Biallelic inheritance of hypomorphic PKD1 variants is highly prevalent in very early onset polycystic kidney disease

Abstract

Purpose

To investigate the prevalence of biallelic PKD1 and PKD2 variants underlying very early onset (VEO) polycystic kidney disease (PKD) in a large international pediatric cohort referred for clinical indications over a 10-year period (2010–2020).

Methods

All samples were tested by Sanger sequencing and multiplex ligation-dependent probe amplification (MLPA) of PKD1 and PKD2 genes and/or a next-generation sequencing panel of 15 additional cystic genes including PKHD1 and HNF1B. Two patients underwent exome or genome sequencing.

Results

Likely causative PKD1 or PKD2 variants were detected in 30 infants with PKD-VEO, 16 of whom presented in utero. Twenty-one of 30 (70%) had two variants with biallelic in trans inheritance confirmed in 16/21, 1 infant had biallelic PKD2 variants, and 2 infants had digenic PKD1/PKD2 variants. There was no known family history of ADPKD in 13 families (43%) and a de novo pathogenic variant was confirmed in 6 families (23%).

Conclusion

We report a high prevalence of hypomorphic PKD1 variants and likely biallelic disease in infants presenting with PKD-VEO with major implications for reproductive counseling. The diagnostic interpretation and reporting of these variants however remains challenging using current American College of Medical Genetics and Genomics/Association for Molecular Pathology (ACMG/AMP) and Association of Clinical Genetic Science (ACGS) variant classification guidelines in PKD-VEO and other diseases affected by similar variants with incomplete penetrance.

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Fig. 1: Summary of referrals for genetic testing in 51 infants presenting under 18 months of age between 2010 and 2020 and the main results.
Fig. 2: Structural modeling of PC1 hypomorphic variants.
Fig. 3: Nuclear magnetic resonance (NMR) model of the PC1 PLAT domain with surface mapping of specific ligand-binding residues.

Data availability

All methods and data including primer sequences, PCR conditions, software settings, etc. are available on request.

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Acknowledgements

We are grateful to all referring clinicians and families for providing relevant clinical information, especially Rodney Gilbert and Jackie Cook. We thank all the laboratory team at Sheffield Diagnostic Genetics and Mike Williamson for helpful discussion on NMR modeling. J.C. was supported by an Academic Clinical Fellowship from the UK National Institute for Health Research (NIHR).

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Authors

Contributions

Conceptualization: M.D., J.C., A.O.; Data curation: M.D., J.C.; Formal Analysis: M.D., M.V., P.H.; Investigation: M.D., J.C., M.V.; Resources: M.D., M.V., A.O.; Visualization: M.D., M.V., A.O.; Writing – original draft: M.D., J.C., M.V., A.O.; Writing – review & editing: M.D., P.H., A.O.

Corresponding author

Correspondence to Albert C. M. Ong DM, FRCP.

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The authors declare no conflicts of interest.

Ethics declaration

All families included in this service review consented for diagnostic genetic testing for ADPKD and/or an extended cystic kidney/liver disease panel in the UK National Health Service (NHS). All data has been de-identified.

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Durkie, M., Chong, J., Valluru, M.K. et al. Biallelic inheritance of hypomorphic PKD1 variants is highly prevalent in very early onset polycystic kidney disease. Genet Med (2020). https://doi.org/10.1038/s41436-020-01026-4

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