TOP 43 - Impact of the common Hispanic genetic variant on long-term renal prognosis in glycogen storage disease type 1a: a retrospective cohort

Publication Number: 1802.TOP 43

Esraa Elsamny, McGovern Medical School at the University of Texas Health Science Center at Houston, Houston, TX, United States; Veronica S. Santos Canellas, McGovern Medical School at the University of Texas Health Science Center at Houston, Houston, TX, United States; Jennifer Kinney, UT Health McGovern Medical School, Houston, TX, United States; Marina Arocha, McGovern Medical School at the University of Texas Health Science Center at Houston, Houston, TX, United States; April E. Cherian, The University of Texas houston, Houston, TX, United States; Heather W. Saavedra, University of Texas Health Science Center at Houston - McGovern Medical School, Houston, TX, United States; rafael Santos, University of Texas - Health Science Center at Houston, Houston, TX, United States; David Felipe. Rodriguez-Buritica, McGovern Medical School at the University of Texas Health Science Center at Houston, Missouri City, TX, United States; Joyce Samuel, McGovern Medical School at the University of Texas Health Science Center at Houston, Houston, TX, United States

Background: Glycogen storage disease type Ia (GSD-Ia) is an autosomal recessive disorder resulting from a defect in the enzyme glucose-6-phosphatase, leading to impaired glycogenolysis and gluconeogenesis. This enzymatic defect results in key metabolic disturbances, including fasting hypoglycemia, lactic acidosis, hyperuricemia, and hyperlipidemia. Kidney involvement, including chronic kidney disease and proteinuria, are known long-term complications that can occur with poor metabolic control.
Multiple pathogenic variants in the G6PC1 gene are associated with GSD-Ia, including the (p.Y128TfxX3) mutation which is somewhat unique to Hispanic populations and often referred to as the "common Hispanic mutation." This mutation is prevalent in south Texas and north Mexico, but there is limited data on whether this mutation is associated with worse renal outcomes.

Objective: We hypothesize that patients with GSD-Ia who are homozygous for the common Hispanic variant experience earlier and more severe adverse renal outcomes compared to those with other mutations.

Design/Methods: We are conducting a single-center retrospective cohort study of one of the largest known cohorts of patients diagnosed with GSD-Ia. All patients with GSD-Ia and followed by the Medical Genetics program at UTHealth Houston McGovern Medical School between 2010 and 2025 were included. Demographics shown in table 1. These patients undergo a battery of evaluations once annually as part of their routine care, and many have been followed for over ten years. We aim to assess whether patients who are homozygous for the common Hispanic mutation experience earlier onset and more severe kidney-related complications compared to two other groups: those who are compound heterozygous with one allele being the common Hispanic mutation, and those with genotypes that do not include the common Hispanic mutation. Continuous variables will be reported as median with range (minimum, maximum) and compared with the Wilcoxon rank-sum test. Categorical variables will be compared using the chi-squared test or Fisher exact test when expected cell counts were low. A P value of less than 0.05 was used to determine the level of statistical significance and all reported probability values will be two-sided. For continuous outcomes repeatedly collected over time (BP, eGFR, proteinuria) a linear mixed model will be used to account for clustering within patients.

Table 1: Demographics of GSD IA cohort
table_01_demographics_2025-10-31.pdf