Next-generation sequencing in identification of pathogenic variants in primary hyperoxaluria among 21 Egyptian families: Identification of two novel AGXT gene mutations

Abstract

Background: Primary hyperoxaluria (PH) is a rare heterogeneous, autosomal recessive disorder of glyoxylate metabolism. It is characterized by excessive hepatic production of oxalate resulting in a wide spectrum of clinical, imaging, and functional presentation. The characteristic features of PH comprise of recurrent urolithiasis, renal stones, and/or nephrocalcinosis. Three known types of PH have been identified PH1, PH2, and PH3. Pathogenic variants in AGXT, GRHPR, and HOGA1 cause the phenotypic expression of PH.

Methods: In this study, we describe the clinical and genetic findings of 22 patients from 21 unrelated Egyptian families with the distinctive clinical features of PH. A thorough clinical evaluation followed by an NGS custom panel of AGXT, GRHPR, and HOGA1 genes was done.

Results: Two novel mutations (p.Gly27Glu and p.Gln256Serfs*17) and six previously reported mutations (p.Lys12Glnfs*156, p.Lys12Argfs*34, p.Ile244Thr, p.Asn22Ser, p.Pro11Leu, and p.Ile340Met) were identified in AGXT gene. The NGS panel results were validated thereafter using Sanger sequencing.

Conclusion: Our results extend the number of AGXT mutations identified so far and emphasize the important role of genetic testing in providing proper counseling and patients management.

Keywords: AGXT; NGS; PH; mutations; recessive.

FIGURE 1

Sequencing chromatograms of AGXT mutations identified in our cohort. (a–b) Two novel AGXT mutations. (c–d) Previously reported AGXT mutations. Wild‐type sequences are shown above each chromatogram and arrows point toward single base changes.

FIGURE 2

Bioinformatics analysis of a novel missense mutation (c.80G>A, p.Gly27Glu) on protein structure.