DHDDS

Chr 1ARAD

dehydrodolichyl diphosphate synthase subunit

Also known as: CIT, CPT, DEDSM, DS, HDS, RP59, hCIT

NCBI Gene: 79947 ENSG00000117682 UniProt: Q86SQ9 OMIM: 608172

The protein encoded by DHDDS forms a complex essential for dolichol biosynthesis, producing the glycosyl carrier lipid required for protein glycosylation in the endoplasmic reticulum. Mutations cause retinitis pigmentosa 59, congenital disorder of glycosylation type 1bb, and developmental delay with seizures and movement abnormalities, with both autosomal recessive and autosomal dominant inheritance patterns reported. The gene shows moderate constraint against loss-of-function variants (LOEUF 0.51), and the associated phenotypes affect multiple systems including vision, neurodevelopment, and protein glycosylation pathways.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt

The protein encoded by this gene catalyzes cis-prenyl chain elongation to produce the polyprenyl backbone of dolichol, a glycosyl carrier lipid required for the biosynthesis of several classes of glycoproteins. Mutations in this gene are associated with retinitis pigmentosa type 59. Alternatively spliced transcript variants encoding different isoforms have been described for this gene. [provided by RefSeq, Aug 2011]

GeneReviews OMIM ResearchGenerating clinical summary…

DNmechanismAR/ADLOEUF 0.513 OMIM phenotypes

Clinical Summary— DHDDS

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Gene-Disease Validity (ClinGen)

DHDDS-CDG · ARDefinitive

Definitive — sufficient evidence for diagnostic panels

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Population Constraint (gnomAD)

Constrained for loss-of-function variants (OE-LoF 0.24) despite low pLI — interpret in context.

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ClinVar Variants

47 unique Pathogenic / Likely Pathogenic· 281 VUS of 640 total submissions

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Clinical Trials

1 active or recruiting trial — potential therapeutic options may be available

Explore recent and relevant literature in Research Assistant →

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GeneReview available — DHDDS

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Moderate LoF intolerance

LoF Constraint?

0.51LOEUF

pLI 0.245

Z-score 3.18

OE 0.24 (0.13–0.51)

Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?

1.09Z-score

OE missense 0.78 (0.68–0.89)

152 obs / 194.8 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.24 (0.13–0.51)

0≤0.351.4

Missense OE?0.78 (0.68–0.89)

0≤0.61.4

Synonymous OE?0.86

0≤1.21.6

LoF obs/exp: 5 / 20.6Missense obs/exp: 152 / 194.8Syn Z: 0.97

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

strongDHDDS-related epilepsy and intellectual disabilityOTHERAD

definitiveDHDDS-related retinitis pigmentosaOTHERAR

This gene — mechanism propensity

0.6648th %ile

GOF

0.5856th %ile

LOF

0.3454th %ile

The highest-scoring mechanism for this gene is dominant-negative.

DNprediction above median · 1 literature citation

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

Literature Evidence

DNWe defined the electroclinical and movement disorder phenotype associated with the monoallelic form of the DHDDS -related neurodevelopmental disease and possible underlying dominant-negative mechanisms.1

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.

References

1.PMID 34504728 ↗

ClinVar Variant Classifications

640 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic17

Likely Pathogenic30

VUS281

Likely Benign260

Benign15

Conflicting20

Pathogenic

Likely Pathogenic

281

VUS

260

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	7	6	4	0	17
Likely Pathogenic	19	9	2	0	30
VUS	13	216	47	5	281
Likely Benign	0	0	110	150	260
Benign	0	1	13	1	15
Conflicting	—				20
Total	39	232	176	156	623

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

5 pathogenic / likely-pathogenic (of 11) ClinVar copy-number / structural variants overlap DHDDS — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →