A genotype-to-phenotype approach suggests under-reporting of single nucleotide variants in nephrocystin-1 (NPHP1) related disease (UK 100,000 Genomes Project).
Journal
Scientific reports
ISSN: 2045-2322
Titre abrégé: Sci Rep
Pays: England
ID NLM: 101563288
Informations de publication
Date de publication:
09 06 2023
09 06 2023
Historique:
received:
26
08
2022
accepted:
23
03
2023
medline:
12
6
2023
pubmed:
10
6
2023
entrez:
9
6
2023
Statut:
epublish
Résumé
Autosomal recessive whole gene deletions of nephrocystin-1 (NPHP1) result in abnormal structure and function of the primary cilia. These deletions can result in a tubulointerstitial kidney disease known as nephronophthisis and retinal (Senior-Løken syndrome) and neurological (Joubert syndrome) diseases. Nephronophthisis is a common cause of end-stage kidney disease (ESKD) in children and up to 1% of adult onset ESKD. Single nucleotide variants (SNVs) and small insertions and deletions (Indels) have been less well characterised. We used a gene pathogenicity scoring system (GenePy) and a genotype-to-phenotype approach on individuals recruited to the UK Genomics England (GEL) 100,000 Genomes Project (100kGP) (n = 78,050). This approach identified all participants with NPHP1-related diseases reported by NHS Genomics Medical Centres and an additional eight participants. Extreme NPHP1 gene scores, often underpinned by clear recessive inheritance, were observed in patients from diverse recruitment categories, including cancer, suggesting the possibility of a more widespread disease than previously appreciated. In total, ten participants had homozygous CNV deletions with eight homozygous or compound heterozygous with SNVs. Our data also reveals strong in-silico evidence that approximately 44% of NPHP1 related disease may be due to SNVs with AlphaFold structural modelling evidence for a significant impact on protein structure. This study suggests historical under-reporting of SNVS in NPHP1 related diseases compared with CNVs.
Identifiants
pubmed: 37296294
doi: 10.1038/s41598-023-32169-4
pii: 10.1038/s41598-023-32169-4
pmc: PMC10256716
doi:
Substances chimiques
Membrane Proteins
0
Cytoskeletal Proteins
0
Adaptor Proteins, Signal Transducing
0
Nucleotides
0
NPHP1 protein, human
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
9369Subventions
Organisme : Wellcome Trust
Pays : United Kingdom
Organisme : Cancer Research UK
Pays : United Kingdom
Organisme : Medical Research Council
Pays : United Kingdom
Organisme : Department of Health
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
(ALT)
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. The Author(s).
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