Kidney Week

Abstract: SA-PO757

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

Session Information

• Genetic Diseases: Cystic - Genetic Analysis and Extrarenal Manifestations
  November 04, 2023 | Location: Exhibit Hall, Pennsylvania Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

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

Victoria C. Gauntner,

• Daouk, Ghaleb H., Division of Nephrology, Department of Medicine, Boston Children’s Hospital, Harvard Medical School, Boston, Massachusetts, United States

Ghaleb H. Daouk,

• Napier, Melanie P., GeneDx Inc, Gaithersburg, Maryland, United States

Melanie P. Napier,

• Besouw, Martine T., Department of Pediatric Nephrology, University Medical Center Groningen, University of Groningen, Groningen, Netherlands

Martine T. Besouw,

• LaRosa, Christopher J., Division of Nephrology, Department of Pediatrics, Perelman School of Medicine at the University of PA, Philadelphia, Pennsylvania, United States

Christopher J. LaRosa,

• Strong, Alanna, Division of Human Genetics, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, United States

Alanna Strong,

• Mane, Shrikant M., Yale Center for Mendelian Genomics, Yale University School of Medicine, New Haven, Connecticut, United States

Shrikant M. Mane,

• Shril, Shirlee, Division of Nephrology, Department of Medicine, Boston Children’s Hospital, Harvard Medical School, Boston, Massachusetts, United States

Shirlee Shril,

• Chapman, Arlene B., Section of Nephrology, Department of Medicine, University of Chicago, Chicago, Illinois, United States

Arlene B. Chapman,

• Hildebrandt, Friedhelm, Division of Nephrology, Department of Medicine, Boston Children’s Hospital, Harvard Medical School, Boston, Massachusetts, United States

Friedhelm Hildebrandt,

• Sayer, John Andrew, Tranlsational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, United Kingdom

John Andrew Sayer,

• Majmundar, Amar J., Division of Nephrology, Department of Medicine, Boston Children’s Hospital, Harvard Medical School, Boston, Massachusetts, United States

Amar J. Majmundar,

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