Identification of 27 Novel Variants in Genes , and in Lithuanian Families With Alport Syndrome.

Introduction: Alport syndrome (AS) is an inherited disorder characterized by hematuria, proteinuria, and kidney function impairment, and frequently associated with extrarenal manifestations. Pathogenic variants in usually cause X-linked Alport syndrome (XLAS), whereas those in the or genes are associated with autosomal dominant (AD) or recessive (AR) inheritance. To date, more than 3000 different disease-causing variants in , and have been identified. The aim of this study was to evaluate the clinical and genetic spectrum of individuals with novel, pathogenic or likely pathogenic variants in the genes in a previously unstudied cohort.

Methods: In this study molecular analysis by next generation sequencing (NGS) was performed on individuals from a Lithuanian cohort, with suspected AS. The presence of AS was assessed by reviewing clinical evidence of hematuria, proteinuria, chronic kidney disease (CKD), kidney failure (KF), a family history of AS or persistent hematuria, and specific histological lesions in the kidney biopsy such as thinning or lamellation of the glomerular basement membrane (GBM). Clinical, genetic, laboratory, and pathology data were reviewed. The novelty of the variants was confirmed in the genetic variant databases (Centogene, Franklin, ClinVar, Varsome, InterVar). Only undescribed variants were included in this study.

Results: Molecular testing of 171 suspected individuals led to the detection of 99 individuals with 44 disease causing variants including 27, previously undescribed changes, with the frequency of 9/27 (33,3%) in genes and equally. Three individuals were determined as having digenic AS causing variants: one in and , two in and . The most prevalent alterations in genes were missense variants ( = 19), while splice site, frameshift, unknown variant and stop codon changes were detected more in genes and and accounted for 3, 3, 1 and 1 of all novel variants, respectively.

Conclusion: Genotype-phenotype correlation analysis suggested that some variants demonstrated intra-familial phenotypic variability. These novel variants represented more than half of all the variants found in a cohort of 171 individuals from 109 unrelated families who underwent testing. Our study expands the knowledge of the genetic and phenotypic spectrum for AS.