An exome sequencing study of 10 families with IgA nephropathy
Background: 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.
Objectives: We set out to test whether damaging variants in known kidney disease genes explain a proportion of IgAN cases recruited in Ireland.
Methods: 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.
Results: We detected candidate variants in 3 of 10 families. We identified a likely pathogenic variant in COL4A5 in one family and a variant of unknown significance (VUS) in COL4A3 in another. Variants in COL4A5 and COL4A3 are known to cause Alport syndrome. In the third family, we identified a VUS in LMX1B, a gene associated with Nail-patella syndrome.
Conclusions: 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.
Punchestown Kidney Research Fund
Irish Research Council
CommentsThis is the accepted manuscript version of an article published by S. Karger AG in Stapleton CP, Kennedy C, Fennelly NK, Murray SL, Connaughton DM, Dorman AM, Doyle B, Cavalleri GL, Conlon PJ. An exome sequencing study of 10 families with IgA nephropathy. Nephron. 2020;144(2):72-83. and available on https://www.karger.com/Article/Abstract/503564 https://doi.org/10.1159/000503564
Published CitationStapleton CP, Kennedy C, Fennelly NK, Murray SL, Connaughton DM, Dorman AM, Doyle B, Cavalleri GL, Conlon PJ. An exome sequencing study of 10 families with IgA nephropathy. Nephron. 2020;144(2):72-83.
Publication Date19 December 2019
- Beaumont Hospital
- School of Pharmacy and Biomolecular Sciences
- Neurological and Psychiatric Disorders
PublisherS. Karger AG
- Accepted Version (Postprint)