Page 124 - Read Online

Cao et al. J Transl Genet Genom 2019;3:4. I https://doi.org/10.20517/jtgg.2018.16 Page 3 of 12

be diagnosed via mutation analysis, and their clinical manifestations are similar among patients, although
[14]
variants in other genes may influence or modify disease course and severity .

For multifactorial kidney diseases with complex causal relationships and poorly understood mechanisms
of action, such as diabetic nephropathy (DN) and hypertensive nephrosclerosis, disease course and the rate
of progression to ESRD vary substantially among patients. Over the past decade, rapid advances in genetics
have raised expectations for a switch from traditional medical diagnosis and treatment towards personalized
medicine. Numerous genetic variants have been implicated in studies of CKD. Herein, we review the current
genomic biomarkers in inherited and acquired CKD.

EMERGING GENOMIC BIOMARKERS FOR INHERITED CKD
AS
AS is an inherited disease caused by mutations affecting collagen type IV (specifically, COL4A3 and COL4A4
on chromosome 2 and COL4A5 on chromosome X) in the glomerular basement membrane (GBM). It is
characterized by kidney damage, hearing loss, and eye abnormalities [15,16] . Almost all patients experience
hematuria and proteinuria at symptom onset. AS occurs in approximately 1 in 50,000 neonates and men
[17]
are more likely to be symptomatic than women . Moreover, it accounts for > 1% of patients receiving renal
[15]
replacement therapy . Genetic testing has generally replaced rather invasive procedures such as kidney or
[18]
skin biopsy, and can yield an accurate diagnosis in approximately 95% of AS patients .
In 80%-85% of cases, AS is inherited in an X-linked manner (XLAS) and is caused by mutations in COL4A5.
Additional, inheritance patterns include autosomal recessive AS (ARAS) manner, or, less commonly,
[19]
autosomal dominant AS (ADAS) owing to mutations in COL4A3 or COL4A4 .
[19]
Cervera-Acedo et al. assessed a Spanish family with variable phenotypes of ADAS via clinical, histological,
and genetic analyses. They reported that carriers of p.G333E and p.P1461L or p.S1492C mutations in COL4A3
[20]
presented an earlier onset of disease than individuals, who carried only the p.G333E mutation. Fu et al.
reported that a synonymous p.Gly292Gly mutation in XLAS could alter the splicing donor site of COL4A5.
[21]
Targeted capture and next-generation sequencing allowed Liu et al. to detect 15 novel mutations, 6
known mutations, as well as 2 novel fragment deletions in the genomes of 20 patients with AS from unrelated
[22]
Chinese families. Weber et al. identified 47 novel mutations in AS and thin basement membrane nephropathy
[23]
(TBMN) patients through an assessment of 216 individuals. Guo et al. reported that the intron mutation
c.4127+11C>T and missense mutation c.4195A>T in COL4A4 were possible causes of ADAS [Table 1].

These results broadened our understanding of mutations in 3 different collagen type IV genes, which have
important implications as genomic biomarkers in diagnosis, prognosis, and genetic counseling. Further
studies are expected to elucidate the correlations between these novel identified genetic mutations and the
resulting phenotypes.

TBMN
Collagen type IV-related nephropathies include another disorder closely resembling AS, referred to as TBMN.
Also called benign familial hematuria, TBMN is characterized by persistent hematuria, minimal proteinuria,
normal renal function, and a uniformly thinner GBM [24,25] . Despite the fact that TBMN does not require
treatment, its exact diagnosis is still important because its clinical findings overlap with those of early AS.

In contrast to AS, TBMN is usually caused by heterozygous mutations of COL4A3 or COL4A4 with the
carrier having ARAS. Several novel mutations of these two genes have been reported as pathogenic in
[26]
recent years. Hou et al. reported that a novel mutation (3725G>A, G1242D) in COL4A3 resulted in TBMN