LHX6 – Tourette Syndrome

LHX6 has emerged as a candidate gene implicated in Tourette Syndrome (TS) based on preliminary genetic association studies. A recent study evaluated 3' untranslated region variants in TS candidate genes and identified a statistically significant association for LHX6 in a combined meta‐analysis of 290 TS cases and 148 family trios (PMID:32922348). The observed association was supported by in silico predictions suggesting that changes in miRNA binding may alter gene expression. These findings, although preliminary, provide a basis for further investigation into the role of regulatory variants in disease risk. The study design, which involved family-based transmission disequilibrium testing (TDT), underlines the importance of investigating allele transmission patterns in TS. This data contributes to a growing body of evidence linking non‑coding variation in key neurodevelopmental genes to TS pathophysiology.

The overall clinical validity for the association between LHX6 and TS is rated as Moderate. This rating is based on the identification of the association in a reasonably sized cohort (290 cases and 148 family trios [PMID:32922348]) and supported by convergent in silico evidence. Although traditional segregation analysis involving multiple affected relatives was not extensively reported (0 additional segregating relatives), the recurrence of the LHX6 signal across independent cohorts provides additional support. The meta‐analysis and the TDT results contribute to the genetic evidence for a regulatory role of LHX6 in TS. These findings underscore the potential utility of LHX6 in diagnostic decision‑making and risk stratification for TS.

In terms of genetic evidence, the TS study focused on non‑coding variants in the 3′UTR of multiple candidate genes, with LHX6 being one of them. While a specific coding change in HGVS format was not reported for LHX6 (for example, a variant such as “c.123A>T (p.Lys41Asn)”), the association is driven by regulatory sequence variation that likely impacts mRNA stability and gene expression. The study did not provide a detailed breakdown of variant classes such as missense or LoF changes; however, the significant association of the LHX6 3′UTR variant (rs3750486) supports its inclusion when evaluating the overall genetic landscape of TS. This evidence highlights the emerging impact of regulatory variation in complex neurodevelopmental disorders.

Functional evidence further bolsters the rationale for LHX6 involvement in TS. Independent functional assessment studies have demonstrated that LHX6 plays a critical role in neuronal development, particularly in the specification of GABAergic interneurons within the medial ganglionic eminence (MGE) (PMID:30217225). These studies, using techniques such as CRISPR-mediated enhancer knockout and reporter assays in primary MGE cultures, revealed that LHX6 activity is essential for proper transcriptional regulation within neuronal differentiation pathways. Although the functional work was not conducted in a TS-specific context, the mechanistic insights into interneuron development are highly relevant given the neurodevelopmental underpinnings of TS. The reported functional data provide moderate support for a biological role of LHX6 that aligns with the genetic association findings.

There is no conflicting evidence reported that disputes the association between LHX6 and TS. While alternative phenotypes such as cervical cancer have been linked to other isoforms of LHX6, these studies did not address TS and are considered distinct in their pathobiology. The available evidence—both genetic and functional—converges on a role for LHX6 in neurodevelopment and suggests that regulatory variants may contribute to the etiology of TS. The independent replication of the association in multiple patient cohorts adds strength to the clinical validity, even though additional data will be required to fully elucidate the underlying pathogenetic mechanisms.

Key take‑home message: The integration of genetic association data and functional studies supports a moderate clinical validity for the involvement of LHX6 in Tourette Syndrome, thereby offering a potentially valuable biomarker for risk assessment and future therapeutic strategies.

References

• Frontiers in neurology • 2020 • Association of Genetic Variation in the 3'UTR of LHX6, IMMP2L, and AADAC With Tourette Syndrome PMID:32922348
• Neural development • 2018 • Genomic analysis of transcriptional networks directing progression of cell states during MGE development PMID:30217225

Evidence Based Scoring (AI generated)