Introduction: Alport syndrome (AS) is an inherited, rare, progressive kidney disease that affects the eye and ear physiology. Pathogenic variants of COL4A5 account for 85% of all cases, while COL4A3 and COL4A4 account for the remaining 15%. Methods: Targeted next-generation sequencing of the COL4A3, COL4A4, and COL4A5 genes was performed in 125 Turkish patients with AS. The patients were compared to 45 controls and open-access population data. Results: The incidence of AS variants in patients was found as 21.6%. 27 variants were identified as pathogenic/likely pathogenic, 28 as variant of uncertain significance, and 52 as benign/likely benign. We also found 31 novel variants (14 in COL4A3, 6 in COL4A4, and 11 in COL4A5) of which 27 were classified as pathogenic/likely pathogenic. Pathogenic/likely Pathogenic variants were most commonly found in the COL4A5 gene, consistent with the literature. This study contributed novel variants associated with AS to the literature. Conclusion: Genetic testing is a crucial part for the diagnosis and management of AS. Studies on the genetic etiology of AS are limited for the Turkish population. We believe that this study will contribute to the literature and the clinical decision-making process of patients with AS and emphasize the importance of genetic counseling.

1.
Altuğ
K
,
Elçin
B
,
Cinleti
T
,
Yildiz
G
,
Bayram
MT
.
Initial next-generation sequencing NGS results of Alport syndrome
.
J Basic Clin Health Sci
.
2019
;
3
:
165
9
.
2.
Arı
ME
,
Özlü
SG
,
Demircin
G
,
Yılmaz
AC
,
Aydog
Ö
.
Evaluation of etiological causes of hematuria in children
.
Türkiye Çocuk Hastalıkları Dergisi
.
2020
;
14
:
480
7
.
3.
Artuso
R
,
Fallerini
C
,
Dosa
L
,
Scionti
F
,
Clementi
M
,
Garosi
G
.
Advances in Alport syndrome diagnosis using next-generation sequencing
.
Eur J Hum Genet
.
2012
;
20
(
1
):
50
7
.
4.
Bekheirnia
MR
,
Reed
B
,
Gregory
MC
,
McFann
K
,
Shamshirsaz
AA
,
Masoumi
A
.
Genotype-phenotype correlation in X-linked Alport syndrome
.
J Am Soc Nephrol
.
2010
;
21
(
5
):
876
83
.
5.
Boeckhaus
J
,
Hoefele
J
,
Riedhammer
KM
,
Tonshoff
B
,
Ehren
R
,
Pape
L
.
Precise variant interpretation, phenotype ascertainment, and genotype-phenotype correlation of children in the EARLY PRO-TECT Alport trial
.
Clin Genet
.
2021
;
99
(
1
):
143
56
.
6.
Cerkauskaite
A
,
Savige
J
,
Janonyte
K
,
Jeremiciute
I
,
Miglinas
M
,
Kazenaite
E
.
Identification of 27 novel variants in genes COL4A3, COL4A4, and COL4A5 in Lithuanian families with Alport syndrome
.
Front Med
.
2022
;
9
:
859521
.
7.
Sürmeli̇ Döven
S
,
Teke
S
,
Gürses
İ
,
Coşkun Yilmaz
B
,
Ballı
E
,
Deli̇baş
A
.
Alport Sendromu tanısında böbrek biyopsisi ve elektron mikroskobinin önemi
.
Mersin Universitesi Saglik Bilimleri Dergisi
.
2018
;
11
(
1
):
32
7
.
8.
Fallerini
C
,
Baldassarri
M
,
Trevisson
E
,
Morbidoni
V
,
La Manna
A
,
Lazzarin
R
.
Alport syndrome: impact of digenic inheritance in patients management
.
Clin Genet
.
2017
;
92
(
1
):
34
44
.
9.
Furlano
M
,
Martinez
V
,
Pybus
M
,
Arce
Y
,
Crespi
J
,
Venegas
MDP
.
Clinical and genetic features of autosomal dominant Alport syndrome: a cohort study
.
Am J Kidney Dis
.
2021
;
78
(
4
):
560
70.e1
.
10.
Gibson
J
,
Fieldhouse
R
,
Chan
MMY
,
Sadeghi-Alavijeh
O
,
Burnett
L
,
Izzi
V
.
Prevalence estimates of predicted pathogenic col4a3-col4a5 variants in a population sequencing database and their implications for Alport syndrome
.
J Am Soc Nephrol
.
2021
;
32
(
9
):
2273
90
.
11.
Gong
WY
,
Liu
FN
,
Yin
LH
,
Zhang
J
.
Novel mutations of COL4A5 identified in Chinese families with X-linked Alport syndrome and literature review
.
BioMed Res Int
.
2021
;
2021
:
6664973
.
12.
Gross
O
,
Netzer
KO
,
Lambrecht
R
,
Seibold
S
,
Weber
M
.
Meta-analysis of genotype-phenotype correlation in X-linked Alport syndrome: impact on clinical counselling
.
Nephrol Dial Transplant
.
2002
;
17
(
7
):
1218
27
.
13.
Gubler
MC
.
Inherited diseases of the glomerular basement membrane
.
Nat Clin Pract Nephrol
.
2008
;
4
(
1
):
24
37
.
14.
Han
KH
,
Park
JE
,
Ki
CS
.
De novo mutations in COL4A5 identified by whole exome sequencing in 2 girls with Alport syndrome in Korea
.
Korean J Pediatr
.
2019
;
62
(
5
):
193
7
.
15.
Heath
KE
,
Campos-Barros
A
,
Toren
A
,
Rozenfeld-Granot
G
,
Carlsson
LE
,
Savige
J
.
Nonmuscle myosin heavy chain IIA mutations define a spectrum of autosomal dominant macrothrombocytopenias: may-Hegglin anomaly and Fechtner, Sebastian, Epstein, and Alport-like syndromes
.
Am J Hum Genet
.
2001
;
69
(
5
):
1033
45
.
16.
Hudson
BG
,
Tryggvason
K
,
Sundaramoorthy
M
,
Neilson
EG
.
Alport’s syndrome, Goodpasture’s syndrome, and type IV collagen
.
N Engl J Med
.
2003
;
348
(
25
):
2543
56
.
17.
Imafuku
A
,
Nozu
K
,
Sawa
N
,
Hasegawa
E
,
Hiramatsu
R
,
Kawada
M
.
Autosomal dominant form of type IV collagen nephropathy exists among patients with hereditary nephritis difficult to diagnose clinicopathologically
.
Nephrology
.
2018
;
23
(
10
):
940
7
.
18.
Jais
JP
,
Knebelmann
B
,
Giatras
I
,
De Marchi
M
,
Rizzoni
G
,
Renieri
A
.
X-linked Alport syndrome: natural history and genotype-phenotype correlations in girls and women belonging to 195 families: a “European Community Alport Syndrome Concerted Action” study
.
J Am Soc Nephrol
.
2003
;
14
(
10
):
2603
10
.
19.
Kamiyoshi
N
,
Nozu
K
,
Fu
XJ
,
Morisada
N
,
Nozu
Y
,
Ye
MJ
.
Genetic, clinical, and pathologic backgrounds of patients with autosomal dominant Alport syndrome
.
Clin J Am Soc Nephrol
.
2016
;
11
(
8
):
1441
9
.
20.
Kars
ME
,
Başak
AN
,
Onat
OE
,
Bilguvar
K
,
Choi
J
,
Itan
Y
.
The genetic structure of the Turkish population reveals high levels of variation and admixture
.
Proc Natl Acad Sci U S A
.
2021
;
118
(
36
):
e2026076118
.
21.
Kashtan
CE
.
Alport syndrome
. In:
Adam
MP
,
Ardinger
HH
,
Pagon
RA
,
Wallace
SE
,
Bean
LJH
,
Gripp
KW
, editors.
GeneReviews((R))
Seattle (WA)
1993
.
22.
Kashtan
CE
.
Alport syndrome. An inherited disorder of renal, ocular, and cochlear basement membranes
.
Medicine
.
1999
;
78
(
5
):
338
60
.
23.
Kashtan
C
.
Alport syndrome treatments and outcomes registry
2021a
. Retrieved from: https://rarediseases.org/rare-diseases/alport-syndrome/.
24.
Kashtan
C
.
Multidisciplinary management of Alport syndrome: current perspectives
.
J Multidiscip Healthc
.
2021b
14
1169
80
.
25.
Koç
A
,
Bora
E
,
Cinleti
T
,
Yıldız
G
,
Torun Bayram
M
,
Giray Bozkaya
Ö
.
Initial next-generation sequencing NGS results of Alport syndrome
.
J Basic Clin Health Sci
.
2019
;
3
:
165
9
.
26.
Lee
JM
,
Nozu
K
,
Choi
DE
,
Kang
HG
,
Ha
IS
,
Cheong
HI
.
Features of autosomal recessive Alport syndrome: a systematic review
.
J Clin Med
.
2019
;
8
(
2
):
178
.
27.
Liu
JH
,
Wei
XX
,
Li
A
,
Cui
YX
,
Xia
XY
,
Qin
WS
.
Novel mutations in COL4A3, COL4A4, and COL4A5 in Chinese patients with Alport syndrome
.
PLoS One
.
2017
;
12
:
e0177685
.
28.
Malone
AF
,
Phelan
PJ
,
Hall
G
,
Cetincelik
U
,
Homstad
A
,
Alonso
AS
.
Rare hereditary COL4A3/COL4A4 variants may be mistaken for familial focal segmental glomerulosclerosis
.
Kidney Int
.
2014
;
86
(
6
):
1253
9
.
29.
Mencarelli
MA
,
Heidet
L
,
Storey
H
,
van Geel
M
,
Knebelmann
B
,
Fallerini
C
.
Evidence of digenic inheritance in Alport syndrome
.
J Med Genet
.
2015
;
52
(
3
):
163
74
.
30.
Momota
R
,
Sugimoto
M
,
Oohashi
T
,
Kigasawa
K
,
Yoshioka
H
,
Ninomiya
Y
.
Two genes, COL4A3 and COL4A4 coding for the human alpha3(IV) and alpha4(IV) collagen chains are arranged head-to-head on chromosome 2q36
.
FEBS Lett
.
1998
424
1–2
11
6
.
31.
Moriniere
V
,
Dahan
K
,
Hilbert
P
,
Lison
M
,
Lebbah
S
,
Topa
A
.
Improving mutation screening in familial hematuric nephropathies through next generation sequencing
.
J Am Soc Nephrol
.
2014
;
25
(
12
):
2740
51
.
32.
Nabais Sa
MJ
,
Storey
H
,
Flinter
F
,
Nagel
M
,
Sampaio
S
,
Castro
R
.
Collagen type IV-related nephropathies in Portugal: pathogenic COL4A3 and COL4A4 mutations and clinical characterization of 25 families
.
Clin Genet
.
2015
;
88
(
5
):
456
61
.
33.
Oka
M
,
Nozu
K
,
Kaito
H
,
Fu
XJ
,
Nakanishi
K
,
Hashimura
Y
.
Natural history of genetically proven autosomal recessive Alport syndrome
.
Pediatr Nephrol
.
2014
;
29
(
9
):
1535
44
.
34.
Pecci
A
,
Panza
E
,
Pujol-Moix
N
,
Klersy
C
,
Di Bari
F
,
Bozzi
V
.
Position of nonmuscle myosin heavy chain IIA (NMMHC-IIA) mutations predicts the natural history of MYH9-related disease
.
Hum Mutat
.
2008
;
29
(
3
):
409
17
.
35.
Pirson
Y
.
Making the diagnosis of Alport’s syndrome
.
Kidney Int
.
1999
;
56
(
2
):
760
75
.
36.
Richards
S
,
Aziz
N
,
Bale
S
,
Bick
D
,
Das
S
,
Gastier-Foster
J
.
Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology
.
Genet Med
.
2015
;
17
(
5
):
405
24
.
37.
Savige
J
,
Renieri
A
,
Ars
E
,
Daga
S
,
Pinto
AM
,
Rothe
H
.
Digenic Alport syndrome
.
Clin J Am Soc Nephrol
.
2022
;
17
(
11
):
1697
706
.
38.
Uzak
AS
,
Tokgoz
B
,
Dundar
M
,
Tekin
M
.
A novel COL4A3 mutation causes autosomal-recessive Alport syndrome in a large Turkish family
.
Genet Test Mol Biomarkers
.
2013
;
17
(
3
):
260
4
.
39.
Wang
YF
,
Ding
J
,
Wang
F
,
Bu
DF
.
Effect of glycine substitutions on alpha5(IV) chain structure and structure-phenotype correlations in Alport syndrome
.
Biochem Biophys Res Commun
.
2004
;
316
(
4
):
1143
9
.
40.
Wei
G
,
Zhihong
L
,
Huiping
C
,
Caihong
Z
,
Zhaohong
C
,
Leishi
L
.
Spectrum of clinical features and type IV collagen alpha-chain distribution in Chinese patients with Alport syndrome
.
Nephrol Dial Transplant
.
2006
;
21
(
11
):
3146
54
.
41.
Yamamura
T
,
Horinouchi
T
,
Aoto
Y
,
Lennon
R
,
Nozu
K
.
The contribution of COL4A5 splicing variants to the pathogenesis of X-linked Alport syndrome
.
Front Med
.
2022
;
9
:
841391
.
42.
Yeo
J
,
Qiu
Y
,
Jung
GS
,
Zhang
YW
,
Buehler
MJ
,
Kaplan
DL
.
Adverse effects of Alport syndrome-related Gly missense mutations on collagen type IV: insights from molecular simulations and experiments
.
Biomaterials
.
2020
;
240
:
119857
.
43.
Zhao
X
,
Chen
C
,
Wei
Y
,
Zhao
G
,
Liu
L
,
Wang
C
.
Novel mutations of COL4A3, COL4A4, and COL4A5 genes in Chinese patients with Alport Syndrome using next generation sequence technique
.
Mol Genet Genomic Med
.
2019
;
7
(
6
):
e653
.
44.
Zhao
X
,
Shang
X
,
Chen
C
,
Liu
L
,
Wang
C
,
Zhao
G
.
Identification of four novel mutations in the <i>COL4A5</i> gene identified in Chinese patients with X-linked Alport syndrome
.
Biomed Rep
.
2020
;
13
(
2
):
4
.
You do not currently have access to this content.