Exome analysis resolves differential diagnosis of familial kidney disease and uncovers a potential confounding variant.
A girl aged 6 presented with haematuria and her sister (aged 5) presented with haematuria and proteinuria. Family history showed multiple individuals suffering from end stage renal failure from the paternal side of the pedigree. Following kidney biopsy in the father and paternal grandmother, the pathological diagnosis was of focal segmental glomerulosclerosis (FSGS). Exome sequencing was undertaken in the proband's sister and grandmother. Genetic variants shared by both affected individuals were interrogated to identify the genetic cause of disease. Candidate variants were then sequenced in all the family members to determine segregation with the disease. A mutation of COL4A5 known to cause Alport syndrome segregated with disease from the paternal side of the pedigree and a variant in NPHS1 was present in both paediatric cases and inherited from their mother. This study highlights the advantages of exome sequencing over single gene testing; disease presentation can be heterogeneous with several genes representing plausible candidates; candidate gene(s) may be unavailable as a diagnostic test; consecutive, single gene testing typically concludes once a single causal mutation is identified. In this family, we were able to confirm a diagnosis of Alport syndrome, which will facilitate testing in other family members.
Genetic Epidemiology and Genomic Informatics Group, Faculty of Medicine, University of Southampton, Southampton, UK.
Jane
J
Gibson
Wessex Regional Paediatric Nephro-Urology Service, Southampton Children's Hospital, Southampton, UK.
Rodney D
RD
Gilbert
Wessex Regional Genetics Laboratory, Salisbury District Hospital, Salisbury, UK.
David J
DJ
Bunyan
Biomedical Imaging Unit, Southampton General Hospital, Tremona Road, Southampton, UK.
Elizabeth M
EM
Angus
Department of Histopathology, Southampton General Hospital, Tremona Road, Southampton, UK.
Darren J
DJ
Fowler
Genetic Epidemiology and Genomic Informatics Group, Faculty of Medicine, University of Southampton, Southampton, UK.
Sarah
S
Ennis
D000328:Adult; D001706:Biopsy; D002648:Child; D002675:Child, Preschool; D024141:Collagen Type IV / Q000235:genetics; D003937:Diagnosis, Differential; D059472:Exome; D005260:Female; D005923:Glomerulosclerosis, Focal Segmental / Q000175:diagnosis* / Q000235:genetics*; D006801:Humans; D007668:Kidney / Q000473:pathology; D008297:Male; D008565:Membrane Proteins / Q000235:genetics; D008875:Middle Aged; D009154:Mutation; D009394:Nephritis, Hereditary / Q000175:diagnosis / Q000235:genetics; D010375:Pedigree; D017422:Sequence Analysis, DNA
C478159:COL4A5 protein, human; D024141:Collagen Type IV; D008565:Membrane Proteins; C113267:nephrin