Prevalence and phenotype associations of complement factor I mutations in geographic atrophy

Adnan H. Khan; Janice Sutton; Angela J. Cree; Samir Khandhadia; Gabriella De Salvo; John Tobin; Priya Prakash; Rashi Arora; Winfried Amoaku; Peter Charbel Issa; Robert E. MacLaren; Paul N. Bishop; Tunde Peto; Quresh Mohamed; David H. Steel; Sobha Sivaprasad; Clare Bailey; Geeta Menon; David Kavanagh; Andrew J. Lotery

doi:10.1002/humu.24242

Prevalence and phenotype associations of complement factor I mutations in geographic atrophy

Adnan H. Khan, Janice Sutton, Angela J. Cree, Samir Khandhadia, Gabriella De Salvo, John Tobin, Priya Prakash, Rashi Arora, Winfried Amoaku, Peter Charbel Issa, Robert E. MacLaren, Paul N. Bishop, Tunde Peto, Quresh Mohamed, David H. Steel, Sobha Sivaprasad, Clare Bailey, Geeta Menon, David Kavanagh^*, Andrew J. Lotery^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

11 Citations (Scopus)

17 Downloads (Pure)

Abstract

Rare variants in the complement factor I (CFI) gene, associated with low serum factor I (FI) levels, are strong risk factors for developing the advanced stages of age-related macular degeneration (AMD). No studies have been undertaken on the prevalence of disease-causing CFI mutations in patients with geographic atrophy (GA) secondary to AMD. A multicenter, cross-sectional, noninterventional study was undertaken to identify the prevalence of pathogenic rare CFI gene variants in an unselected cohort of patients with GA and low FI levels. A genotype-phenotype study was performed. Four hundred and sixty-eight patients with GA secondary to AMD were recruited to the study, and 19.4% (n = 91) demonstrated a low serum FI concentration (below 15.6 μg/ml). CFI gene sequencing on these patients resulted in the detection of rare CFI variants in 4.7% (n = 22) of recruited patients. The prevalence of CFI variants in patients with low serum FI levels and GA was 25%. Of the total patients recruited, 3.2% (n = 15) expressed a CFI variant classified as pathogenic or likely pathogenic. The presence of reticular pseudodrusen was detected in all patients with pathogenic CFI gene variants. Patients with pathogenic CFI gene variants and low serum FI levels might be suitable for FI supplementation in therapeutic trials.

Original language	English
Pages (from-to)	1139-1152
Number of pages	14
Journal	Human Mutation
Volume	42
Issue number	9
Early online date	29 Jun 2021
DOIs	https://doi.org/10.1002/humu.24242
Publication status	Published - Sept 2021

Keywords

age-related macular degeneration
complement factor I
factor I
geographic atrophy
reticular pseudodrusen

Access to Document

10.1002/humu.24242Licence: CC BY

Prevalence and phenotype associations of complement factor I mutations in geographic atrophy
Copyright 2021 The Authors. This is an open access article published under a Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution and reproduction in any medium, provided the author and source are cited.
Final published version, 2.15 MBLicence: CC BY

Cite this

Khan, A. H., Sutton, J., Cree, A. J., Khandhadia, S., De Salvo, G., Tobin, J., Prakash, P., Arora, R., Amoaku, W., Charbel Issa, P., MacLaren, R. E., Bishop, P. N., Peto, T., Mohamed, Q., Steel, D. H., Sivaprasad, S., Bailey, C., Menon, G., Kavanagh, D., & Lotery, A. J. (2021). Prevalence and phenotype associations of complement factor I mutations in geographic atrophy. Human Mutation, 42(9), 1139-1152. https://doi.org/10.1002/humu.24242

@article{36789f39cbb24c3aa2bc00896e8ce9b5,

title = "Prevalence and phenotype associations of complement factor I mutations in geographic atrophy",

abstract = "Rare variants in the complement factor I (CFI) gene, associated with low serum factor I (FI) levels, are strong risk factors for developing the advanced stages of age-related macular degeneration (AMD). No studies have been undertaken on the prevalence of disease-causing CFI mutations in patients with geographic atrophy (GA) secondary to AMD. A multicenter, cross-sectional, noninterventional study was undertaken to identify the prevalence of pathogenic rare CFI gene variants in an unselected cohort of patients with GA and low FI levels. A genotype-phenotype study was performed. Four hundred and sixty-eight patients with GA secondary to AMD were recruited to the study, and 19.4% (n = 91) demonstrated a low serum FI concentration (below 15.6 μg/ml). CFI gene sequencing on these patients resulted in the detection of rare CFI variants in 4.7% (n = 22) of recruited patients. The prevalence of CFI variants in patients with low serum FI levels and GA was 25%. Of the total patients recruited, 3.2% (n = 15) expressed a CFI variant classified as pathogenic or likely pathogenic. The presence of reticular pseudodrusen was detected in all patients with pathogenic CFI gene variants. Patients with pathogenic CFI gene variants and low serum FI levels might be suitable for FI supplementation in therapeutic trials.",

keywords = "age-related macular degeneration, complement factor I, factor I, geographic atrophy, reticular pseudodrusen",

author = "Khan, {Adnan H.} and Janice Sutton and Cree, {Angela J.} and Samir Khandhadia and {De Salvo}, Gabriella and John Tobin and Priya Prakash and Rashi Arora and Winfried Amoaku and {Charbel Issa}, Peter and MacLaren, {Robert E.} and Bishop, {Paul N.} and Tunde Peto and Quresh Mohamed and Steel, {David H.} and Sobha Sivaprasad and Clare Bailey and Geeta Menon and David Kavanagh and Lotery, {Andrew J.}",

year = "2021",

month = sep,

doi = "10.1002/humu.24242",

language = "English",

volume = "42",

pages = "1139--1152",

journal = "Human Mutation",

issn = "1059-7794",

publisher = "John Wiley & Sons Inc.",

number = "9",

}

Khan, AH, Sutton, J, Cree, AJ, Khandhadia, S, De Salvo, G, Tobin, J, Prakash, P, Arora, R, Amoaku, W, Charbel Issa, P, MacLaren, RE, Bishop, PN, Peto, T, Mohamed, Q, Steel, DH, Sivaprasad, S, Bailey, C, Menon, G, Kavanagh, D & Lotery, AJ 2021, 'Prevalence and phenotype associations of complement factor I mutations in geographic atrophy', Human Mutation, vol. 42, no. 9, pp. 1139-1152. https://doi.org/10.1002/humu.24242

TY - JOUR

T1 - Prevalence and phenotype associations of complement factor I mutations in geographic atrophy

AU - Khan, Adnan H.

AU - Sutton, Janice

AU - Cree, Angela J.

AU - Khandhadia, Samir

AU - De Salvo, Gabriella

AU - Tobin, John

AU - Prakash, Priya

AU - Arora, Rashi

AU - Amoaku, Winfried

AU - Charbel Issa, Peter

AU - MacLaren, Robert E.

AU - Bishop, Paul N.

AU - Peto, Tunde

AU - Mohamed, Quresh

AU - Steel, David H.

AU - Sivaprasad, Sobha

AU - Bailey, Clare

AU - Menon, Geeta

AU - Kavanagh, David

AU - Lotery, Andrew J.

PY - 2021/9

Y1 - 2021/9

N2 - Rare variants in the complement factor I (CFI) gene, associated with low serum factor I (FI) levels, are strong risk factors for developing the advanced stages of age-related macular degeneration (AMD). No studies have been undertaken on the prevalence of disease-causing CFI mutations in patients with geographic atrophy (GA) secondary to AMD. A multicenter, cross-sectional, noninterventional study was undertaken to identify the prevalence of pathogenic rare CFI gene variants in an unselected cohort of patients with GA and low FI levels. A genotype-phenotype study was performed. Four hundred and sixty-eight patients with GA secondary to AMD were recruited to the study, and 19.4% (n = 91) demonstrated a low serum FI concentration (below 15.6 μg/ml). CFI gene sequencing on these patients resulted in the detection of rare CFI variants in 4.7% (n = 22) of recruited patients. The prevalence of CFI variants in patients with low serum FI levels and GA was 25%. Of the total patients recruited, 3.2% (n = 15) expressed a CFI variant classified as pathogenic or likely pathogenic. The presence of reticular pseudodrusen was detected in all patients with pathogenic CFI gene variants. Patients with pathogenic CFI gene variants and low serum FI levels might be suitable for FI supplementation in therapeutic trials.

AB - Rare variants in the complement factor I (CFI) gene, associated with low serum factor I (FI) levels, are strong risk factors for developing the advanced stages of age-related macular degeneration (AMD). No studies have been undertaken on the prevalence of disease-causing CFI mutations in patients with geographic atrophy (GA) secondary to AMD. A multicenter, cross-sectional, noninterventional study was undertaken to identify the prevalence of pathogenic rare CFI gene variants in an unselected cohort of patients with GA and low FI levels. A genotype-phenotype study was performed. Four hundred and sixty-eight patients with GA secondary to AMD were recruited to the study, and 19.4% (n = 91) demonstrated a low serum FI concentration (below 15.6 μg/ml). CFI gene sequencing on these patients resulted in the detection of rare CFI variants in 4.7% (n = 22) of recruited patients. The prevalence of CFI variants in patients with low serum FI levels and GA was 25%. Of the total patients recruited, 3.2% (n = 15) expressed a CFI variant classified as pathogenic or likely pathogenic. The presence of reticular pseudodrusen was detected in all patients with pathogenic CFI gene variants. Patients with pathogenic CFI gene variants and low serum FI levels might be suitable for FI supplementation in therapeutic trials.

KW - age-related macular degeneration

KW - complement factor I

KW - factor I

KW - geographic atrophy

KW - reticular pseudodrusen

U2 - 10.1002/humu.24242

DO - 10.1002/humu.24242

M3 - Article

C2 - 34153144

SN - 1059-7794

VL - 42

SP - 1139

EP - 1152

JO - Human Mutation

JF - Human Mutation

IS - 9

ER -

Prevalence and phenotype associations of complement factor I mutations in geographic atrophy

Abstract

Keywords

Access to Document

Fingerprint

Cite this