A novel likely pathogenic CLCN5 variant in Dent's disease.
CLCN5
Dent’s disease
Genetics
Nephrocalcinosis
Proteinuria
Journal
BMC nephrology
ISSN: 1471-2369
Titre abrégé: BMC Nephrol
Pays: England
ID NLM: 100967793
Informations de publication
Date de publication:
28 08 2023
28 08 2023
Historique:
received:
24
04
2023
accepted:
07
08
2023
medline:
31
8
2023
pubmed:
29
8
2023
entrez:
28
8
2023
Statut:
epublish
Résumé
The majority of cases of Dent's disease are caused by pathogenic variants in the CLCN5 gene, which encodes a voltage-gated chloride ion channel (ClC-5), resulting in proximal tubular dysfunction. We present three members of the same family and one unrelated paediatric patient with the same insertion-deletion CLCN5 variant. The identification of these patients and positive familial segregation led to the re-classification of this variant from one of unknown significance to one of likely pathogenicity. A 41 year old male presented with end stage kidney failure, proteinuria and haematuria. Whole genome sequencing identified an insertion-deletion variant in CLCN5, resulting in a missense change (c.1744_1745delinsAA p.(Ala582Lys)). His brother and nephew, who both exhibited renal impairment, haematuria, proteinuria, glycosuria and nephrocalcinosis, were found to have the same variant. In addition, genetic testing of an unrelated paediatric patient who presented with proteinuria and hypercalciuria, demonstrated the same variant. The identification of this novel variant in four individuals with features of Dent's disease, has led to the re-classification of the variant to one of likely pathogenicity. As a result, our patients and any future patients with the same variant can be offered a likely diagnosis, without the need for kidney biopsy, and their family members can be offered genetic screening.
Sections du résumé
BACKGROUND
The majority of cases of Dent's disease are caused by pathogenic variants in the CLCN5 gene, which encodes a voltage-gated chloride ion channel (ClC-5), resulting in proximal tubular dysfunction. We present three members of the same family and one unrelated paediatric patient with the same insertion-deletion CLCN5 variant. The identification of these patients and positive familial segregation led to the re-classification of this variant from one of unknown significance to one of likely pathogenicity.
CASE PRESENTATION
A 41 year old male presented with end stage kidney failure, proteinuria and haematuria. Whole genome sequencing identified an insertion-deletion variant in CLCN5, resulting in a missense change (c.1744_1745delinsAA p.(Ala582Lys)). His brother and nephew, who both exhibited renal impairment, haematuria, proteinuria, glycosuria and nephrocalcinosis, were found to have the same variant. In addition, genetic testing of an unrelated paediatric patient who presented with proteinuria and hypercalciuria, demonstrated the same variant.
CONCLUSIONS
The identification of this novel variant in four individuals with features of Dent's disease, has led to the re-classification of the variant to one of likely pathogenicity. As a result, our patients and any future patients with the same variant can be offered a likely diagnosis, without the need for kidney biopsy, and their family members can be offered genetic screening.
Identifiants
pubmed: 37641036
doi: 10.1186/s12882-023-03292-1
pii: 10.1186/s12882-023-03292-1
pmc: PMC10463507
doi:
Substances chimiques
Chlorides
0
Types de publication
Case Reports
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
256Subventions
Organisme : Medical Research Council
ID : MR/W000105/1
Pays : United Kingdom
Organisme : Department of Health
Pays : United Kingdom
Organisme : Wellcome Trust
Pays : United Kingdom
Organisme : Cancer Research UK
Pays : United Kingdom
Investigateurs
J C Ambrose
(JC)
P Arumugam
(P)
R Bevers
(R)
M Bleda
(M)
F Boardman-Pretty
(F)
C R Boustred
(CR)
H Brittain
(H)
M A Brown
(MA)
M J Caulfield
(MJ)
G C Chan
(GC)
A Giess
(A)
J N Griffin
(JN)
A Hamblin
(A)
S Henderson
(S)
T J P Hubbard
(TJP)
R Jackson
(R)
L J Jones
(LJ)
D Kasperaviciute
(D)
M Kayikci
(M)
A Kousathanas
(A)
L Lahnstein
(L)
A Lakey
(A)
S E A Leigh
(SEA)
I U S Leong
(IUS)
F J Lopez
(FJ)
F Maleady-Crowe
(F)
M McEntagart
(M)
F Minneci
(F)
J Mitchell
(J)
L Moutsianas
(L)
M Mueller
(M)
N Murugaesu
(N)
A C Need
(AC)
P O'Donovan
(P)
C A Odhams
(CA)
C Patch
(C)
D Perez-Gil
(D)
M B Pereira
(MB)
J Pullinger
(J)
T Rahim
(T)
A Rendon
(A)
T Rogers
(T)
K Savage
(K)
K Sawant
(K)
R H Scott
(RH)
A Siddiq
(A)
A Sieghart
(A)
S C Smith
(SC)
A Sosinsky
(A)
A Stuckey
(A)
M Tanguy
(M)
A L Taylor Tavares
(AL)
E R A Thomas
(ERA)
S R Thompson
(SR)
A Tucci
(A)
M J Welland
(MJ)
E Williams
(E)
K Witkowska
(K)
S M Wood
(SM)
M Zarowiecki
(M)
Informations de copyright
© 2023. BioMed Central Ltd., part of Springer Nature.
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