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Kidney Week

Abstract: FR-PO1013

Genomic Analysis of Focal Segmental Glomerulosclerosis in Thailand

Session Information

Category: Genetic Diseases of the Kidney

  • 1002 Genetic Diseases of the Kidney: Non-Cystic

Authors

  • Isaranuwatchai, Suramath, Chulalongkorn University, Bangkok, Thailand
  • Chanakul, Ankanee, Chulalongkorn University, Bangkok, Thailand
  • Ittiwut, Chupong, Chulalongkorn University, Bangkok, Thailand
  • Srichomthong, Chalurmpon, Chulalongkorn University, Bangkok, Thailand
  • Suphapeetiporn, Kanya, Chulalongkorn University, Bangkok, Thailand
  • Praditpornsilpa, Kearkiat, Chulalongkorn University, Bangkok, Thailand
  • Shotelersuk, Vorasuk, Chulalongkorn University, Bangkok, Thailand
Background

Focal segmental glomerulosclerosis (FSGS) has currently been found to be caused by mutations in at least 62 genes. Recently, next generation sequencing has provided a robust tool to identify its causative genes. Mutational spectra of various populations are usually different. We sought to identify causative variants in Thai patients with FSGS.

Methods

Patients aged one year or older with biopsy-proven FSGS without clinical and laboratory evidence of secondary causes were included in this study. DNA samples, pedigree and clinical information were obtained. Mutation analysis was performed by whole exome sequencing (WES) method. Patients were screened in 62 known genes formerly reported to cause FSGS. Exome data were interpreted using Variant Interpreter and the American College of Medical Genetics and Genomics (ACMG) criteria. Patients without causative mutations identified by WES will be analyzed by trio study to determine pathogenicity in variant of uncertain significance. New gene may also be discovered by trio study.

Results

WES identified the pathogenic variants in two out of 24 unrelated patients (8.3%) with biopsy-proven FSGS. A novel c.905del (p.G302Vfs*23) in exon 15 of the COL4A4 gene resulting in frameshift was detected in one patient. Mutations in COL4A4, encoded collagen type 4 alpha 4, are responsible for autosomal dominant Alport’s syndrome, revealing the fact that this patient was previously misdiagnosed as idiopathic FSGS. Another patient harbored a novel c.357+1G>A mutation in exon 3 in the ZMPSTE24 gene, which encoded zinc metallopeptidase. ZMPSTE24 mutations are found to be associated with mandibuloacral dysplasia, an autosomal recessive musculoskeletal disorder in which some patients developed FSGS. In addition to FSGS, our patient also had jaw malocclusion. Although we could identify only one mutant allele in ZMPSTE24 in the patient, it remains possible that the other mutant allele could not be detected by WES.

Conclusion

Using WES, we successfully identified disease-causing variants in only 4.2% of patients with FSGS. To date, this is the first study in Thailand for genetic approach toward diagnosis of FSGS which could provide more accurate disease management and counseling. An appropriate testing algorithm is needed for developing future Thai guideline.