Christine Gast1, Reuben J Pengelly2, Matthew Lyon3, David J Bunyan3, Eleanor G Seaby2, Nikki Graham2, Gopalakrishnan Venkat-Raman4, Sarah Ennis2. 1. Wessex Kidney Centre, Portsmouth Hospitals NHS Trust, Portsmouth, UK Human Genetics and Genomic Medicine, Faculty of Medicine, University of Southampton, Southampton, UK. 2. Human Genetics and Genomic Medicine, Faculty of Medicine, University of Southampton, Southampton, UK. 3. Wessex Regional Genetics Laboratory, Salisbury District Hospital, Salisbury, UK. 4. Wessex Kidney Centre, Portsmouth Hospitals NHS Trust, Portsmouth, UK.
Abstract
BACKGROUND: 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). METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.
BACKGROUND: 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). METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.
Authors: Sophia Cameron-Christie; Charles J Wolock; Emily Groopman; Slavé Petrovski; Sitharthan Kamalakaran; Gundula Povysil; Dimitrios Vitsios; Mengqi Zhang; Jan Fleckner; Ruth E March; Sahar Gelfman; Maddalena Marasa; Yifu Li; Simone Sanna-Cherchi; Krzysztof Kiryluk; Andrew S Allen; Bengt C Fellström; Carolina Haefliger; Adam Platt; David B Goldstein; Ali G Gharavi Journal: J Am Soc Nephrol Date: 2019-05-13 Impact factor: 10.121
Authors: Yeawon Kim; Sun-Ji Park; Scott R Manson; Carlos Af Molina; Kendrah Kidd; Heather Thiessen-Philbrook; Rebecca J Perry; Helen Liapis; Stanislav Kmoch; Chirag R Parikh; Anthony J Bleyer; Ying Maggie Chen Journal: JCI Insight Date: 2017-12-07