Adult-Diagnosed Nonsyndromic Nephronophthisis in Australian Families Caused by Biallelic NPHP4 Variants

Abstract

There is increasing appreciation of nephronophthisis (NPHP) as an autosomal recessive cause of kidney failure and earlier stages of chronic kidney disease among adults. We identified 2 families with presumed adult-diagnosed nonsyndromic NPHP and negative diagnostic genetic testing results from our Renal Genetics Clinic. Both had 2 affected siblings without extrarenal phenotypes. After informed consent, research whole-genome sequencing was undertaken. Biallelic NPHP4 variants were identified in trans and clinically confirmed in all 4 affected individuals, confirming a genetic diagnosis. Participant 1 of the first family (F1P1) had kidney failure diagnosed at 19 years of age. An affected younger sibling (F1P2) reached kidney failure at age 15 years after kidney biopsy suggested NPHP. Pathogenic variants detected in NPHP4 in this family were NM_015102.4:c.3766C>T (p.Gln1256*) and a 31-kb deletion affecting exons 12 to 16. In the second family, F2P3 reached kidney failure at age 27 years having undergone kidney biopsy suggesting NPHP. An affected younger sibling (F2P4) has chronic kidney disease stage 4 at age 39 years. The NPHP4 variants detected were NM_015102.4:c.1998_1999del (p.Tyr667Phefs*23) and c.3646G>T (p.Asp1216Tyr). The latter variant was initially missed in diagnostic sequencing due to inadequate NPHP4 coverage (94.3% exonic coverage). With these reports, we identify NPHP4 as an appreciable genetic cause for adultdiagnosed nonsyndromic NPHP that should be considered by adult nephrologists. Complete author and article information provided before references.

Cystic Kidney Diseases That Require a Differential Diagnosis from Autosomal Dominant Polycystic Kidney Disease (ADPKD)

“…Two-thirds of all NPH cases have no clearly identifiable gene mutation [ 80 ]. Causative genes that are representative of adolescent/adult NPH include: NPHP3 , NPHP4 , and NPHP9 / NEK8, but some cases of NPH do not clearly match up with any of these genes [ 80 , 81 , 86 , 87 , 88 , 89 , 90 ].…”

Nephronophthisis-Pathobiology and Molecular Pathogenesis of a Rare Kidney Genetic Disease

“…NPHP does not have a gender predisposition and accounts for 10-25% and ~5% of all children in ESRD in Europe and North America, respectively [13]. Bollee et al [14], Hoefelle et al [15], and Hudson et al [16] showed new diagnosis of NPHP in adults with chronic kidney disease (CKD), despite the diseases likely being present from childhood.…”

The Heritability of Kidney Function Using an Older Australian Twin Population

“… 7 Nephronophthisis exhibits significant variability, even within families, and genetic diagnosis has furthered our understanding in adult CKD. 8 APOL1 G1/G2 have been linked with progression to end-stage kidney disease with focal segmental glomerulosclerosis and lupus nephritis in African American populations. 9 Genes involved in biological pathways contributing to the major risk factors for progression of CKD such as hypertension and diabetes are of particular interest.…”