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.
['Stapleton|Caragh P|CP|', 'Kennedy|Claire|C|', 'Fennelly|Neil K|NK|', 'Murray|Susan L|SL|', 'Connaughton|Dervla M|DM|', 'Dorman|Anthony M|AM|', 'Doyle|Brendan|B|', 'Cavalleri|Gianpiero L|GL|', 'Conlon|Peter J|PJ|']
D000328:Adult D001324:Autoantigens D024141:Collagen Type IV D003430:Cross-Sectional Studies D005260:Female D005922:Glomerulonephritis, IGA D006801:Humans D060850:LIM-Homeodomain Proteins D008297:Male D008875:Middle Aged D014157:Transcription Factors D000073359:Whole Exome Sequencing
Exome sequencing Immunoglobulin A nephropathy Genetics Genetic diseases Glomerular nephropathy