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 adult-diagnosed nonsyndromic NPHP that should be considered by adult nephrologists.

肾病（NPHP）作为成年人的肾衰竭和慢性肾脏病早期阶段的常染色体隐性病因，越来越受到人们的重视。我们确定了2个家庭，这些家庭的成年人诊断为非综合症NPHP，而我们的肾脏遗传诊所的诊断性基因检测结果为阴性。两者均具有2个没有肾外表型的受影响兄弟姐妹。在知情同意后，进行研究全基因组测序。双等位基因NPHP4变体在反式中鉴定并在所有4个受影响的个体中进行了临床证实，从而证实了遗传学诊断。第一家庭（F1P1）的参与者1在19岁时被诊断出肾衰竭。肾脏活检提示NPHP后，患病的年轻同胞（F1P2）在15岁时达到肾衰竭。在该家族的NPHP4中检测到的致病变异为NM_015102.4：c.3766C> T（p.Gln1256 *）和一个31kb的缺失，影响外显子12至16。在第二个家族中，F2P3在27岁时达到肾衰竭接受肾脏活检提示NPHP。患病的年轻同胞（F2P4）在39岁时患有慢性肾脏疾病4期。该NPHP4检测到的变体为NM_015102.4：c.1998_1999del（p.Tyr667Phefs * 23）和c.3646G> T（p.Asp1216Tyr）。由于NPHP4覆盖率不足（94.3％外显子覆盖率），后一种变体最初在诊断测序中被遗漏。有了这些报告，我们将NPHP4鉴定为成人肾病非综合症NPHP的明显遗传原因，应由成人肾脏病医生考虑。