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TMEM216 – Joubert syndrome 2

TMEM216 encodes a ciliary transition zone protein essential for cerebellar and neural development. Autosomal recessive mutations in TMEM216 underlie Joubert syndrome 2 (JBTS2), characterized by the hallmark “molar tooth” midbrain–hindbrain malformation and neuro-ophthalmological symptoms.

In a cohort of eight Ashkenazi Jewish families comprising 13 affected probands, homozygous TMEM216 variants were identified in all individuals, with complete segregation in each pedigree ([PMID:20036350]). Carrier screening of 2,766 unrelated Ashkenazi Jewish individuals revealed 30 heterozygotes (carrier rate 1:92) ([PMID:20036350]). For example, the missense variant c.218G>T (p.Arg73Leu) was observed in all cases.

Clinically, JBTS2 patients present with hypotonia, ataxia, nystagmus, and oculomotor apraxia accompanied by cerebellar vermis hypoplasia, corpus callosum anomalies, and occasional retinal or renal involvement. Brain MRI consistently shows the molar tooth sign.

Functional studies in zebrafish demonstrate that tmem216 null mutants recapitulate ciliary transition zone defects and multisystem ciliopathy phenotypes, mirroring key aspects of the human disorder ([PMID:36533556]). No conflicting evidence has been reported to date.

Together, the genetic and experimental data support a loss-of-function mechanism for TMEM216 in JBTS2. TMEM216 mutation screening should be integrated into diagnostic panels to enable early and accurate diagnosis, inform genetic counseling, and guide management, particularly in populations with known founder alleles.

Key take-home: TMEM216 mutation screening enables definitive JBTS2 diagnoses, facilitating targeted care and informed family planning.

References

  • American journal of human genetics • 2010 • Joubert syndrome 2 (JBTS2) in Ashkenazi Jews is associated with a TMEM216 mutation. PMID:20036350
  • Disease models & mechanisms • 2022 • Variable phenotypes and penetrance between and within different zebrafish ciliary transition zone mutants. PMID:36533556

Evidence Based Scoring (AI generated)

Gene–Disease Association

Strong

13 probands from 8 families with homozygous autosomal recessive TMEM216 variants with complete segregation and concordant animal model data

Genetic Evidence

Strong

13 probands with homozygous missense variants (c.218G>T (p.Arg73Leu)); multi-family segregation and a 1:92 carrier frequency in Ashkenazi Jews

Functional Evidence

Moderate

Zebrafish tmem216 null mutants recapitulate multisystem ciliary defects analogous to human JBTS2 phenotype