Identification of novel compound heterozygous mutations in the GLB1 gene by whole-exome sequencing in a case of infantile GM1 gangliosidosis: a case report.

BACKGROUND: GM1 gangliosidosis was a rare, fatal autosomal recessive lysosomal storage disorder caused by biallelic mutations in the GLB1 gene. Whole-exome sequencing (WES) was increasingly utilized to identify novel pathogenic variants in the GLB1 gene among undiagnosed pediatric cases.

CASE PRESENTATION: We reported a 9-month-old male infant with developmental delay, hepatomegaly, extensive Mongolian spots, and hypotonia. WES identified two novel compound heterozygous GLB1 variants: a paternal c.792 + 1G > A splice-site mutation and a maternal c.1572_1573insC(p.Gly525Argfs*7) frameshift mutation. Both were classified as pathogenic by ACMG guidelines. β-galactosidase activity was markedly deficient, confirming the diagnosis. The family received genetic counseling and opted for prenatal diagnosis in a subsequent pregnancy. At age 2 years, the patient exhibited an inability to speak or walk and had a history of recurrent severe pneumonia requiring multiple hospitalizations, with his overall condition currently managed supportively.

CONCLUSIONS: Two novel pathogenic GLB1 mutations expanded the mutational spectrum of infantile GM1 gangliosidosis. WES with enzymatic validation enabled precise diagnosis, genetic counseling, and prenatal management. The development of targeted therapies remained imperative to alter the disease's natural course.