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GTDC1 encodes a putative glycosyltransferase enriched in the nervous system and has been implicated in a neurodevelopmental disorder characterized by epilepsy, severe intellectual disability, speech delay, and microcephaly. In a female proband, a ~67 kb de novo intragenic deletion spanning exons 5–6 of GTDC1 was identified, and in a previously described male case a balanced de novo translocation disrupted GTDC1, indicating an autosomal dominant de novo pattern with 2 probands (PMID:38605125). No additional familial segregation has been reported.
Functional studies in the female proband’s lymphoblastoid cell line demonstrated dysregulation of glycine/serine and cytokine/chemokine signaling pathways by RNA-seq, and ELISA and HPLC assays revealed elevated glycine levels in LCL and serum compared to controls (PMID:38605125). These data indicate that GTDC1 haploinsufficiency perturbs glycine metabolism, potentially driving neurodevelopmental impairment. Key Take-home: GTDC1 haploinsufficiency via de novo disruption causes a glycine metabolism defect underlying a neurodevelopmental disorder, supporting its use in diagnostic genetic testing.
Gene–Disease AssociationLimited2 unrelated de novo probands with no segregation and supportive functional data (PMID:38605125) Genetic EvidenceLimitedTwo de novo loss-of-function events in GTDC1 in unrelated individuals (PMID:38605125) Functional EvidenceModerateRNA-seq profiling, ELISA, and HPLC demonstrating glycine metabolism perturbation in patient cells (PMID:38605125) |