TY - JOUR
T1 - Fabry disease with atypical phenotype identified by massively parallel sequencing in early-onset kidney failure
AU - de Haan, Amber
AU - Morel, Chantal F.
AU - Eijgelsheim, Mark
AU - de Jong, Margriet F. C.
AU - Broekroelofs, Jan
AU - Vogt, Liffert
AU - Knoers, Nine V. A. M.
AU - de Borst, Martin H.
N1 - Funding Information: This work is co-funded by Sanofi Genzyme and the Dutch Ministry of Economic Affairs and Climate Policy by means of the PPP Allowance made available by the Top Sector Life Sciences & Health to stimulate public–private partnerships (grant number RVO/6320). None of the above funding sources or sponsors was involved in the conception, execution or analysis and interpretation of the data, and they had no role in drafting the manuscript. Publisher Copyright: © The Author(s) 2022.
PY - 2023/4/1
Y1 - 2023/4/1
N2 - Background. The cause of chronic kidney disease (CKD) remains unknown in ∼20% of patients with kidney failure. Massively parallel sequencing (MPS) can be a valuable diagnostic tool in patients with unexplained CKD, with a diagnostic yield of 12%–56%. Here, we report the use of MPS to establish a genetic diagnosis in a 24-year-old index patient who presented with hypertension, nephrotic-range proteinuria and kidney failure of unknown origin. Additionally, we describe a second family with the same mutation presenting with early-onset CKD. Results. In Family 1, MPS identified a known pathogenic variant in GLA (p.Ile319Thr), and plasma globotriaosylsphingosine and α-galactosidase A activity were compatible with the diagnosis of Fabry disease (FD). Segregation analysis identified three other family members carrying the same pathogenic variant who had mild or absent kidney phenotypes. One family member was offered enzyme therapy. While FD could not be established with certainty as the cause of kidney failure in the index patient, no alternative explanation was found. In Family 2, the index patient had severe glomerulosclerosis and a kidney biopsy compatible with FD at the age of 30 years, along with cardiac involvement and a history of acroparesthesia since childhood, in keeping with a more classical Fabry phenotype. Conclusion. These findings highlight the large phenotypic heterogeneity associated with GLA mutations in FD and underline several important implications of MPS in the work-up of patients with unexplained kidney failure.
AB - Background. The cause of chronic kidney disease (CKD) remains unknown in ∼20% of patients with kidney failure. Massively parallel sequencing (MPS) can be a valuable diagnostic tool in patients with unexplained CKD, with a diagnostic yield of 12%–56%. Here, we report the use of MPS to establish a genetic diagnosis in a 24-year-old index patient who presented with hypertension, nephrotic-range proteinuria and kidney failure of unknown origin. Additionally, we describe a second family with the same mutation presenting with early-onset CKD. Results. In Family 1, MPS identified a known pathogenic variant in GLA (p.Ile319Thr), and plasma globotriaosylsphingosine and α-galactosidase A activity were compatible with the diagnosis of Fabry disease (FD). Segregation analysis identified three other family members carrying the same pathogenic variant who had mild or absent kidney phenotypes. One family member was offered enzyme therapy. While FD could not be established with certainty as the cause of kidney failure in the index patient, no alternative explanation was found. In Family 2, the index patient had severe glomerulosclerosis and a kidney biopsy compatible with FD at the age of 30 years, along with cardiac involvement and a history of acroparesthesia since childhood, in keeping with a more classical Fabry phenotype. Conclusion. These findings highlight the large phenotypic heterogeneity associated with GLA mutations in FD and underline several important implications of MPS in the work-up of patients with unexplained kidney failure.
KW - Fabry disease
KW - GLA gene
KW - chronic kidney disease
KW - kidney failure
KW - massively parallel sequencing
UR - http://www.scopus.com/inward/record.url?scp=85169886101&partnerID=8YFLogxK
U2 - https://doi.org/10.1093/ckj/sfac269
DO - https://doi.org/10.1093/ckj/sfac269
M3 - Article
C2 - 37007699
SN - 2048-8505
VL - 16
SP - 722
EP - 726
JO - Clinical Kidney Journal
JF - Clinical Kidney Journal
IS - 4
ER -