Genotype-phenotype correlation and description of two novel mutations in Iranian patients with glycogen storage disease 1b (GSD1b)

Maryam Eghbali,Mohammad Hossein Modarressi,Maryam Abiri,Marjan Shakiba,Parastoo Rostami,Zahra Noroozi,Ali Rabbani,Mehri Najafi,Saeed Talebi,Fatemeh Yazarlou,Hosein Alimadadi

doi:10.1186/s13023-019-1266-3

Abstract

BackgroundGlycogen storage disease (GSD) is a rare inborn error of the synthesis or degradation of glycogen metabolism. GSD1, the most common type of GSD, is categorized into GSD1a and GSD1b which caused by the deficiency of glucose-6-phosphatase (G6PC) and glucose-6-phosphate transporter (SLC37A4), respectively. The high rates of consanguineous marriages in Iran provide a desirable context to facilitate finding the homozygous pathogenic mutations. This study designates to evaluate the clinical and genetic characteristics of patients with GSD1b to assess the possible genotype-phenotype correlation.ResultsAutozygosity mapping was performed on nineteen GSD suspected families to suggest the causative loci. The mapping was done using two panels of short tandem repeat (STR) markers linked to the corresponding genes. The patients with autozygous haplotype block for the markers flanking the genes were selected for direct sequencing. Six patients showed autozygosity in the candidate markers for SLC37A4. Three causative variants were detected. The recurrent mutation of c.1042_1043delCT (p.Leu348Valfs*53) and a novel missense mutation of c.365G > A (p.G122E) in the homozygous state were identified in the SLC37A4. In silico analysis was performed to predict the pathogenicity of the variants. A novel whole SLC37A4 gene deletion using long-range PCR and sequencing was confirmed as well. Severe and moderate neutropenia was observed in patients with frameshift and missense variants, respectively. The sibling with the whole gene deletion has shown both severe neutropenia and leukopenia.ConclusionsThe results showed that the hematological findings may have an appropriate correlation with the genotype findings. However, for a definite genotype-phenotype correlation, specifically for the clinical and biochemical phenotype, further studies with larger sample sizes are needed.

Highlights

Glycogen storage disease (GSD) is a rare inborn error of the synthesis or degradation of glycogen metabolism
Glycogen storage diseases (GSDs) comprise a heterogeneous group of rare inborn errors of metabolism disorders caused by deficiency of the specific enzymes in glycogen degradation and synthesis
GSD1a disease is caused by the deficiency of the G6Pase-α which is located at the endoplasmic reticulum membrane

Summary

Introduction

Glycogen storage disease (GSD) is a rare inborn error of the synthesis or degradation of glycogen metabolism. GSD1, the most common type of GSD, is categorized into GSD1a and GSD1b which caused by the deficiency of glucose-6-phosphatase (G6PC) and glucose-6-phosphate transporter (SLC37A4), respectively. Glycogen storage diseases (GSDs) comprise a heterogeneous group of rare inborn errors of metabolism disorders caused by deficiency of the specific enzymes in glycogen degradation and synthesis. GSD1 is the most common liver impairment with an overall incidence of about 1:100,000 live births It is categorized into 1a (GSD1a) and 1b (GSD1b). Deficiency in glucose-6-phosphatase-α (G6Pase-α)/glucose-6-phosphate transporter (G6PT) complexes causes GSD1. Not all GSD 1b patients manifest neutropenia, it may cause by either one or more modifiers on G6PT function or SLC37A4 mutations with residual transport activity [4, 5]

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