GM2A gene is located on chromosome 5q31.2 spanning 16 Kb sequence. It consists of four exons.
Types of mutations
All types of variants including missense, nonsense, splice-site and frameshift variants have been reported till date. The variant c.412T>C (p.C138R) in exon 3 and c.164C>T (p.P55L) in exon 2 have been the most common variants identified.
Few groups have studied the effect of different variants on the resultant GM2 activator protein. For instance, in case of missense variant p. C138R, biochemical assays in patient fibroblasts, identified that both these variants led to retention and degradation of the mutant protein in the endoplasmic reticulum.
The following table shows the predicted protein change due to different variants in the gene
A diagnosis of GM2 activator deficiency is made based on clinical findings and presence of biallelic pathogenic variants in the GM2A gene.
Molecular genetic testing is used to identify variant in the GM2A gene. This includes use of single gene sequencing, NGS-panel based multi-gene or whole-exome sequencing study
Single gene testing: In individuals with a high clinical suspicion of GM2 gangliosidosis and normal levels of enzymes hexosaminidase-A and hexosaminidase-B, Sanger sequencing of the GM2A gene can identify small insertions/deletions, missense, nonsense and splice-site variants.
Gene targeted deletion/duplication testing: This involves the use of quantitative-PCR and MLPA to identify deletions or duplications encompassing the GM2A gene. Till date only one case has been reported with deletion of Exon 2 in GM2A gene.
Multi-gene testing: In individuals where the clinical presentation is not strong for GM2 activator deficiency and there are multiple differential diagnosis, multi-gene panel testing can aid to assess GM2A and other genes of interests.
Whole-Exome sequencing: In individuals with a broad range of symptoms overlapping with different genetic disorders, exome sequencing is commonly used to determine the gene involved. This test investigates all the coding genes present.