TMEM231 was FIRST reported in relation to autosomal recessive Joubert syndrome in 2012 (Srour M et al., PMID: 23012439), autosomal recessive Meckel Gruber syndrome (Shaheen R et al., PMID: 23349226) in 2013, and autosomal recessive orofacial-digital syndrome type III (Roberson EC et al., PMID: 25869670) in 2015. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found no difference in molecular mechanisms, inheritance pattern and overlapping phenotypes. Therefore, the disease entities have been lumped into one disease entity, ciliopathy (MONDO:0005308). At least 16 distinct variants (missense, nonsense, splice site, and frameshift) have been reported in 20 probands in 7 publications (in addition to aforementioned publications: PMIDs: 34912761, 28289185, 32386258, 31663672). Genetic evidence supporting this gene-disease relationship includes segregation data and experimental data, such as biochemical functions, physical interaction studies, organ expression, rescue experiments, and three non-human model organisms (2x mouse, 1x C. elegans) published in 2011 (PMID: 22179047) and 2015 (PMID: 25869670). More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached.
In summary, there is definitive evidence to support the relationship between TMEM231 and autosomal recessive ciliopathy-TMEM231. 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 Cystic and Ciliopathy Disorders GCEP Working Group on 01/12/2022 (SOP Version 8).
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