Genetic, Clinical, and Pathologic Backgrounds of Patients with Autosomal Dominant Alport Syndrome

Abstract

Background and objectives: Alport syndrome comprises a group of inherited heterogeneous disorders involving CKD, hearing loss, and ocular abnormalities. Autosomal dominant Alport syndrome caused by heterozygous mutations in collagen 4A3 and/or collagen 4A4 accounts for <5% of patients. However, the clinical, genetic, and pathologic backgrounds of patients with autosomal dominant Alport syndrome remain unclear.

Design, setting, participants, & measurements: We conducted a retrospective analysis of 25 patients with genetically proven autosomal dominant Alport syndrome and their family members (a total of 72 patients) from 16 unrelated families. Patients with suspected Alport syndrome after pathologic examination who were referred from anywhere in Japan for genetic analysis from 2006 to 2015 were included in this study. Clinical, laboratory, and pathologic data were collected from medical records at the point of registration for genetic diagnosis. Genetic analysis was performed by targeted resequencing of 27 podocyte-related genes, including Alport-related collagen genes, to make a diagnosis of autosomal dominant Alport syndrome and identify modifier genes or double mutations. Clinical data were obtained from medical records.

Results: The median renal survival time was 70 years, and the median age at first detection of proteinuria was 17 years old. There was one patient with hearing loss and one patient with ocular lesion. Among 16 patients who underwent kidney biopsy, three showed FSGS, and seven showed thinning without lamellation of the glomerular basement membrane. Five of 13 detected mutations were reported to be causative mutations for autosomal recessive Alport syndrome in previous studies. Two families possessed double mutations in both collagen 4A3 and collagen 4A4, but no modifier genes were detected among the other podocyte-related genes.

Conclusions: The renal phenotype of autosomal dominant Alport syndrome was much milder than that of autosomal recessive Alport syndrome or X-linked Alport syndrome in men. It may, thus, be difficult to make an accurate diagnosis of autosomal dominant Alport syndrome on the basis of clinical or pathologic findings. No modifier genes were identified among the known podocyte-related genes.

Keywords: Alport syndrome; Autosomal dominant; COL4A3; COL4A4; Glomerular Basement Membrane; Hearing Loss; Humans; Japan; Phenotype; Renal Insufficiency, Chronic; kidney; proteinuria.

Figure 1.

Probability of each clinical sign in autosomal dominant Alport syndrome cases. (A) Probability of developing proteinuria in 24 patients. (B) Probability of developing ESRD in 72 patients. (C) Probability of developing ESRD according to the type of mutation (38 missense, 25 nonmissense, and nine double mutations). The median ages for developing proteinuria and ESRD were 17 and 70 years old, respectively. Differences between types of mutation were not significant (P=0.18).

Figure 2.

Haplotype analysis of two families harboring p.Gly1406Glu in collagen 4A3 (COL4A3) and p.Gly957Arg in COL4A4 mutations. Haplotypes of (A) family 122 and (B) family 140. The haplotype from D2S163 to D2S362 (gray with black frame), spanning 13.4 Mb, was conserved in both families. Squares indicate men, and circles indicate women. lack symbols indicate affected individuals, oblique bars indicate deceased individuals, roman numerals represent generations, and numbers identify family members.