Identification of novel pathogenic variants in the GCDH gene and assessment of neurodevelopmental outcomes in 24 children with glutaric aciduria type 1.

To evaluate the pathogenic variants in GCDH gene and to assess the neurodevelopmental outcomes in children with Glutaric aciduria type 1 (GA-1). Cross-sectional observational study between January 2019 and June 2020 in consecutive North Indian children with a clinical and biochemical suspicion of GA-1. Variants in the coding regions of GCDH gene were identified through Sanger sequencing. Neurodevelopmental and quality of life assessment was done using standardized scales. 24 children with GA-1 were identified. The median age at diagnosis was 12 months and the median delay in diagnosis was 3 months. Genetic analysis was done in 14 cases. It revealed 12 variants (11 missense and one nonsense) from 13 patients. Most of the pathogenic variants were in exon 9 and exon 5. Three novel variants were identified in three patients: two missense variants c.169G > A (p.Glu57Lys), c.1048T > C (p.Cys350Arg) and one nonsense variant c.331C > T (p.Lys111Ter). On neurodevelopmental assessment, majority of children with GA-1 were non ambulatory (62.5%), had limited hand skills (58.3%) and impaired communication (58.3%). Overall, poor global development was noted in 43.7%. A pre-existing developmental delay was significantly associated with impaired communication skills (p = 0.03), and the number of episodes of encephalopathy were significantly associated with impaired gross motor skill (p = 0.02). Presence of encephalopathy was significantly associated with poor performance in social emotional (p = 0.01) and cognitive (p = 0.03) domains of Developmental Profile-III scale and development of severe dystonia (p = 0.01). Our findings highlight the clinical, biochemical, radiological and genetic spectrum of GA-1 in children in North India and report the presence of novel pathogenic variations. • Identification of exon 9 and 5 as hotspots in the GCDH gene in North Indian children. • Identification of three novel pathogenic variations. • Detailed neurodevelopmental and quality of life assessment. • Identification of predictors of poor neurodevelopmental outcomes. [ABSTRACT FROM AUTHOR]