Fabry disease with atypical phenotype identified by massively parallel sequencing in early-onset kidney failure

Amber de Haan; Chantal F Morel; Mark Eijgelsheim; Margriet F C de Jong; Jan Broekroelofs; Liffert Vogt; Nine V A M Knoers; Martin H de Borst

doi:10.1093/ckj/sfac269

Fabry disease with atypical phenotype identified by massively parallel sequencing in early-onset kidney failure

Clin Kidney J. 2022 Dec 15;16(4):722-726. doi: 10.1093/ckj/sfac269. eCollection 2023 Apr.

Authors

Amber de Haan¹, Chantal F Morel², Mark Eijgelsheim¹, Margriet F C de Jong¹, Jan Broekroelofs³, Liffert Vogt⁴, Nine V A M Knoers⁵, Martin H de Borst¹

Affiliations

¹ Department of Internal Medicine, Division of Nephrology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
² Fred A. Litwin Centre in Genetic Medicine, Department of Medicine, University Health Network and Mount Sinai Hospital, University of Toronto, Toronto, ON, Canada.
³ Department of Internal Medicine, Medical Center Leeuwarden, Leeuwarden, The Netherlands.
⁴ Department of Internal Medicine, Section Nephrology, Amsterdam Cardiovascular Sciences, Amsterdam University Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
⁵ Department of Genetics, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.

Abstract

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.

Keywords: Fabry disease; GLA gene; chronic kidney disease; kidney failure; massively parallel sequencing.