Submission Details

The TMEM237 gene is located on chromosome 2 at 2q33.1 and encodes the transmembrane protein 237 protein. TMEM237 is a component of the transition zone in primary cilia and is required for ciliogenesis. TMEM237 was first reported in relation to autosomal recessive Joubert Syndrome 14 in 2011 (Huang et al., PMID 22152675). More than 10 unique variants (nonsense, frameshift, splice, missense) have been reported in humans. Evidence supporting this gene-disease relationship includes case-level data and experimental data. Variants in this gene have been reported in at least nine probands in nine publications (Boycott et al., 2011 PMID 22152675; Al-Gazali et al., 2014 PMID 27081510; Lingappa et al., 2020 PMID 32139166; Alkuraya et al., 2012 PMID 22693042; Doherty et al., 2015 PMID 26092869; Alkuraya et al., 2016 PMID 27894351; Gunay-Aygun et al., 2017 PMID 28497568; Alkuraya et al., 2017 PMID 28600779; Hildebrandt et al., PMID 26673778). The mechanism of disease is loss of function (PMID 22152675). This gene-disease relationship is supported by expression studies, which show that TMEM237 is expressed in the ciliary transition zone, and a zebrafish model, which shows similar defects in eye and head development (Huang et al., 2011 PMID: 22152675). In summary, TMEM237 is definitively associated with autosomal recessive Joubert Syndrome 14. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time.