS · retinitis pigmentosa type 59 · RP59

Data availability: 516 ClinVar variants · 3 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › nervous system disorder › retinal disorder › retinal degeneration › inherited retinal dystrophy › retinitis pigmentosa › retinitis pigmentosa 59

Related subtypes (101): retinitis pigmentosa 6, cone-rod dystrophy 2, retinitis pigmentosa 1, retinitis pigmentosa 9, retinitis pigmentosa 10, dominant pericentral pigmentary retinopathy, late-adult onset retinitis pigmentosa, autosomal recessive pericentral pigmentary retinopathy, retinitis pigmentosa 3, retinitis pigmentosa 24, retinitis pigmentosa 23, retinitis pigmentosa 34, retinitis pigmentosa 2, retinitis pigmentosa Y-linked, retinitis pigmentosa 13, retinitis pigmentosa 12, retinitis pigmentosa 14, retinitis pigmentosa 11, retinitis pigmentosa 17, retinitis pigmentosa 18, retinitis pigmentosa 19, retinitis pigmentosa 22, retinitis pigmentosa 25, retinitis pigmentosa 28, retinitis pigmentosa 30, retinitis pigmentosa 7, retinitis pigmentosa 26, retinitis pigmentosa 32, retinitis pigmentosa 31, retinitis pigmentosa 35, retinitis pigmentosa 33, retinitis pigmentosa 36, retinitis pigmentosa 37, retinitis pigmentosa 41, retinitis pigmentosa 29, retinitis pigmentosa 46, retinitis pigmentosa 42, retinitis pigmentosa 50, retinitis pigmentosa 54, retinitis pigmentosa 51, retinitis pigmentosa 55, retinitis pigmentosa 56, retinitis pigmentosa 57, retinitis pigmentosa 58, cone-rod dystrophy 15, retinitis pigmentosa 4, retinitis pigmentosa 27, retinitis pigmentosa 49, retinitis pigmentosa 47, retinitis pigmentosa 45, retinitis pigmentosa 44, retinitis pigmentosa 20, retinitis pigmentosa 40, retinitis pigmentosa 39, retinitis pigmentosa 43, retinitis pigmentosa 48, retinitis pigmentosa 38, retinitis pigmentosa 60, retinitis pigmentosa 61, retinitis pigmentosa 62, retinitis pigmentosa 63, cone-rod dystrophy 16, retinitis pigmentosa 66, retinitis pigmentosa with or without situs inversus, retinitis pigmentosa 67, retinitis pigmentosa 68, retinitis pigmentosa 69, retinitis pigmentosa 70, retinal dystrophy and obesity, retinitis pigmentosa 71, retinitis pigmentosa 72, retinitis pigmentosa 73, retinitis pigmentosa 74, retinitis pigmentosa 75, retinitis pigmentosa 76, retinitis pigmentosa 77, retinitis pigmentosa 92, retinitis pigmentosa 93, retinitis pigmentosa 83, retinitis pigmentosa 84, retinitis pigmentosa 85, retinitis pigmentosa 86, retinitis pigmentosa 87 with choroidal involvement, retinitis pigmentosa 88, retinitis pigmentosa 90, retinitis pigmentosa 81, retinitis pigmentosa 78, retinitis pigmentosa 79, retinitis pigmentosa 80, retinitis pigmentosa 94, variable age at onset, retinitis pigmentosa 53, retinitis pigmentosa 65, retinitis pigmentosa 64, retinitis pigmentosa 95, retinitis pigmentosa 96, retinitis pigmentosa 97, retinitis pigmentosa 98, retinitis pigmentosa 99, retinitis pigmentosa 100, retinitis pigmentosa 101, retinitis pigmentosa 7, digenic

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

516 retrieved; paginated sample, class counts are floors:

250 likely benign, 203 uncertain significance, 19 conflicting classifications of pathogenicity, 18 likely pathogenic, 16 pathogenic, 5 pathogenic/likely pathogenic, 5 benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1069729	NM_205861.3(DHDDS):c.517dup (p.Val173fs)	DHDDS	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1076541	NM_205861.3(DHDDS):c.374_377dup (p.Pro128fs)	DHDDS	Pathogenic	criteria provided, single submitter
1214981	NM_205861.3(DHDDS):c.109C>T (p.Arg37Cys)	DHDDS	Pathogenic	criteria provided, multiple submitters, no conflicts
1400385	NM_205861.3(DHDDS):c.714G>A (p.Trp238Ter)	DHDDS	Pathogenic	criteria provided, single submitter
1415429	NM_205861.3(DHDDS):c.510dup (p.Trp171fs)	DHDDS	Pathogenic	criteria provided, single submitter
1525125	NC_000001.10:g.(?26764639)(26764795_?)del	DHDDS	Pathogenic	criteria provided, single submitter
2000109	NM_205861.3(DHDDS):c.513G>A (p.Trp171Ter)	DHDDS	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2021747	NM_205861.3(DHDDS):c.100del (p.Asp34fs)	DHDDS	Pathogenic	criteria provided, single submitter
2426900	NC_000001.10:g.(?26784272)(26795632_?)del	DHDDS	Pathogenic	criteria provided, single submitter
2426903	NC_000001.10:g.(?26757796)(26764723_?)del	DHDDS	Pathogenic	criteria provided, single submitter
2664983	NM_205861.3(DHDDS):c.698C>G (p.Pro233Arg)	DHDDS	Pathogenic	criteria provided, multiple submitters, no conflicts
2674801	NM_205861.3(DHDDS):c.264_267del (p.Ser88fs)	DHDDS	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
30709	NM_205861.3(DHDDS):c.124A>G (p.Lys42Glu)	DHDDS	Pathogenic	criteria provided, multiple submitters, no conflicts
3247807	NC_000001.10:g.(?26759437)(26774171_?)del	DHDDS	Pathogenic	criteria provided, single submitter
3725536	NM_205861.3(DHDDS):c.35G>A (p.Trp12Ter)	DHDDS	Pathogenic	criteria provided, single submitter
451635	NM_205861.3(DHDDS):c.110G>A (p.Arg37His)	DHDDS	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
4803762	NM_205861.3(DHDDS):c.517del (p.Val173fs)	DHDDS	Pathogenic	criteria provided, single submitter
488193	NM_205861.3(DHDDS):c.632G>A (p.Arg211Gln)	DHDDS	Pathogenic	criteria provided, multiple submitters, no conflicts
546177	NM_205861.3(DHDDS):c.109C>A (p.Arg37Ser)	DHDDS	Pathogenic	criteria provided, multiple submitters, no conflicts
570739	NM_205861.3(DHDDS):c.614G>A (p.Arg205Gln)	DHDDS	Pathogenic	criteria provided, multiple submitters, no conflicts
985622	NM_205861.3(DHDDS):c.104G>A (p.Gly35Glu)	DHDDS	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1066115	NM_205861.3(DHDDS):c.658-2A>G	DHDDS	Likely pathogenic	criteria provided, multiple submitters, no conflicts
1297155	NM_205861.3(DHDDS):c.616A>G (p.Thr206Ala)	DHDDS	Likely pathogenic	criteria provided, multiple submitters, no conflicts
1520232	NM_205861.3(DHDDS):c.441-2A>T	DHDDS	Likely pathogenic	criteria provided, single submitter
1525136	NC_000001.10:g.(?26784272)(26784406_?)del	DHDDS	Likely pathogenic	criteria provided, single submitter
1722460	NM_205861.3(DHDDS):c.644del (p.Phe215fs)	DHDDS	Likely pathogenic	criteria provided, single submitter
1971743	NM_205861.3(DHDDS):c.650_657+54del	DHDDS	Likely pathogenic	criteria provided, single submitter
2674799	NM_205861.3(DHDDS):c.705T>A (p.Tyr235Ter)	DHDDS	Likely pathogenic	criteria provided, single submitter
2674800	NM_205861.3(DHDDS):c.568A>T (p.Lys190Ter)	DHDDS	Likely pathogenic	criteria provided, single submitter
2674802	NM_205861.3(DHDDS):c.665_668del (p.His222fs)	DHDDS	Likely pathogenic	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 8 · 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
DHDDS	Definitive	Autosomal recessive	retinitis pigmentosa 59	8

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
DHDDS	Orphanet:442835	Non-specific early-onset epileptic encephalopathy
DHDDS	Orphanet:791	Retinitis pigmentosa
ARID1A	Orphanet:1465	Coffin-Siris syndrome
SLC34A3	Orphanet:157215	Hereditary hypophosphatemic rickets with hypercalciuria

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
DHDDS	HGNC:20603	ENSG00000117682	Q86SQ9	Dehydrodolichyl diphosphate synthase complex subunit DHDDS	gencc,clinvar
ARID1A	HGNC:11110	ENSG00000117713	O14497	AT-rich interactive domain-containing protein 1A	clinvar
SLC34A3	HGNC:20305	ENSG00000198569	Q8N130	Sodium-dependent phosphate transport protein 2C	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
DHDDS	Dehydrodolichyl diphosphate synthase complex subunit DHDDS	With NUS1, forms the dehydrodolichyl diphosphate synthase (DDS) complex, an essential component of the dolichol monophosphate (Dol-P) biosynthetic machinery.
ARID1A	AT-rich interactive domain-containing protein 1A	Involved in transcriptional activation and repression of select genes by chromatin remodeling (alteration of DNA-nucleosome topology).
SLC34A3	Sodium-dependent phosphate transport protein 2C	Involved in actively transporting phosphate into cells via Na(+) cotransport in the renal brush border membrane.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 2 · Druggable fraction: 0.33

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
Enzyme (other)	1	4.0×	0.460
Other/Unknown	2	1.2×	0.587

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
DHDDS	Enzyme (other)	yes	2.5.1.87	UPP_synth-like, UPP_synth-like_CS, UPP_synth-like_sf
ARID1A	Other/Unknown	no		ARID_dom, ARM-like, ARM-type_fold
SLC34A3	Other/Unknown	no		Na/Pi_transpt

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
cerebellar cortex	1
cerebellar hemisphere	1
sperm	1
bone marrow cell	1
embryo	1
ventricular zone	1
adult mammalian kidney	1
lower esophagus mucosa	1
right uterine tube	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
DHDDS	259	ubiquitous	marker	sperm, cerebellar cortex, cerebellar hemisphere
ARID1A	286	ubiquitous	marker	bone marrow cell, ventricular zone, embryo
SLC34A3	147	tissue_specific	yes	lower esophagus mucosa, right uterine tube, adult mammalian kidney

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
ARID1A	3,476
SLC34A3	3,023
DHDDS	2,049

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
DHDDS	Q86SQ9	9
ARID1A	O14497	7

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
SLC34A3	Q8N130	75.86

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 23. Enrichment computed across 3 evidence-associated genes (3 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 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Defective SLC34A3 causes Hereditary hypophosphatemic rickets with hypercalciuria (HHRH)	1	3806.7×	0.006	SLC34A3
Defective DHDDS causes RP59	1	1903.3×	0.006	DHDDS
Type II Na+/Pi cotransporters	1	951.7×	0.008	SLC34A3
Synthesis of dolichyl-phosphate	1	543.8×	0.011	DHDDS
Positive Regulation of CDH1 Gene Transcription	1	317.2×	0.014	ARID1A
Formation of the canonical BAF (cBAF) complex	1	211.5×	0.016	ARID1A
Formation of the embryonic stem cell BAF (esBAF) complex	1	200.3×	0.016	ARID1A
Formation of neuronal progenitor and neuronal BAF (npBAF and nBAF)	1	152.3×	0.019	ARID1A
Regulation of endogenous retroelements	1	122.8×	0.021	ARID1A
RUNX1 interacts with co-factors whose precise effect on RUNX1 targets is not known	1	100.2×	0.023	ARID1A
Regulation of MITF-M-dependent genes involved in pigmentation	1	88.5×	0.024	ARID1A
MITF-M-dependent gene expression	1	60.4×	0.032	ARID1A
RMTs methylate histone arginines	1	48.8×	0.033	ARID1A
Transcriptional regulation by RUNX1	1	48.8×	0.033	ARID1A
Regulation of endogenous retroelements by Piwi-interacting RNAs (piRNAs)	1	39.2×	0.037	ARID1A
MITF-M-regulated melanocyte development	1	38.1×	0.037	ARID1A
Chromatin organization	1	27.2×	0.049	ARID1A
Chromatin modifying enzymes	1	24.1×	0.050	ARID1A
Epigenetic regulation of gene expression	1	23.8×	0.050	ARID1A
RNA Polymerase II Transcription	1	7.5×	0.146	ARID1A
Gene expression (Transcription)	1	6.0×	0.174	ARID1A
Generic Transcription Pathway	1	5.0×	0.194	ARID1A
Developmental Biology	1	4.8×	0.194	ARID1A

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
polyprenol biosynthetic process	1	5617.3×	0.004	DHDDS
dolichyl diphosphate biosynthetic process	1	2808.7×	0.004	DHDDS
phosphate ion transport	1	624.1×	0.007	SLC34A3
dolichyl monophosphate biosynthetic process	1	624.1×	0.007	DHDDS
sodium-dependent phosphate transport	1	624.1×	0.007	SLC34A3
intracellular phosphate ion homeostasis	1	510.7×	0.007	SLC34A3
nucleosome disassembly	1	267.5×	0.012	ARID1A
regulation of G0 to G1 transition	1	224.7×	0.012	ARID1A
regulation of nucleotide-excision repair	1	200.6×	0.012	ARID1A
regulation of mitotic metaphase/anaphase transition	1	165.2×	0.013	ARID1A
positive regulation of T cell differentiation	1	151.8×	0.013	ARID1A
transcription initiation-coupled chromatin remodeling	1	127.7×	0.013	ARID1A
positive regulation of myoblast differentiation	1	122.1×	0.013	ARID1A
positive regulation of stem cell population maintenance	1	114.6×	0.013	ARID1A
positive regulation of double-strand break repair	1	114.6×	0.013	ARID1A
regulation of G1/S transition of mitotic cell cycle	1	102.1×	0.013	ARID1A
sodium ion transport	1	90.6×	0.014	SLC34A3
positive regulation of cell differentiation	1	89.2×	0.014	ARID1A
chromatin remodeling	1	24.3×	0.047	ARID1A
nervous system development	1	15.3×	0.070	ARID1A
positive regulation of DNA-templated transcription	1	9.3×	0.108	ARID1A
regulation of transcription by RNA polymerase II	1	3.9×	0.236	ARID1A

Therapeutics

Drug target analysis

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

Druggability breadth: 2 of 3 evidence-associated genes (67%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
DHDDS	0	0
ARID1A	0	0
SLC34A3	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
ARID1A	6	Binding:6
SLC34A3	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
DHDDS	2.5.1.87	ditrans,polycis-polyprenyl diphosphate synthase [(2E,6E)-farnesyl diphosphate specific]

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	1	DHDDS
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	2	ARID1A, SLC34A3

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)
DHDDS	0	—
ARID1A	6	—
SLC34A3	1	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.