A Novel, Recurrent, 3.6-kb Deletion in the PYGL Gene Contributes to Glycogen Storage Disease Type VI.

The PYGL gene is the only established gene known to cause glycogen storage disease type VI (GSD6), which is a rare autosomal recessive disorder associated with hepatomegaly, elevated levels of hepatic transaminases, and hypoglycemia. Extended bioinformatics analysis was performed on the exome sequencing data of 5 patients who were clinically diagnosed as having or highly suspected of having GSD, and a single heterozygous pathogenic or likely pathogenic or rare variant of uncertain significance single-nucleotide variant was identified on the PYGL gene. A recurrent, novel, 3.6-kb deletion involving exons 14 to 17 of PYGL was identified in three of the five patients. Together with the two novel and one established stop-gain SNVs, they were diagnosed as compounds heterozygous of PYGL variants and confirmed as GSD6. The detected 3.6-kb deletion was further screened in a Chinese cohort of 31,317 individuals without hepatic abnormalities, and 10 carriers were identified, showing an allele frequency of 0.016%. Compared with the previously established 47 PYGL pathogenic or likely pathogenic SNVs, the novel pathogenic deletion had the second highest allele frequency among the population. This recurrent, novel, 3.6-kb deletion improved the molecular diagnostic rate of the GSD6. The relatively high frequency of the variant suggests that it is a potential mutation hotspot in patients with GSD6.