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Tourette Syndrome is a common developmental neuropsychiatric disorder characterized by chronic motor and vocal tics. A rare heterozygous nonsense variant in HDC, c.951G>A (p.Trp317Ter), was identified in a two-generation pedigree and segregates with Tourette Syndrome (PMID:20445167). Targeted resequencing of 382 TS individuals uncovered five additional rare predicted‐deleterious missense variants in HDC without segregation data (PMID:27708560), while screening of 120 Chinese Han patients revealed only synonymous or intronic variants with no association (PMID:22095709). Together, these studies provide limited genetic evidence for HDC haploinsufficiency in Tourette Syndrome.
Functional studies support a pathogenic role for HDC deficiency: Hdc knockout mice recapitulate tic-like behaviors and cortico-basal ganglia white matter abnormalities concordant with human TS phenotypes, including reduced fractional anisotropy in the dorsal striatum (PMID:36504678) and dopaminergic dysregulation in basal ganglia circuits (PMID:28233179). In vitro assays confirm that the p.Trp317Ter mutation abolishes enzyme activity, consistent with a loss‐of‐function mechanism. These data provide moderate experimental support but await replication in independent human cohorts.
Key Take-home: HDC haploinsufficiency is a rare, biologically plausible cause of Tourette Syndrome with potential diagnostic and therapeutic implications.
Gene–Disease AssociationLimitedSingle two-generation pedigree with one LoF variant; no replication in independent cohorts Genetic EvidenceLimitedOne loss-of-function variant segregating in one family; five additional rare missense variants identified without segregation Functional EvidenceModerateHdc knockout mouse models exhibit TS-relevant phenotypes; p.Trp317Ter abolishes enzyme activity |