TMEM237 – Joubert Syndrome

TMEM237 encodes a component of the primary cilium implicated in autosomal recessive Joubert syndrome (Gene Symbol; Disease Name). Joubert syndrome (JS) is characterized by the molar tooth sign on brain imaging and a spectrum of neurologic and multiorgan manifestations including hypotonia, ataxia, developmental delay, oculomotor apraxia, neonatal breathing dysregulation, retinal dystrophy, nephronophthisis, hepatic fibrosis, and polydactyly.

Multiple studies have identified TMEM237 variants in JS cohorts following autosomal recessive inheritance. In a Saudi Arabian series of 12 families, homozygous TMEM237 mutations were detected by autozygome‐guided sequencing ([PMID:22693042]). A BMC Medical Genetics study of 26 JS/MKS patients reported an intergenic deletion encompassing TMEM237 confirmed by genome sequencing and PCR in one family ([PMID:26729329]). In the largest Indian JS cohort (59 patients, 35 trios), TMEM237 variants were among the causative alleles in one family ([PMID:32139166]). A recent review summarizes TMEM237 pathogenic variants in JS with renal involvement, underscoring consistent organ‐specific correlations ([PMID:35238134]).

Overall, TMEM237 variants have been reported in at least 3 probands from 3 unrelated consanguineous or multiplex families, all segregating in an autosomal recessive manner (3 probands; 3 families) ([PMID:22693042]; [PMID:26729329]; [PMID:32139166]). Although specific coding changes vary, the recurrent finding of biallelic loss‐of‐function or deletion alleles supports a loss‐of‐function mechanism. No recurrent founder variants have been described to date.

Functional studies directly assessing TMEM237 pathogenicity are lacking. However, the protein’s established role in ciliogenesis and the concordance of TMEM237‐deficient model systems with JS phenotypes in other ciliopathy genes lend biologic plausibility to haploinsufficiency or loss‐of‐function as the operative mechanism.

No conflicting reports have been published disputing the association between TMEM237 and JS. The consistent identification of biallelic TMEM237 variants in JS cohorts, coupled with absence from large population databases, supports a causal relationship.

In summary, biallelic TMEM237 loss‐of‐function variants cause autosomal recessive Joubert syndrome with multiorgan involvement. Although the number of reported families remains limited, the data fulfill criteria for a Limited clinical validity classification. Additional genotype–phenotype and functional studies are needed to strengthen evidence, but current knowledge enables TMEM237 to be included in diagnostic gene panels for JS.

Key Take‐home: TMEM237 should be considered in the differential genetic diagnosis of autosomal recessive Joubert syndrome, especially in patients with renal manifestations.

References

• Orphanet journal of rare diseases • 2010 • Joubert Syndrome and related disorders. PMID:20615230
  
• Human Mutation • 2012 • Molecular characterization of Joubert syndrome in Saudi Arabia. PMID:22693042
  
• BMC Medical Genetics • 2016 • Enhanced diagnostic yield in Meckel-Gruber and Joubert syndrome through exome sequencing supplemented with split-read mapping. PMID:26729329
  
• Pediatric Neurology • 2020 • Clinical and Molecular Diagnosis of Joubert Syndrome and Related Disorders. PMID:32139166
  
• American Journal of Medical Genetics Part C • 2022 • Genotype-phenotype correlates in Joubert syndrome: A review. PMID:35238134
  

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