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Table 1. Genome-wide association studies of inherited chronic kidney disease
Diseases Sample size Study population Main findings References
AS A family Spanish In ADAS, carriers of p.G333E and p.P1461L or p.S1492C mutations in COL4A3 [19]
have an earlier onset of disease than those of only p.G333E mutation
AS A family Japanese A synonymous p.Gly292Gly mutation in XLAS can alter the splicing donor site of [20]
the COL4A5 gene
AS 20 patients Chinese Detected 15 novel mutations and 6 known mutations [21]
AS 216 patients European Identified 47 novel mutations in AS and TBMN [22]
AS A family Chinese The intron mutation c.4127+11C>T and missense mutation c.4195A>T in COL4A4 [23]
were possible causes of ADAS
TBMN A family Chinese A novel mutation (3725G>A, G1242D) in COL4A3 resulted in TBMN [26]
pathogenesis
TBMN A family Chinese Identified a novel heterozygous splicing mutation in COL4A4 (c.1459+ 1G>A) [27]
TBMN 45 patients Korean Identified 2 potential pathogenic variants, G199R and G1606E, along with another [28]
6 novel variants
TBMN A family Cypriot Mutations in COL4A1 collagen type IV α1 chains could also cause TBMN [29]
ADPKD A family Chinese Identify a novel heterozygous frameshift mutation c.3976_3977insCT [30]
(p.F1326Sfs*21) in PKD1
ADPKD A family Chinese Reported a novel frameshift mutation, c. 12605_12632del28, in PKD1 [35]
AS:Alport syndrome; ADAS: autosomal dominant AS; XLAS: X-linked AS; TBMN: thin basement membrane nephropathy; ADPKD:
autosomal dominant polycystic kidney disease

[27]
pathogenesis within an identical family. Xu et al. identified a novel heterozygous splicing mutation in
[28]
COL4A4 (c.1459+1G>A), which might be responsible for TBMN. Baek et al. investigated the sequence of
full-length COL4A4 in 45 Korean TBMN patients and identified 2 potential pathogenic variants, G199R and
G1606E, along with another 6 novel variants. Interestingly, mutations in other genes may still contribute to
[29]
TBMN. Gale et al. performed genome-wide linkage analysis, whole-exome sequencing, and co-segregation
analyses on 20 family members and reported that mutations in COL4A1 collagen type IV α1 chains could
also cause TBMN [Table 1]. Given these findings, a combination of genetic testing and immunofluorescence
analysis appears most suitable to guarantee an exact diagnosis.

ADPKD
ADPKD is the most prevalent monogenic renal disease. It is characterized by the development of renal cysts,
which chronically impair kidney structure and function. It is estimated that approximately 50% of patients
[30]
with ADPKD eventually develop ESRD . ADPKD is reportedly associated with mutations in polycystin-
encoding genes PKD1 and PKD2, with PKD1 mutations having been reported in up to 85% of patients . In
[31]
2016, the rare third gene encoding glucosidase II alpha subunit (GANAB) at position 11q12.3, was reported
and estimated to account for 0.3% of cases [32,33] .

To date, more than 1,200 and 200 pathogenic germline mutations in PKD1 and PKD2, have been archived in
[34]
the Mayo PKD database , and the numbers are still increasing. For instance, targeted exome sequencing of
[30]
PKD1 and PKD2, allowed Sha et al. to identify a novel heterozygous frameshift mutation c.3976_3977insCT
[35]
(p.F1326Sfs*21) in PKD1. Wang et al. reported a novel frameshift mutation, c.12605_12632del28, in PKD1
in a Chinese family with ADPKD [Table 1].
Genetic testing is currently applied to assess patients with atypical radiologic presentations or a negative
family history. With decreasing costs and faster sequencing speed, its clinical use may be expanded to
indicate prognosis and guide patient management in the near future.

EMERGING GENOMIC BIOMARKERS FOR ACQUIRED CKD
Idiopathic membranous nephropathy
Idiopathic membranous nephropathy (IMN) is an immune complex-mediated disease and represents a
common cause of glomerulonephritis. Gene sequencing and GWASs have yielded major breakthroughs
regarding IMN biomarkers in recent years.