A genotype-to-phenotype approach suggests under-reporting of single nucleotide variants in nephrocystin-1 (NPHP1) related disease (UK 100,000 Genomes Project)
-
Published:2023-06-09
Issue:1
Volume:13
Page:
-
ISSN:2045-2322
-
Container-title:Scientific Reports
-
language:en
-
Short-container-title:Sci Rep
Author:
Leggatt Gary, Cheng Guo, Narain Sumit, Briseño-Roa Luis, Annereau Jean-Philippe, Ambrose J. C., Arumugam P.ORCID, Bevers R., Bleda M.ORCID, Boardman-Pretty F.ORCID, Boustred C. R., Brittain H.ORCID, Brown M. A., Caulfield M. J., Chan G. C., Giess A.ORCID, Griffin J. N.ORCID, Hamblin A., Henderson S., Hubbard T. J. P.ORCID, Jackson R.ORCID, Jones L. J., Kasperaviciute D., Kayikci M.ORCID, Kousathanas A.ORCID, Lahnstein L., Lakey A., Leigh S. E. A.ORCID, Leong I. U. S.ORCID, Lopez F. J., Maleady-Crowe F., McEntagart M.ORCID, Minneci F., Mitchell J., Moutsianas L.ORCID, Mueller M.ORCID, Murugaesu N., Need A. C.ORCID, O‘Donovan P.ORCID, Odhams C. A.ORCID, Patch C.ORCID, Perez-Gil D., Pereira M. B.ORCID, Pullinger J.ORCID, Rahim T.ORCID, Rendon A.ORCID, Rogers T., Savage K., Sawant K., Scott R. H., Siddiq A.ORCID, Sieghart A.ORCID, Smith S. C.ORCID, Sosinsky A.ORCID, Stuckey A.ORCID, Tanguy M.ORCID, Tavares A. L. Taylor, Thomas E. R. A.ORCID, Thompson S. R.ORCID, Tucci A.ORCID, Welland M. J., Williams E.ORCID, Witkowska K., Wood S. M., Zarowiecki M.ORCID, Gast Christine, Gilbert Rodney D., Ennis Sarah,
Abstract
AbstractAutosomal 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.
Publisher
Springer Science and Business Media LLC
Subject
Multidisciplinary
Reference47 articles.
1. Konrad, M. et al. Large homozygous deletions of the 2q13 region are a major cause of juvenile nephronophthisis. Hum. Mol. Genet. 5, 367–371 (1996). 2. Hildebrandt, F. et al. A novel gene encoding an SH3 domain protein is mutated in nephronophthisis type 1. Nat. Genet. 17, 149–153 (1997). 3. Saunier, S. A novel gene that encodes a protein with a putative src homology 3 domain is a candidate gene for familial juvenile nephronophthisis. Hum. Mol. Genet. 6, 2317–2323 (1997). 4. Saunier, S. et al. Characterization of the NPHP1 locus: Mutational mechanism involved in deletions in familial juvenile nephronophthisis. Am. J. Hum. Genet. 66, 778–789 (2000). 5. Yuan, B. et al. Comparative genomic analyses of the human NPHP1 locus reveal complex genomic architecture and its regional evolution in primates. PLoS Genet. 11, e1005686 (2015).
|
|