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Collagen (COL4A) mutations are the most frequent mutations underlying adult focal segmental glomerulosclerosis

Collagen (COL4A) mutations are the most frequent mutations underlying adult focal segmental glomerulosclerosis
Collagen (COL4A) mutations are the most frequent mutations underlying adult focal segmental glomerulosclerosis
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.
0931-0509
961-970
Gast, Christine
4126ea74-b62d-4356-84ed-572fdfb1c5e3
Pengelly, Reuben
af97c0c1-b568-415c-9f59-1823b65be76d
Lyon, Matthew
9c030a93-d30a-4fc3-831b-8b82cfeaf705
Bunyan, David J.
dd9134b9-f889-44cc-83cc-a41fc5d74d69
Seaby, Eleanor G.
a7290ab8-98ea-4093-9aa7-641d319d6064
Graham, Nikki
9b8ddc5c-19f9-400a-ba97-bb5afd7becac
Venkat-Raman, Gopalakrishnan
d7b865e1-4bb3-445b-9cdc-6b9885d452bd
Ennis, Sarah
7b57f188-9d91-4beb-b217-09856146f1e9
Gast, Christine
4126ea74-b62d-4356-84ed-572fdfb1c5e3
Pengelly, Reuben
af97c0c1-b568-415c-9f59-1823b65be76d
Lyon, Matthew
9c030a93-d30a-4fc3-831b-8b82cfeaf705
Bunyan, David J.
dd9134b9-f889-44cc-83cc-a41fc5d74d69
Seaby, Eleanor G.
a7290ab8-98ea-4093-9aa7-641d319d6064
Graham, Nikki
9b8ddc5c-19f9-400a-ba97-bb5afd7becac
Venkat-Raman, Gopalakrishnan
d7b865e1-4bb3-445b-9cdc-6b9885d452bd
Ennis, Sarah
7b57f188-9d91-4beb-b217-09856146f1e9

Gast, Christine, Pengelly, Reuben, Lyon, Matthew, Bunyan, David J., Seaby, Eleanor G., Graham, Nikki, Venkat-Raman, Gopalakrishnan and Ennis, Sarah (2016) Collagen (COL4A) mutations are the most frequent mutations underlying adult focal segmental glomerulosclerosis. Nephrology, Dialysis, Transplantation, 31 (6), 961-970. (doi:10.1093/ndt/gfv325).

Record type: Article

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.

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More information

Accepted/In Press date: 12 August 2015
e-pub ahead of print date: 7 September 2015
Published date: June 2016
Organisations: Faculty of Medicine, Human Development & Health

Identifiers

Local EPrints ID: 381632
URI: http://eprints.soton.ac.uk/id/eprint/381632
ISSN: 0931-0509
PURE UUID: 47766ff7-8be3-421f-9a70-e0d8f3c699f7
ORCID for Reuben Pengelly: ORCID iD orcid.org/0000-0001-7022-645X
ORCID for Sarah Ennis: ORCID iD orcid.org/0000-0003-2648-0869

Catalogue record

Date deposited: 24 Sep 2015 09:25
Last modified: 18 Feb 2021 17:22

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