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Kidney Week

Abstract: SA-PO757

Recessive Variants in NEK1 and NEK8 Are Associated with Cystic Kidney and Kidney Stone Disease

Session Information

Category: Genetic Diseases of the Kidneys

  • 1201 Genetic Diseases of the Kidneys: Cystic

Authors

  • Gauntner, Victoria C., Division of Nephrology, Department of Medicine, Boston Children’s Hospital, Harvard Medical School, Boston, Massachusetts, United States
  • Daouk, Ghaleb H., Division of Nephrology, Department of Medicine, Boston Children’s Hospital, Harvard Medical School, Boston, Massachusetts, United States
  • Napier, Melanie P., GeneDx Inc, Gaithersburg, Maryland, United States
  • Besouw, Martine T., Department of Pediatric Nephrology, University Medical Center Groningen, University of Groningen, Groningen, Netherlands
  • LaRosa, Christopher J., Division of Nephrology, Department of Pediatrics, Perelman School of Medicine at the University of PA, Philadelphia, Pennsylvania, United States
  • Strong, Alanna, Division of Human Genetics, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, United States
  • Mane, Shrikant M., Yale Center for Mendelian Genomics, Yale University School of Medicine, New Haven, Connecticut, United States
  • Shril, Shirlee, Division of Nephrology, Department of Medicine, Boston Children’s Hospital, Harvard Medical School, Boston, Massachusetts, United States
  • Chapman, Arlene B., Section of Nephrology, Department of Medicine, University of Chicago, Chicago, Illinois, United States
  • Hildebrandt, Friedhelm, Division of Nephrology, Department of Medicine, Boston Children’s Hospital, Harvard Medical School, Boston, Massachusetts, United States
  • Sayer, John Andrew, Tranlsational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, United Kingdom
  • Majmundar, Amar J., Division of Nephrology, Department of Medicine, Boston Children’s Hospital, Harvard Medical School, Boston, Massachusetts, United States
Background

~9-20% of chronic kidney disease patients have a Mendelian genetic cause. Mice with biallelic deleterious variants in Nek1 and Nek8, encoding NimA-related serine/threonine kinases, develop adult-onset cystic kidney disease. In humans, biallelic NEK1 and NEK8 pathogenic variants are associated primarily with severe fetal/neonatal disease with multiple congenital anomalies including kidney malformations (14/16 congenital renal onset). It remains unclear if variants in these genes cause later onset kidney disease.

Methods

Variants in NEK1 (NM_001199397.3) and NEK8 (NM_178170.1) were detected by panel, exome or genome sequencing in >5457 families with cystic kidney or kidney stone disease (Boston Children’s Hospital), with renal/urologic disease patients (Genomics England), with suspected hereditary kidney disease (University of Chicago), or with clinical genetic testing identifying bi-allelic NEK1/8 variants (GeneDx, University of Iowa, University Medical Center Groningen).

Results

Six families (seven individuals) with cystic kidney disease and/or kidney stone disease were identified with rare recessive variants in NEK1 (two) or NEK8 (four). Deleterious variants exhibited rare population frequency (gnomAD genome database), ≥2 deleterious in silico prediction scores (PolyPhen2.0, MutationTaster, SIFT, CADD) and strong amino acid conservation in vertebrate orthologues. All NEK1 variants (p.Ala313Thr; p.Met564ValfsTer35; p.Ser909Cys) and four of five NEK8 variants (p.Thr41Ile, p.Ile170Phe, p.Ser224Cys, p.Arg294His) were novel, while one NEK8 variant (p.Arg599*) was previously reported. Clinical phenotyping revealed cystic kidney disease (5/7), nephrolithiasis and/or nephrocalcinosis (3/7), nephromegaly (3/7), and chronic kidney disease (3/7). Age of kidney disease diagnosis ranged from age 5-18 years. In contrast, no deleterious bi-allelic variants were observed in exome data from 1285 non-disease control subjects.

Conclusion

Recessive NEK1 and NEK8 variants were identified in individuals with non-congenital cystic kidney and kidney stone disease, suggesting a novel association between NEK1/8 variants and later-onset kidney disease.

Funding

  • NIDDK Support