A novel recurrent 3.6-kb deletion in the PYGL gene contributes to glycogen storage disease type VI.

Abstract 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 hepatic transaminases, and hypoglycemia. We performed extended bioinformatics analysis on the exome sequencing data of five patients who were clinically diagnosed as/highly-suspected of GSD and identified a single heterozygous pathogenic/likely-pathogenic (P/LP) or rare variant of uncertain significance (VUS) single nucleotide variant (SNV) on the PYGL gene. A recurrent novel 3.6-kb deletion involving exons 14-17 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 compound 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 P/LP SNVs, the novel pathogenic deletion showed the second highest allele frequency among the population. The revealed 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 GSD6 patients.