TGDS

protein-coding

TDP-glucose 4,6-dehydratase, the group of Short chain dehydrogenase/reductase superfamily

Gene summary

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]

MANE transcript

NM_014305.4

Inheritance

ClinVar variants

P:13U:65B:21

Top phenotype

Catel-Manzke syndrome

gnomAD constraint

pLI —, LoF o/e 0.76

Max pathogenic AF

—

Genomic locus

chr13:94,574,054-94,596,242

External References & Databases

Ensembl (ENSG00000088451)

Transcript & Mutation Effects

hg38 • Region Span ~22.2 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

Catel-Manzke syndromeSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014507

Submitter: PanelApp Australia

Catel-Manzke syndromeSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014507

Submitter: Labcorp Genetics (formerly Invitae)

Catel-Manzke syndromeDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0014507

Submitter: G2P

Catel-Manzke syndromeSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0014507

Submitter: Orphanet

Catel-Manzke syndromeDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0014507

Submitter: ClinGen

*TGDS* was first reported in connection with autosomal recessive Catel-Manzke syndrome in 2014. Affected individuals are characterized by bilateral hyperphalangy of the index finger, Pierre Robin sequence, cleft-palate, and cardiac defects. Less frequent findings include iris coloboma, mild facial dysmorphism (hypertelorism, short palpebral fissures, full cheeks, low-set or posteriorly rotated ears), pectus excavatum, pectus carinatum, scoliosis, bilateral brachydactyly, bilateral fifth finger clinodactyly, knee dislocation, talipes, short halluces, failure to thrive and an intellectual disability, ranging from mild to severe. Eight variants (7 missense, 1 frameshift) reported in four publications have been included in this curation (PMIDs: 25480037, 26366375, 28422407, 31833187). The mechanism of disease appears to be loss-of-function. The key feature of Catel-Manzke syndrome is bilateral hyperphalangy of the index finger which is often referred to as Manzke dysostosis. Probands presenting this feature along with radiographic imaging were upgraded by 0.8 points; 0.4 for phenotypic specificity and 0.4 for the X-rays. The p.Ala100Ser mutation was suspected to have a founder effect therefore cases harboring this mutation were upgraded by 0.5 points. The maximum score for genetic evidence (12 pts.) has been reached, however additional probands are available in the literature (PMIDs: 29431110, 31769200, 34930662, 37010288). This gene-disease relationship is also supported by a mouse model displaying severe micrognathia and cleft-palate (PMID: 29208648). In summary, there is definitive evidence supporting the relationship between *TGDS* and autosomal recessive Catel-Manzke syndrome. This has been repeatedly demonstrated in both the research and clinical diagnostic settings. This classification was approved by the Craniofacial Malformations Gene Curation Expert Panel on the meeting date 07/18/2024 (SOP Version 10)

Clinical Genomic Database (CGD)

Catel-Manzke syndromeAR

Manifestation: Craniofacial; Musculoskeletal

Intervention: General

Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing

Refs: 6011685; 9777339; 18501694; 22887726; 25480037

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to TGDS variants in ClinVar

5 Conditions Cataloged

not providedTotal: 66

Inborn genetic diseasesTotal: 38

Catel-Manzke syndromeTotal: 18

TGDS-related disorderTotal: 5

not specifiedTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_014305.4. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous			2 clinvar	17 clinvar	1 clinvar	20
missense	3 clinvar	5 clinvar	55 clinvar	1 clinvar	2 clinvar	66
nonsense			1 clinvar			1
start loss						0
frameshift		2 clinvar	2 clinvar			4
splice donor/acceptor (+/-2bp)		3 clinvar	5 clinvar			8
Total	3	10	65	18	3	99

Highest pathogenic variant AF is 0.00076511194

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 29 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_014305.4	RefSeq	NP_055120.1	12	MANE Select
ENST00000261296.7	Ensembl	ENSP00000261296.5	12	MANE Select
NM_001304430.2	RefSeq	NP_001291359.1	11	Standard
ENST00000862790.1	Ensembl	ENSP00000532849.1	9	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Molecular Function

dTDP-glucose 4,6-dehydratase activity

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000261296
Coding exons: 12
Length: 22204
Individuals with no LoFs: 125698
Homozygous LoFs: 0
Heterozygous LoFs: 50
Defined: 125748
p: 0.000199

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.300	168	179	0.937	0.00000832	2303
Missense (PolyPhen)		63	67.097	0.93893		883
Synonymous	1.69	45	61.9	0.727	0.00000302	612
Loss of Function	1.04	16	21.2	0.756	8.92e-7	284

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00064	0.00062	rare
Latino/Admixed American	0.000031	0.000029	rare
Ashkenazi Jewish	0.00040	0.00040	rare
East Asian	0.00023	0.00022	rare
Finnish	0.000093	0.000092	rare
European (Non-Finnish)	0.00016	0.00016	rare
South Asian	0.00035	0.00033	rare
Other	0.00020	0.00016	rare

dbNSFP Gene Annotations

Source: dbNSFP

Disease: DISEASE: Catel-Manzke syndrome (CATMANS) [MIM:616145]: A syndrome characterized by Pierre Robin sequence and a unique form of bilateral hyperphalangy causing a clinodactyly of the index finger. Pierre Robin sequence includes an opening in the roof of the mouth (a cleft palate), a large tongue (macroglossia), and a small lower jaw (micrognathia). {ECO:0000269|PubMed:25480037}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.225

Intolerance Scores

LoFtool: 0.490
RVIS EVS: -0.25
RVIS percentile EVS: 35.75

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.755

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium