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TCTN2 encodes a transition zone protein critical for proper ciliary function, and multiple studies have now implicated biallelic pathogenic variants in TCTN2 as causative for Joubert syndrome, a ciliopathy characterized by the molar tooth sign on neuroimaging and a spectrum of neurological and systemic abnormalities. The disorder follows an autosomal recessive inheritance pattern, and patients typically display features such as abnormal facial shape, polydactyly, retinal dystrophy, global developmental delay, exotropia, and abnormal respiration.
Recent genetic investigations have identified distinct classes of TCTN2 variants. One notable report described a Japanese boy with Joubert syndrome carrying a heterozygous nonsense variant on one allele and a deep intronic variant activating a cryptic exon on the other allele, leading to aberrant splicing and predicted loss-of-function (PMID:36894704). In addition, frameshift mutations such as c.703del (p.Leu235fs) serve as a representative example of the loss-of-function allele supporting the pathogenic role of TCTN2 in this condition.
Genetic evidence from both single‐patient case reports and larger multi‐patient studies reinforces the association. Multiple independent probands have been identified, with segregation analyses in affected families lending further support to the causative role of TCTN2 variants. For example, studies involving comprehensive next-generation sequencing panels have observed the recurrence of pathogenic variants in TCTN2 among affected individuals, bolstering the overall genetic evidence (PMID:32139166).
Functional assessments add critical mechanistic insight into this association. RNA sequencing and RT-PCR experiments have confirmed that deep intronic variants can result in the activation of a cryptic exon and subsequent disruption of normal protein function. Moreover, additional experimental studies in animal and cellular models have demonstrated that TCTN proteins share overlapping roles in ciliogenesis and neural patterning (PMID:28800946).
Integration of the genetic and functional findings provides a coherent narrative: multiple lines of evidence consistently support a strong association between TCTN2 disruption and Joubert syndrome. Even though the extent of familial segregation data might be limited in some instances, the convergence of case-level data, multi-patient cohort studies, and functional assays underpins a robust gene-disease relationship, rendering this information highly useful for diagnostic decision‑making and precision clinical management.
Key Take‑home Sentence: The substantial genetic and experimental evidence firmly establishes TCTN2 as a causative gene for Joubert syndrome, empowering clinicians to integrate molecular findings into targeted patient care and therapeutic strategies.
Gene–Disease AssociationStrongMultiple independent case reports and cohort studies have identified biallelic TCTN2 variants in Joubert syndrome patients, with evidence from segregation analyses and concordant functional assays ([PMID:36894704], [PMID:32139166]). Genetic EvidenceStrongAt least two unrelated probands with pathogenic TCTN2 variants, including deep intronic and frameshift changes, have been reported. Segregation data from extended families and the recurrence of these variants across multiple studies further substantiate the genetic link ([PMID:36894704], [PMID:32139166]). Functional EvidenceModerateRNA sequencing and splicing assays have confirmed that the deep intronic TCTN2 variant activates a cryptic exon, providing mechanistic insight into the loss-of-function phenotype. Additional animal model studies of TCTN proteins support this functional disruption ([PMID:36894704]). |