Collagen (COL4A) mutations are the most frequent mutations underlying adult focal segmental glomerulosclerosis.
Multiple genes underlying focal segmental glomerulosclerosis (FSGS) and/or steroid-resistant nephrotic syndrome (SRNS) have been identified, with the recent inclusion of collagen IV mutations responsible for Alport disease (AD) or thin basement membrane nephropathy (TBMN). We aimed to investigate the distribution of gene mutations in adult patients with primary FSGS/SRNS by targeted next generation sequencing (NGS).



Eighty-one adults from 76 families were recruited; 24 families had a history of renal disease. A targeted NGS panel was designed and applied, covering 39 genes implicated in FSGS/SRNS including COL4A3-5.



Confirmed pathogenic mutations were found in 10 patients (6 with family history) from 9 families (diagnostic rate 12%). Probably pathogenic mutations were identified in an additional six patients (combined diagnostic rate 20%). Definitely pathogenic mutations were identified in 22% of patients with family history and 10% without. Mutations in COL4A3-5 were present in eight patients from six families, representing 56% of definitely pathogenic mutations, and establishing a diagnosis of AD in six patients and TBMN in two patients. Collagen mutations were identified in 38% of families with familial FSGS, and 3% with sporadic FSGS, with over half the mutations occurring in COL4A5. Patients with collagen mutations were younger at presentation and more likely to have family history, haematuria and glomerular basement membrane abnormalities.



We show that collagen IV mutations, including COL4A5, frequently underlie FSGS and should be considered, particularly with a positive family history. Targeted NGS improves diagnostic efficiency by investigating many candidate genes in parallel.
Wessex Kidney Centre, Portsmouth Hospitals NHS Trust, Portsmouth, UK Human Genetics and Genomic Medicine, Faculty of Medicine, University of Southampton, Southampton, UK.
Christine
C
Gast
Human Genetics and Genomic Medicine, Faculty of Medicine, University of Southampton, Southampton, UK.
Reuben J
RJ
Pengelly
Wessex Regional Genetics Laboratory, Salisbury District Hospital, Salisbury, UK.
Matthew
M
Lyon
Wessex Regional Genetics Laboratory, Salisbury District Hospital, Salisbury, UK.
David J
DJ
Bunyan
Human Genetics and Genomic Medicine, Faculty of Medicine, University of Southampton, Southampton, UK.
Eleanor G
EG
Seaby
Human Genetics and Genomic Medicine, Faculty of Medicine, University of Southampton, Southampton, UK.
Nikki
N
Graham
Wessex Kidney Centre, Portsmouth Hospitals NHS Trust, Portsmouth, UK.
Gopalakrishnan
G
Venkat-Raman
Human Genetics and Genomic Medicine, Faculty of Medicine, University of Southampton, Southampton, UK.
Sarah
S
Ennis
D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002648:Child; D002675:Child, Preschool; D024141:Collagen Type IV / Q000235:genetics* / Q000378:metabolism; D004247:DNA / Q000235:genetics*; D004252:DNA Mutational Analysis; D005260:Female; D005923:Glomerulosclerosis, Focal Segmental / Q000175:diagnosis / Q000235:genetics* / Q000378:metabolism; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D008875:Middle Aged; D009154:Mutation; D055815:Young Adult
D024141:Collagen Type IV; D004247:DNA
Alport disease; FSGS; genetic kidney disease; next generation sequencing