Efficient Targeted Next Generation Sequencing-Based Workflow for Differential Diagnosis of Alport-Related Disorders.

Gábor Kovács,Zoltán Ondrik,Sándor Túri,Zoltán Maróti,Ibolya Haszon,Emőke Endreffy,Béla Iványi,Csaba Bereczki,Csaba Rikker,Mária Sinkó,Tibor Kalmár

doi:10.1371/journal.pone.0149241

Abstract

Alport syndrome (AS) is an inherited type IV collagen nephropathies characterized by microscopic hematuria during early childhood, the development of proteinuria and progression to end-stage renal disease. Since choosing the right therapy, even before the onset of proteinuria, can delay the onset of end-stage renal failure and improve life expectancy, the earliest possible differential diagnosis is desired. Practically, this means the identification of mutation(s) in COL4A3-A4-A5 genes. We used an efficient, next generation sequencing based workflow for simultaneous analysis of all three COL4A genes in three individuals and fourteen families involved by AS or showing different level of Alport-related symptoms. We successfully identified mutations in all investigated cases, including 14 unpublished mutations in our Hungarian cohort. We present an easy to use unified clinical/diagnostic terminology and workflow not only for X-linked but for autosomal AS, but also for Alport-related diseases. In families where a diagnosis has been established by molecular genetic analysis, the renal biopsy may be rendered unnecessary.

Highlights

Familiar Benign Haematuria (FBH) and Alport syndrome (AS) are familial hematuric diseases which in case of AS regularly escalate to chronic kidney disease (CKD) stage 5
We have found 21 unique non-synonymous exonic and intronic genetic variances within the investigated COL4A3, COL4A4 and COL4A5 genes
Type IV collagen is an important structural protein in basement membranes, has a triple helical structure, which consists of a Col4A3, a Col4A4 and a Col4A5 protein [36]

Summary

Introduction

Familiar Benign Haematuria (FBH) and Alport syndrome (AS) are familial hematuric diseases which in case of AS regularly escalate to chronic kidney disease (CKD) stage 5 (formerly referred as end stage renal disease). AS patients usually have sensorineural high-tone deafness and ocular abnormalities affecting the lens and fundus [1,2]. More focus has been placed on treating patients early to prevent or delay future end stage kidney damage. The pathogenesis of CKD is multifactorial, some of the suggested therapeutic interventions

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