ESPN 51th Annual Meeting

ESPN 2018


 
PHENOTYPIC VARIABILITY IN X-LINKED ALPORT SYNDROME DUE TO THE HYPOMORPHIC VARIANT P.GLY624ASP IN COL4A5
Robin Satanovskij 1 Eva Pauline Macheroux 2 Roman Günthner 1 Matthias Braunisch 1 Michaela Stippel 2 Oliver Gross 3 Mato Nagel 4 Lutz Renders 1 Julia Hoefele 2

1- Department of Nephrology, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany
2- Institute of Human Genetics, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany
3- Clinic of Nephrology and Rheumatology, University Medical Center Goettingen, University of Goettingen, Goettingen, Germany
4- Center for Nephrology and Metabolic Medicine, Weisswasser, Germany
 
Introduction:

The Alport syndrome (AS) is characterized by hematuria and proteinuria leading to end stage renal disease (ESRD) until the age of 40 years in about 90% of patients. Extrarenal symptoms may include hearing loss and ocular changes. Approximately 85% of the patients show an X-linked inheritance (variants in COL4A5). The variant c.1871G>A, p.Gly624Asp in COL4A5 is described in the literature as hypomorphic variant leading to thin basement membrane nephropathy. ESRD was only seen in single patients at a median age of 50 years. Extrarenal manifestations are only described in two patients.

Material and methods:

We report a family with X-linked AS. Since the age of 27 years the index patient has been suffering from microhematuria, since the age of 42 years from proteinuria. Her daughter has been showing microhematuria since the age of 6 years, her son since the age of 14 months. Additionally, the son has been suffering from proteinuria since the age of 4 years. Maternal female relatives show microhematuria (and proteinuria). The index patient’s father and further paternal male relatives required dialysis between 48 and 70 years of age, the paternal grandmother has proteinuria. Extrarenal manifestations could not be seen in this family. The index patient and her closed relatives have been examined by Sanger sequencing and Multiplex Ligation-dependent Probe Amplification.

Results:

All examined family members carry the variant c.1871G>A, p.Gly624Asp. The index patient was homozygous for this variant, the other family members heterozygous respectively hemizygous.

Conclusions:

The variant p.Gly624Asp in COL4A5 was considered as mild variant requiring dialysis in less than 10% and only at a median age of 50 years. In this family affected male patients show a lower median age of ESRD of 48 years. The increased appearance of ESRD in this family in comparison to other patients could possibly be explained by genetic modifiers, which will be now examined.