SLITRK1 – Tourette syndrome

Rare sequence variants in SLITRK1 were first implicated in Tourette syndrome (TS) based on analysis of 174 unrelated probands, in whom one frameshift (c.1264del (p.Leu422fs)) and two occurrences of a 3′-UTR microRNA binding–site variant (c.*689G>A) were identified, all absent from 3600 control chromosomes ([PMID:16224024]). Wild-type SLITRK1 enhanced dendritic growth in primary neuronal cultures, whereas the frameshift mutant did not, supporting a loss-of-function mechanism ([PMID:16224024]).

Subsequent sequencing in 82 North American Caucasian probands failed to detect the original noncoding variant or novel coding changes ([PMID:17083340]), and similarly no rare SLITRK1 coding variants were found in 160 Taiwanese or 174 Japanese TS patients, though haplotype distributions differed in the latter ([PMID:26317387]). Population stratification concerns arose after var321 was observed in unaffected Ashkenazi individuals and nontransmitted in TS trios ([PMID:17035247]). An Austrian family study identified a 3′-UTR variant (c.*1292G>A) segregating in two affected relatives, but no coding mutations in 92 patients ([PMID:19018236]). Slitrk1-null mice exhibit elevated anxiety-like behavior and noradrenergic dysregulation, phenocopying aspects of TS-relevant neurobiology ([PMID:18794888]). Overall, rare SLITRK1 variants show inconsistent replication and limited segregation, disputing a causal association.

Key take-home: SLITRK1 rare variants have limited and inconsistent genetic support and are not reliable diagnostic markers for Tourette syndrome.

References

• Science (New York, N.Y.) • 2005 • Sequence variants in SLITRK1 are associated with Tourette's syndrome. PMID:16224024
• Acta neurologica Scandinavica • 2006 • Examination of the SLITRK1 gene in Caucasian patients with Tourette syndrome. PMID:17083340
• Psychiatric genetics • 2015 • Analysis of SLITRK1 in Japanese patients with Tourette syndrome using a next-generation sequencer. PMID:26317387
• Human molecular genetics • 2006 • Overrepresentation of rare variants in a specific ethnic group may confuse interpretation of association analyses. PMID:17035247
• Psychiatric genetics • 2008 • Sequence analysis of the complete SLITRK1 gene in Austrian patients with Tourette's disorder. PMID:19018236
• Molecular psychiatry • 2010 • Slitrk1-deficient mice display elevated anxiety-like behavior and noradrenergic abnormalities. PMID:18794888

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