R HUDSON1, C PATEL2, C HAWLEY3, S O’SHEA4, P SNELLING5, J CRAWFORD6, C SIMONS7, AJ MALLETT8
1Department of Renal Medicine, Royal Brisbane And Womens Hospital, Herston, Australia, 2Genetic Health Queensland, Royal Brisbane and Women’s Hospital, Herston, Australia , 3Department of Nephrology, Princess Alexandra Hospital, Wooloongabba, Australia, 4Wesley Hospital, Auchenflower, Australia, 5Department of Nephrology, Royal Prince Alfred Hospital, Camperdown, Australia, 6Institute for Molecular Bioscience, The University of Queensland, St Lucia, Australia, 7Murdoch Children’s Research Institute, Parkville, Australia, 8Faculty of Medicine, The University of Queensland, Herston,
Aim: To identify the genetic cause of adult-diagnosed non-syndromic nephronophthisis in two Australian families with genetically unresolved inherited kidney disease.
Background: There is increasing appreciation of nephronophthisis as an autosomal recessive cause of chronic and end-stage kidney disease (ESKD/CKD) amongst adults. Whilst NPHP1 has long been recognised as causative for this disorder, we propose NPHP4 as an additional genetic aetiology for such presentations.
Methods: Two families with presumed adult-diagnosed non-syndromic nephronophthisis and negative diagnostic genetic testing were identified from the RBWH Conjoint Renal Genetics Clinic. Both included two affected siblings and there was no extra-renal phenotype. After informed consent (HREC/14/QRBW/34) research whole genome sequencing was undertaken with custom in-house bioinformatic analysis.
Results: Biallelic NPHP4 variants were identified in trans and clinically confirmed in all four affected individuals from both families confirming a genetic diagnosis.In family 1, participant 1 (F1P1) was diagnosed at 19years with ESKD. Their affected younger sibling (F1P2) reached ESKD at 15years after renal biopsy at 14years suggested nephronophthisis. The variants detected were NPHP4 (NM_015102.4)c.3766C>T;p.(Gln1246*) and 1p36.31del; both ACMG Class5. The heterozygous 1p36.31(5955751_5979349) deletion was previously not detected with diagnostic sequencing.In family 2, participant 3 (F2P3) reached ESKD at 27years having undergone renal biopsy at 26years suggesting nephronophthisis. Their affected younger sibling (F2P4) had CKD Stage4 at 39years. The variants detected were NPHP4 (NM_015102.3)c.1998_1999del;p.(Tyr667Phefs*23) and c.3646G>T;p.(Asp1216Tyr); ACMG Classes5 and 3 respectively. The latter variant was located in one of 4gaps in previous diagnostic sequencing of NPHP4 (94.3% exonic coverage).
Conclusions: Here we identify NPHP4 as an appreciable genetic cause for adult-diagnosed non-syndromic nephronophthisis. This gene should be considered by adult nephrologists with the aim of improving genomic translation in nephrology.
After finishing medical school and her internship in Western Australia, Rebecca has worked at the Royal Brisbane and Women’s hospital since 2015, and has completed two rotations in Nephrology as a Resident and Registrar. She has thoroughly enjoyed this time both on the wards and in the dialysis unit, whilst also visiting external sites such as North Lakes and Redcliffe Hospital as a visiting Registrar. Currently in her 3rd year of Basic Physician Training, Rebecca is passionate about Nephrology and is committed to a high standard of care in this field going forward in her career.