Skeletal dysplasia

Gene: TGDS

Green List (high evidence)

Brachydactylies (with extraskeletal manifestations) gp of SD - >3 cases; Review on behalf of Tracy Lester/Michael Oldridge

Created: 6 Mar 2019, 11:44 a.m.

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Catel-Manzke syndrome 616145

I don't know

Comment on list classification: Leaving red for now. Associated with Catel-Manzke syndrome. Mainly limb phenotype.

Created: 11 Dec 2019, 6:13 p.m. | Last Modified: 11 Dec 2019, 6:13 p.m.

Panel Version: 1.289

Associated with Catel-Manzke syndrome #616145 (AR) in OMIM.

PMID: 25480037 - Ehmke et al 2014 - Catel-Manzke syndrome is characterized by Pierre Robin sequence and a unique form of bilateral hyperphalangy causing a clinodactyly of the index finger. They identified homozygous and compound heterozygous mutations in TGDS in seven unrelated individuals with typical Catel-Manzke syndrome by exome sequencing. Six different TGDS mutations were detected: c.892A>G (p.Asn298Asp), c.270_271del (p.Lys91Asnfs(∗)22), c.298G>T (p.Ala100Ser), c.294T>G (p.Phe98Leu), c.269A>G (p.Glu90Gly), and c.700T>C (p.Tyr234His), all predicted to be disease causing. By using haplotype reconstruction they showed that the mutation c.298G>T is probably a founder mutation. 1 patient showed short toes, short humeri, short femora, 3 had clinodactyly V and 1 had brachymetacarpia and scoliosis.

PMID: 26366375 - Pferdehirt et al 2015 - describe a 12-month-old male with molecularly confirmed Catel-Manzke syndrome who presented with Pierre Robin sequence (but without cleft palate) and hyperphalangy. This patient is on the severe end of the phenotypic spectrum, presenting with respiratory complications and failure to thrive. He has a homozygous p.Ala100Ser pathogenic variant. Both parents are heterozygous for this variant.

PMID: 28422407 - Schoner et al 2017 - report on a fetus with severe heart defect, nuchal edema, talipes, Pierre-Robin sequence, and bilateral deviation and clinodactyly of the index and middle fingers. Postmortem radiographs showed hypoplasia and V-shaped displacement of the second and third proximal phalanges of both hands as well as hypoplasia of the first metatarsals and the phalangeal bones of the halluces. Two compound heterozygous mutations in TGDS were found: c.298G>T; p.(Ala100Ser) and c.895G>A; p.(Asp299Asn), located in the predicted substrate binding site of TGDS. Analyses of the parents’ blood DNA confirmed biparental inheritance.

Created: 20 Nov 2019, 11:43 a.m. | Last Modified: 21 Nov 2019, 10:05 p.m.

Panel Version: 1.242

This gene was part of an initial gene list collated by Tracy Lester, Oxford Medical Genetics Laboratories, Oxford University Hospitals NHS Foundation Trust, February 2019 on behalf of the GMS Musculoskeletal Specialist Group; Gene symbol submitted: TGDS; Initial rating suggestion: green

Created: 6 Mar 2019, 11:37 a.m.