An Exome Sequencing Study of 10 Families with IgA Nephropathy

Abstract

<b><i>Background:</i></b> Immunoglobulin A nephropathy (IgAN) is a heterogeneous disorder with a strong genetic component. The advent of whole exome sequencing (WES) has accelerated the discovery of genetic risk factors underlying familial disorders. <b><i>Objectives:</i></b> We set out to test whether damaging variants in known kidney disease genes explain a proportion of IgAN cases recruited in Ireland. <b><i>Methods:</i></b> We performed WES in 10 Irish families with multiple affected members having kidney disease where at least one member had biopsy confirmed IgAN. Candidate variants were identified based on being shared between affected family members, minor allele frequency, function and predicted pathogenicity. Pathogenicity of variants was determined according to American College of Medical Genetics and Genomics guidelines. <b><i>Results:</i></b> We detected candidate variants in 3 of 10 families. We identified a likely pathogenic variant in <i>COL4A5</i> in one family and a variant of unknown significance (VUS) in <i>COL4A3</i> in another. Variants in <i>COL4A5</i> and <i>COL4A3</i> are known to cause Alport syndrome. In the third family, we identified a VUS in <i>LMX1B</i>, a gene associated with Nail-patella syndrome. <b><i>Conclusions:</i></b> We identified a number of cases of familial IgAN where the families harbored variants in known kidney disease-related genes indicating that potentially a number of cases of familial IgAN are mistaken for other familial kidney disorders. However, the majority of families studied did not carry a candidate variant in a known kidney disease causing gene indicating that there may be >1 underlying genetic mechanism present in these families.

The utility of a genetic kidney disease clinic employing a broad range of genomic testing platforms: experience of the Irish Kidney Gene Project

“…In this prospective study, we describe our overall experience of the IKGP over the 7-year period from 2014 to 2020 and the clinical impact of GKDC on patients, including some patient subsets that have been previously described [11,[19][20][21][22][23][24].…”

Case Report: A Pathogenic Missense Variant of WT1 Cosegregates With Proteinuria in a Six-Generation Chinese Family With IgA Nephropathy

“…Owing to the high and variable prevalence of genetic factors in different races and the familial aggregation of IgAN, their role in IgAN is widely accepted. To date, several genomewide association studies in large sporadic IgAN populations have identified different genetic loci for IgAN susceptibility (10,12). Whole-exome sequencing has proven to be a powerful tool for the identification of pathogenic mutations in familial diseases, especially Mendelian diseases.…”

“…Genetic testing also revealed that the proband, her younger brother, and his mother, carried another likely benign variant in the WT1 gene (NM_024426.6: exon10: c.1433-10G>A), which cosegregated with the disease phenotype. As pathogenic variants of type IV collagen genes (COL4A3/A4/A5) have been recently reported to be causal factors for familial IgAN (10,11), we checked for variants in these genes in the family but detected no pathogenic or likely pathogenic variant. Finally, all above mentioned three variants were verified by Sanger sequencing (Figure 3) and the primers used for sequencing were listed (Table S1).…”

Tale of two nephropathies; co-occurring Alport syndrome and IgA nephropathy, a case report

“…This region includes the two adjacent genes COL4A3 and COL4A4 (2q36.3) which can mutate to cause Alport syndrome [ 11 ]. Additionally, a likely pathologic variant of COL4A5 (Xq22.3) was detected in one family with FIgAN [ 7 ]. Mutations in this gene are the most common cause of Alport Syndrome [ 3 , 4 ].…”