Mutations in Collagen Genes in the Context of an Isolated Population

Abstract

Genetic studies of population isolates have great potential to provide a unique insight into genetic differentiation and phenotypic expressions. Galičnik village is a population isolate located in the northwest region of the Republic of North Macedonia, established around the 10th century. Alport syndrome-linked nephropathy with a complex inheritance pattern has been described historically among individuals in the village. In order to determine the genetic basis of the nephropathies and to characterize the genetic structure of the population, 23 samples were genotyped using a custom-made next generation sequencing panel and 111 samples using population genetic markers. We compared the newly obtained population data with fifteen European population data sets. NGS analysis revealed four different mutations in three different collagen genes in twelve individuals within the Galičnik population. The genetic isolation and small effective population size of Galičnik village have resulted in a high level of genomic homogeneity, with domination of R1a-M458 and R1b-U106* haplogroups. The study explains complex autosomal in cis digenic and X-linked inheritance patterns of nephropathy in the isolated population of Galičnik and describes the first case of Alport syndrome family with three different collagen gene mutations.

A Systematic Review of Pathogenic COL4A5 Variants and Proteinuria in Women and Girls With X-linked Alport Syndrome

“…The exception was a 90-year-old woman with the hypomorphic p.Gly624Asp variant. 28 In addition, girls with proteinuria detected before age 15 years progressed to kidney failure sooner than those without proteinuria, consistent with early-onset proteinuria reflecting more severe disease. Overall kidney failure and extrarenal features were more common in women and girls with proteinuria, suggesting that proteinuria identifies those at risk of severe disease.…”

Hereditary diseases and carrier’s screening programs in genetically isolated populations

“…Из четырех вышеупомянутых мутаций три были обнаружены в одной семье. Интересно, что четыре члена семьи унаследовали только одну мутацию COL4A4 p.Gly252Asp, у одного была выявлена комбинация мутаций COL4A3 p.Pro_1103_ Ser1105del и COL4A5 p.Gly624Asp [7].…”