Possible Founder Effect of Glycine Encephalopathy: Evidence of a GLDC c.2714T>G (p.Val905Gly) Common Variant in the Paisa Community Based in Cali, Colombia.

Abstract

Non-ketotic hyperglycinemia (NKH) is a rare autosomal recessive disorder caused by defects in the mitochondrial glycine cleavage system, most commonly involving variants in GLDC. Clinical presentation is heterogeneous, ranging from severe neonatal encephalopathy with intractable epilepsy to attenuated forms with variable neurodevelopmental outcomes. We conducted a comprehensive clinical, biochemical, molecular, and genealogical analysis of eight Colombian patients with NKH, all of whom shared ancestry from the Paisa population. All patients were born at term after uncomplicated pregnancies and presented in the neonatal period with hypotonia, lethargy, feeding difficulties, and treatment-resistant seizures. Elevated glycine levels were detected in plasma for all patients and cerebrospinal fluid in three cases. Molecular testing identified the same homozygous GLDC variant (NM_000170.3:c.2714 T>G; p.Val905Gly) in all individuals. Although no consanguinity was reported, shared surname and regional ancestry suggested intra- and interfamilial isonymy, raising the possibility of a founder effect. Clinical outcomes varied despite the implementation of early supportive interventions. This is the first report of a recurrent GLDC variant in Colombian patients, supporting a potential founder effect in the Paisa population. These findings highlight the importance of regional genetic studies in enhancing diagnostic precision and guiding population-specific strategies for rare disease management.