Whole-Exome Sequencing Uncovers Novel Causative Variants and Additional Findings in Three Patients Affected by Glycogen Storage Disease Type VI and Fanconi−Bickel Syndrome

Abstract

Glycogen storage diseases (GSDs) are the heterogeneous group of disorders caused by mutations in at least 30 different genes. Different types of GSDs, especially liver GSDs, take overlapping symptoms and can be clinically indistinguishable. This survey evaluated the use of whole-exome sequencing (WES) for the genetic analysis of the liver GSD-suspected patients in three unrelated families. An in-house filtering pipeline was used to assess rare pathogenic variants in GSD-associated genes, autosomal recessive/mendelian disorder genes (carrier status for genetic counseling subjects), and the ACMG’s list of 59 actionable genes. For the interpretation of the causative variants and the incidental/secondary findings, ACMG guidelines were applied. Additionally, we have explored PharmGKB class IA/IB pharmacogenetic variants. The segregation analysis was performed using Sanger sequencing for the novel causative variants. Bioinformatics analysis of the exome data in three individuals revealed three novel homozygous causative variants in the GSD-associated genes. The first variant, c.298_307delATGATCAACC in PYGL gene has related to HERS disease (GSD VI). Both variants of c.1043dupT and c.613-1G > C in SLC2A2 gene have been associated with Fanconi-Bickel syndrome (GSDXI). Eight pathogenic/likely pathogenic medical actionable findings in Mendelian disease genes and 10 pharmacogenetic variants with underlying drug response phenotypes have been identified. No known/expected pathogenic variants were detected in the ACMG’s list of 59 actionable genes. The logical filtering steps can help in finding other medical actionable secondary/incidental findings as well as effectively identifying the causative variants in heterogeneous conditions such as GSDs. Three novel variants related to GSD genes recognized in liver GSD-suspected patients with early infantile and childhood-age onset.

Hypoglycaemia Metabolic Gene Panel Testing

“…Furthermore, a synergistic association with other biotechnologies, such as enzymatic assay for residual activity in FAODs, may allow a better characterization of new variants in order to define pathogenicity, customize follow-up and avoid overtreatment ( 116 ). Finally, the NGS approach allows genetic counseling for recurrence risk in further pregnancies ( 1 ), prenatal and preimplantation diagnosis ( 43 ).…”

“…It is characterized by glycogen accumulation in liver and kidneys, with fasting hypoglycemia, hepatomegaly, tubular nephropathy (glucosuria, proteinuria, phosphaturia, bicarbonate wasting, and aminoaciduria), rickets, failure to thrive and short stature. The phenotypic variability ranges from mild presentation to diabetes mellitus ( 43 , 44 ). Patients are treated with hyperglucidic diet with low content of galactose.…”

Revisiting Secondary Information Related to Pharmacogenetic Testing

“…The list has been revised twice: in 2017, the list was updated to include 59 genes (Kalia et al, 2017) and in 2021, 14 more genes were added to bring the total to 73 genes . Several papers have reported the identification of pathogenic/actionable PGx variants from WES/WGS datasets (Lee et al, 2016;Thauvin-Robinet et al, 2019;Eghbali et al, 2020). The 2017 ACMG guidelines indicated that PGx variants were being considered for inclusion in the future but none were considered for the 2021 guidance.…”

Case Report: Fanconi-Bickel Syndrome in a Chinese Girl With Diabetes and Severe Hypokalemia

“…Other characteristics include shortness, rickets, poor growth, hepatomegaly, glucose, galactose intolerance, etc. ( 3 ) However, not all patients will develop typical clinical signs, including isolated glucosuria and hypokalemia ( 4 , 5 ). A high index of suspicion is needed for diagnosis due to its varied clinical presentations.…”