Identification of a Novel COL4A4 Variant in Compound-Heterozygous State in a Patient With Alport Syndrome and Histological Findings Similar to Focal Segmental Glomerulosclerosis (FSGS)

Abstract

Alport syndrome (AS) is a rare and inherited renal disorder with an autosomal recessive mode of inheritance. AS patients usually manifest with hematuria and progressive renal disorder also occasionally accompanied by hearing loss and ophthalmic disease. Germline variants in collagen type IV α-4 (COL4A4) gene lead to autosomal recessive Alport syndrome. In the present study, we investigated a Chinese family with Alport syndrome. The index patient is a 24-year-old Chinese woman who has been suffering from proteinuria. Renal biopsy and renal pathology were performed and found focal segmental glomerulosclerosis (FSGS) like lesion in the index patient. The index patient also presented with binocular edema and blurred vision. However, binocular edema dissipated gradually without any further treatment. Unlikely, the index patient was not diagnosed with hearing impairment. Index patient’s parents are phenotypically normal. Targeted next generation sequencing and Sanger sequencing was performed. A novel heterozygous single nucleotide insertion, c.4760_4761insC and a previously reported likely pathogenic variant, c.1323_1340delTGGCTTGCCTGGAGCACC in the COL4A4 gene were identified in the index patient. The novel heterozygous single nucleotide insertion (c.4760_4761insC) leads to a frameshift which eventually results in the formations of a truncated COL4A4 protein. In addition, the other heterozygous likely pathogenic variant, c.1323_1340delTGGCTTGCCTGGAGCACC, has been already identified with causing AS an autosomal recessive mode of inheritance. Sanger sequencing confirmed that these two variants were inherited in the index patient from her father and mother, respectively. These two variants were not found in 100 normal control individuals. In conclusion, our present finding emphasizes the significance of high throughput targeted next generation sequencing technology for rapid and cost-effective genetic screening which allows us easy and accurate clinical diagnosis of AS patients.

A novel heterozygous variant of the COL4A4 gene in a Chinese family with hematuria and proteinuria leads to focal segmental glomerulosclerosis and chronic kidney disease

“…According to previous studies, heterozygous COL4A3/COL4A4 mutations can lead to AS, thin basement membrane disease, segmental GBM thin, as well as FSGS (Lin et al, 2014;Lu et al, 2017;Malone et al, 2014;Storey et al, 2013;Zhu et al, 2018). Because FSGS can be a secondary risk factor to AS and thin basement membrane disease, FSGS may be a process in the development of AS and GBM related diseases caused by variants in COL4A3/COL4A4 (Zhu et al, 2018).…”

A novel frameshift mutation of COL4A5 in a Chinese family with presumed IgA nephropathy and chronic glomerulonephritis

“…The traditional Sanger sequencing method is expensive and time‐consuming for the detection of pathogenic gene mutations. Conversely, targeted exome capture sequencing has advantages in detecting pathogenic genes associated with hereditary kidney diseases owing to its low cost and high throughput 21 …”

“…Conversely, targeted exome capture sequencing has advantages in detecting pathogenic genes associated with hereditary kidney diseases owing to its low cost and high throughput. 21…”

Genetic and Biological Effects of ICAM-1 E469K Polymorphism in Diabetic Kidney Disease

“…Recently, Taillandier et al have reported that the Pro549Ala heterozygous carriers of COL1A2 have more serious phenotypes of hypophosphatasia, mainly due to the dominant-negative effects [44]. Zhu et al have identified a novel heterozygous variant, which leads to the formation of a truncated COL4A4 protein in Alport Syndrome [45]. Moreover, Serra-Juhe et al have showed that heterozygous rare variants in several candidate genes of the melanocortin pathway have strong effects in nonsyndromic severe obesity [46].…”