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Evidence for an association between TTBK1 and childhood-onset schizophrenia comes primarily from exome sequencing studies identifying de novo variants in affected individuals. In a study of 17 COS trios, a total of 20 de novo variants were detected across several candidate genes, with TTBK1 being one of those disrupted (PMID:26508570). This variant spectrum, although limited to a single disruptive event for TTBK1, supports a tentative gene-disease relationship that is in line with observations in other neuropsychiatric conditions.
The genetic evidence is characterized by a de novo coding variant, c.773G>A (p.Arg258Gln), identified in a COS proband. While the study reported de novo events in multiple genes, the presence of this variant in TTBK1 provides a specific clue to potential pathogenicity. However, no additional familial segregation data has been reported, and thus the overall genetic case evidence remains circumscribed (PMID:26508570).
Given the de novo nature of the variant, conventional segregation analyses are limited since affected relatives do not typically harbor the same variant. In this context, the segregation evidence is minimal with no affected relatives demonstrating the variant in a familial pattern. This absence of familial clustering underscores the sporadic presentation of the disorder in these trios.
Functional insights into TTBK1 have been more extensively explored in other neurodegenerative contexts, for example in studies of Alzheimer disease. Although those functional studies are not directly performed in COS, the observed alterations in protein function in the context of neurodegeneration may inform a potential mechanism of pathogenicity in TTBK1. Such data, while not directly recapitulating COS phenotypes, suggest that aberrant TTBK1 function could have broader neurodevelopmental and neuropsychiatric repercussions (PMID:34297427).
Conflicting evidence arises from investigations in other diseases such as Alzheimer disease, where TTBK1 has been implicated in tauopathy. These studies illustrate that while TTBK1 is functionally important in the central nervous system, its role in childhood-onset schizophrenia remains less substantiated, with only a single de novo event reported. This discrepancy highlights the need for further investigation to clarify the spectrum of TTBK1-related pathology.
In summary, the currently available genetic data and extrapolated functional findings lend limited support to a role for TTBK1 in childhood-onset schizophrenia. While the de novo variant c.773G>A (p.Arg258Gln) in a COS proband provides an initial genetic signal, additional replication and mechanistic studies are required. Key take‑home: Despite promising preliminary findings, TTBK1 should be considered a candidate gene with limited clinical utility pending further validation.
Gene–Disease AssociationLimitedA single de novo variant was identified in COS probands with no additional segregation data reported (PMID:26508570). Genetic EvidenceLimitedOnly one de novo coding variant (c.773G>A (p.Arg258Gln)) has been observed among 17 COS probands, providing limited genetic evidence for TTBK1's role in childhood-onset schizophrenia (PMID:26508570). Functional EvidenceLimitedFunctional data specific to TTBK1 in the context of COS remain sparse, although mechanistic insights from other neurodegenerative studies suggest a potential role (PMID:34297427). |