Molecular Genetic Analysis of a Cohort of Patients With Glutaric Aciduria Type II in the Queensland Lifespan Metabolic Service

Abstract

Introduction: Glutaric aciduria type II (GAII) is a heterogeneous genetic disorder with variable clinical manifestations across the lifespan. Some patients, particularly those with late onsetGAII, experience significant benefit from riboflavin therapy. Molecular diagnosis implicates a number of genes in the riboflavin/FAD pathway, but some patients reported in the literature donot have a confirmatorymolecular diagnosis for their presentation, despite advances in next generation sequencing technology. Aims: The aim of this project was to determine whether Queensland patients with a clinical and biochemical diagnosis of GAII, havemolecular variants within a targeted gene panel extracted from whole genome sequencing (WGS). The genes in the panel included: ETFA, ETFB, ETFDH, SLC52A1, SLC52A2, SLC52A3, RFK, FLAD1, SLC25A32, MT-CYB, MT-CO2. A secondary outcome was to assess for a preliminary association with riboflavin responsiveness. Methods: Eligible patients of ages across the lifespan were identified from the Queensland Lifespan Metabolic Service databases. Following whole genome sequencing, a custom gene panel was analysed for pathogenic variants and reported in the context of the individual patient's clinical presentation and response to riboflavin. Conclusions: Twenty-eight patients were enrolled. Only two (7%) had monogenic compound heterozygous variants (in ETFDH or ETFA). Of the remaining patients, nine had single gene mono-allelic variants (32%) and three patients (11%) had mono-allelic variants in two separate genes within the samemetabolic pathway. The remaining 14 patients (50%) had no pathogenic variants detected within the gene panel. Specific correlation with riboflavin responsiveness was not consistent. Analysis of the complete genome is to follow.