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Kidney Week

Abstract: TH-PO608

Digenic Heterozygous Mutations in CEP164 and ALMS1 May Cause Nephronophthisis

Session Information

Category: Nephrology Education

  • 1302 Fellows and Residents Case Reports


  • Murad, Haris Farooq, Yale School of Medicine, New Haven, Connecticut, United States
  • Dahl, Neera K., Yale School of Medicine, New Haven, Connecticut, United States

Nephronophthisis is a cystic kidney disease that is the most common genetic cause of End Stage Renal Disease (ESRD) in the first three decades of life. It is a genetically heterogeneous disorder associated with extra renal manifestations (eyes, liver, bones, and central nervous system) in 15% of cases. Renal histology shows tubular basement membrane disruption and tubulointerstitial nephropathy. The cysts are usually in the corticomedullary junction and kidney size is normal or slightly reduced in contrast to polycystic kidney disease. Here we describe two cases with Nephronophthisis from novel genetic mutations.


A 51-year old lady presents with a gradually rising serum Creatinine up to 2.7mg/dL. Renal biopsy showed interstitial nephritis, and her ultrasound showed several scattered subcentimeter cysts and a 1.6 cm cyst. Whole exome sequencing showed heterozygous mutations in both the CEP164 and ALMS1 genes. Both mutations, CEP164, pL248fs, and ALMS1 pY1713X, resulted in the creation of a premature stop codon and are known to be pathogenic. MUC1 and UMOD were normal.

The patient's sister has a history of cerebral palsy developed ESRD at the age of 30. Her CT abdomen shows innumerable bilateral renal cysts. Biopsy revealed interstitial nephritis as well. Whole exome sequencing is currently in process.


Nephronophthisis is a disorder in the normal functioning of primary cilia, which are sensory organelles detecting flow, osmotic, chemo and other stimuli and link them to cellular processes. A homozygous or compound heterozygous mutation in the CEP164 gene is known to cause NPHP15 which causes an alteration in DNA damage response signaling pathway. A mutation in ALMS1 gene causes abnormal ciliary structure in knockout mice. A homozygous or compound heterozygous mutation in this gene causes Alstrom syndrome which is a rare cause of renal failure associated with blindness, hearing loss, systemic fibrosis as well as hepatic, urologic and pulmonary dysfunction. To our knowledge, this is the first case of a clinical nephronophthisis phenotype caused by digenic pathogenic alleles rather than by a homozygous or compound heterozygous mutations in the above genes. It is possible that ALMS and CEP164 mutations have a complementary effect in exerting this phenotype.