TGDS

Chr 13

TDP-glucose 4,6-dehydratase

Also known as: CATMANS, SDR2E1, TDPGD

NCBI Gene: 23483 ENSG00000088451 UniProt: O95455

The protein is UTP-glucose 4,6-dehydratase, which converts UDP-glucose into UDP-4-keto-6-deoxyglucose and is required for glycosaminoglycan biosynthesis and skeletal development. Mutations cause Catel-Manzke syndrome, characterized by Pierre Robin sequence (undersized jaw, backwards tongue displacement causing airway obstruction, and often cleft palate) and radial deviation of the index finger due to an accessory bone. This condition follows autosomal recessive inheritance.

ResearchSummary from RefSeq, OMIM, UniProt

The protein encoded by this gene is a member of the short-chain dehydrogenases/reductases (SDR) superfamily, and is thought to contain a nicotinamide adenine dinucleotide (NAD) binding domain. This large SDR family of enzymes is involved in the metabolism of a variety of compounds, including prostaglandins, retinoids, lipids, steroid hormones, and xenobiotics. Mutations in this gene have been associated with Catel-Manzke syndrome, which is characterized by Pierre Robin sequence, and radial deviation of the index finger due to the presence of an accessory bone between the index finger and its proximal phalanx. Pierre Robin sequence is defined by an undersized jaw, backwards displacement of the tongue base that causes an obstruction of the airways, and can also be associated with a cleft palate. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jan 2015]

ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

UniProtCatel-Manzke syndrome

Clinical highlights

Gene–disease validity (ClinGen)

Definitive · Catel-Manzke syndrome · AR · ClinGen 2024

Interpreting a novel variant

Loss of function is the curated mechanism (Gene2Phenotype), though the gene is not strongly LoF-constrained in the population — weigh truncating variants against that tolerance.Curated gene-level mechanism — a prior for triage, not a per-variant call.

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

1.15

LOEUF

LOF

Mechanism· G2P

Some data sources returned errors (1)

omim: Error: OMIM fetch failed: 429

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

1.15LOEUF

pLI 0.000

Z-score 1.04

OE 0.76 (0.51–1.15)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

0.30Z-score

OE missense 0.94 (0.83–1.06)

168 obs / 179.3 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.76 (0.51–1.15)

0≤0.351.4

Missense OE?0.94 (0.83–1.06)

0≤0.61.4

Synonymous OE?0.73

0≤1.21.6

LoF obs/exp: 16 / 21.2Missense obs/exp: 168 / 179.3Syn Z: 1.69

Background carrier burden — how many people carry a rare variant somewhere in TGDS?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 120

413 rare PASS variants

Rare truncating (LoF)

1 in 1,600

99 rare PASS variants

Rare synonymous (reference)

1 in 510

122 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for TGDS. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 9 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~556k	1 in 190	1 in 1,900
South Asian	~43k	1 in 190	1 in 1,700
Remaining (unassigned)	~30k	1 in 190	1 in 1,600
European (Finnish)	~27k	1 in 910	1 in 1,900
Admixed American	~22k	1 in 210	1 in 2,700
African / African American	~21k	1 in 160	1 in 780
East Asian	~20k	1 in 250	1 in 3,900
Ashkenazi Jewish	~13k	1 in 910	1 in 1,600
Middle Eastern	~2,884	1 in 180	≈ 1 in 2,900

Each group is summed over the variants that are rare in that group. Grey ≈ figures rest on fewer than five expected carriers — too few to distinguish groups. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.

Exome coverage (gnomAD): 6 of 12 coding exons well covered in gnomAD exomes; exons 2, 6, 7, 8, 10, 12 marginal. Genomes: all 12.? see exons ↓