Further Evidence Supporting the Role of GTDC1 in Glycine Metabolism and Neurodevelopmental Disorders

Endocrinology Neurology Genetics Life Sciences Medicine
GTDc1 Glycine Metabolism Neurodevelopmental Disorders Genetic Factors CNVs Phenotype

In recent years, research on Neurodevelopmental Disorders (NDDs) has uncovered numerous genetic variants associated with NDDs, ranging from Single Nucleotide Variants (SNVs) to large structural changes (such as chromosomal rearrangements). Against this research background, Edoardo Errichiello, Mauro Lecca, Chiara Vantaggiato, and other researchers from the University of Pavia, University of Insubria, and other institutions in Italy conducted an in-depth investigation into the association between a specific genetic factor—the Glycosyltransferase-Like Domain Containing 1 (GTDC1) gene—and specific neurodevelopmental disorders. This research was published in 2024 in the European Journal of Human Genetics, titled “Further evidence supporting the role of GTDC1 in glycine metabolism and neurodevelopmental disorders”.

Research Background and Significance

Neurodevelopmental disorders affect brain development and function, leading to a range of neurological and psychiatric manifestations. One of the main current strategies for diagnosing NDDs is through the identification of related genetic variants, with Copy Number Variants (CNVs) being one of the important types of genetic variations, accounting for 15-20% of the genetic causes of NDDs. The GTDC1 gene encodes a glycosyltransferase that is particularly abundantly expressed in the nervous system. The research team had previously found that dysregulation of the GTDC1 gene was associated with global developmental delay and speech and language developmental delay. Therefore, they aimed to further explore the impact of GTDC1 gene mutations on neurodevelopment and the deeper mechanisms of its association with NDDs through functional studies of newly discovered variants in the GTDC1 gene.

Research Methods and Findings

Using techniques such as Chromosomal Microarray Analysis (CMA) and quantitative PCR, the research team discovered an intragenic deletion of approximately 67 kb at position 2q22.3 in the GTDC1 gene of a female NDD patient, involving the 5th and 6th exons of the gene. Analysis through RNA sequencing and other bioinformatics tools showed that this deletion led to changes in the expression of glycogen/serine and cytokine/chemokine signaling pathways, accompanied by increased concentrations of serine and glycine.

Conclusions and Significance

The study revealed the potential mechanism of GTDC1 downregulation in neurodevelopmental disorders, particularly through altering glycine metabolism and thereby affecting the occurrence of NDDs. Additionally, this research expanded the phenotypic spectrum of GTDC1-related diseases, identifying microcephaly and epilepsy as clinical features of GTDC1 loss of function. These findings not only help enrich our understanding of the genetic basis of NDDs but may also provide new perspectives for future diagnosis and treatment.

Research Highlights

  • First direct link between GTDC1 gene mutations and the occurrence of specific NDD diseases.
  • Provided a complete research pathway from gene variation to disease phenotype.
  • Emphasized the crucial role of multi-omics approaches in revealing the genetic mechanisms of complex diseases.

This study not only provides new insights into the role of the GTDC1 gene in neurodevelopment but also emphasizes the importance of integrating genomics and functional genomics approaches in the diagnosis and treatment of NDDs.