TRIP11 (OMIM: 604505) was first reported in relation to autosomal recessive Achondrogensis type 1A (OMIM:200600) in 2010 (Smits et al., PMID: 20089971). Variants in TRIP11 have also been reported in individuals with autosomal recessive Odontochondrodysplasia (OMIM: 184260). Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found no difference in molecular mechanism, inheritance pattern and phenotypic variability. Some variants have been reported in both Odontochondrodysplasia and Achondrogenesis type 1A cases. Patients with either condition have affected Golgi apparatus. Odontochondrodysplasia is a milder form of Achondrogenesis type 1A with all patients to date being shown to have at least one hypomorphic variant by splicing/functional studies. Although the two condition are clinically distinct, the molecular causes of this difference cannot always be distinguished. Therefore, we decided to curate both these entities together under the term “TRIP11 related skeletal dysplasia”. At least 42 variants (e.g. missense, in-frame indel, nonsense, frameshift, large deletion, complex rearrangement, etc) have been reported in humans. Evidence supporting this gene-disease relationship includes case-level data and experimental data. For the purposes of this curation, 16 variants in this gene were scored in the following 4 publications: PMIDs 23956106, 29620724, 29872333 30728324. More variant evidence is available in the literature, but the maximum score for variant evidence (12 pts.) has been reached. This gene-disease association is supported by mouse models (PMID 20089971) and expression studies (PMID 30728324). In summary, there is definitive evidence to support the relationship between TRIP11 and autosomal recessive TRIP11 related skeletal dysplasia. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Prenatal Expert Panel on the 01/10/2024 (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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