Potential Founder Variants in COL4A4 Identified in Bukharian Jews Linked to Autosomal Dominant and Autosomal Recessive Alport Syndrome

Michal Levy*, Lily Bazak, Noa Lev-El, Rotem Greenberg, Nesia Kropach, Lina Basel-Salmon, Idit Maya

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

Background: Alport syndrome is a hereditary disorder caused by pathogenic variants in the COL4A gene, which can be inherited in an autosomal recessive, dominant, or X-linked pattern. In the Bukharian Jewish population, no founder pathogenic variant has been reported in COL4A4. Methods: The cohort included 38 patients from 22 Bukharian Jewish families with suspected Alport syndrome who were referred the nephrogenetics clinic between 2012 and 2022. The study collected demographic, clinical, and genetic data from electronic medical records, which were used to evaluate the molecular basis of the disease using Sanger sequencing, and next-generation sequencing. Results: Molecular diagnosis was confirmed in 20/38 patients, with each patient having at least one of the three disease-causing COL4A4 variants detected: c.338G<A (p.Gly113Asp), c.3022G>A (p.Gly1008Arg), and c.871-6T>C. In addition, two patients were obligate carriers. Overall, there were 17 heterozygotes, 2 compound heterozygotes, and 3 homozygotes. Each variant was detected in more than one unrelated family. All patients had hematuria with/without proteinuria at referral, and the youngest patient with proteinuria (age 5 years) was homozygous for the c.338G>A variant. End-stage renal disease was diagnosed in two patients at the age of 38 years, a compound heterozygote for c.338G>A and c.871-6T>C. Hearing deterioration was detected in three patients, the youngest aged 40 years, all of whom were heterozygous for c.338G>A. Conclusion: This study unveils three novel disease-causing variants, c.3022G>A, c.871-6T>C, and c.338G>A, in the COL4A4 gene that are recurrent among Jews of Bukharian ancestry, and cause Alport syndrome in both dominant and recessive autosomal inheritance patterns.

Original languageEnglish
Article number1854
JournalGenes
Volume14
Issue number10
DOIs
StatePublished - Oct 2023

Keywords

  • Alport syndrome
  • Alport syndrome
  • Bukharian Jewish population
  • Bukharian Jews
  • COL4A4
  • COL4A4 gene
  • Molecular diagnosis
  • hematuria
  • proteinuria
  • thin basement membrane disease

Fingerprint

Dive into the research topics of 'Potential Founder Variants in COL4A4 Identified in Bukharian Jews Linked to Autosomal Dominant and Autosomal Recessive Alport Syndrome'. Together they form a unique fingerprint.

Cite this