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)
The GenCC data are available free of restriction under a CC0 1.0 Universal (CC0 1.0) Public Domain Dedication. The GenCC requests that you give attribution to GenCC and the contributing sources whenever possible and appropriate. The accepted Flagship manuscript is now available from Genetics in Medicine (https://www.gimjournal.org/article/S1098-3600(22)00746-8/fulltext).
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