Abstract: SA-PO604
Clinical and Molecular Analysis of 17 Families with a Heterozygous Mutation in COL4A3 or COL4A4
Session Information
- Noncystic Mendelian Diseases
November 04, 2017 | Location: Hall H, Morial Convention Center
Abstract Time: 10:00 AM - 10:00 AM
Category: Genetic Diseases of the Kidney
- 802 Non-Cystic Mendelian Diseases
Authors
- Rood, Ilse M., Radboudumc, Nijmegen, Netherlands
- Groen in 't Woud, Sander, Radboudumc, Nijmegen, Netherlands
- Schoots, Jeroen, Radboudumc, Nijmegen, Netherlands
- Wetzels, Jack F., Radboudumc, Nijmegen, Netherlands
- Lugtenberg, Dorien, Radboudumc, Nijmegen, Netherlands
- Deegens, Jeroen, Radboudumc, Nijmegen, Netherlands
- Bongers, Ernie M.H.F., Radboudumc, Nijmegen, Netherlands
Background
Heterozygous mutations in COL4A3 and COL4A4 (COL4A3/4) have been described as a cause of Alport syndrome and benign familial hematuria. Recently, these mutations were associated with focal segmental glomerulosclerosis (FSGS) and renal function deterioration as well. The aims of this study are 1) further delineation of the phenotypic spectrum of heterozygous COL4A3/4 variants, and 2) to investigate whether variants in NPHS2 (R229Q/ R138Q) and NEPH3 (V353M) modify the phenotypic expression of COL4A3/4 mutations.
Methods
Patients with a heterozygous mutation in COL4A3/4, detected by diagnostic exome sequencing (ES) using a renal gene panel between 2013 and 2016, were included.
Results
Of 72 patients analyzed because of a familial glomerular disease, a heterozygous mutation in COL4A3/4 was found in 17 (24%). All patients had microscopic hematuria at clinical presentation and 14 had (micro)albuminuria, including two patients within nephrotic range (3,7 and 6gr/24h). Median age at clinical presentation was 43 years (range 4-55). Renal biopsy in ten index patients showed FSGS (n=3), TBMN (n=1) and MCN (n=1), and in one patient electron microscopy (EM) was compatible with Alport syndrome. In four patients, LM and IF was inconclusive, and EM showed segmental thinning of the GBM. No correlation was found between renal biopsy and clinical status.
Segregation analyses in 13 families revealed 24 additional patients with a heterozygous COL4A3/4 variant. At end of follow up (median age 53 years, range 13-81), 14/41 patients (35%) had renal function deterioration (MDRD4 < 60ml/min), of whom six had ESRD (mean age at ESRD 51 years). Hearing loss and visual impairment was present in 1/41 patients.
The R229Q / R138Q variants in NPHS2 were not detected. Variant V353M in NEPH3 was found homozygous in one patient and heterozygous in another patient.
Conclusion
This study broadens the phenotypic spectrum: 1) clinical presentation and course of disease is highly variable and not limited to benign hematuria, 2) renal pathology is not limited to FSGS or TBMN. The heterogeneity could not fully be explained by modifier variants in NPHS2 and NEPH3.