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. 2025 Jun 1;36(6):1056-1071.
doi: 10.1681/ASN.0000000613. Epub 2025 Feb 3.

Characterization of the Cystic Phenotype Associated with Monoallelic ALG8 and ALG9 Pathogenic Variants

Tabinda Jawaid  1 , Doaa E Elbarougy  1 , Sravanthi Lavu  1 , Guillaume Buia  2   3 , Sarah R Senum  1 , Eric Olinger  4   5 , Hana Yang  1 , Shannon K McDonnell  6 , Joshua T Bublitz  6 , Jun Ma  7 , Marie-Pierre Audrézet  2   3 , Charles D Madsen  1 , Rachel S Schauer  1 , Tracy A Baker  1 , Adriana V Gregory  1 , Sarah E Orr  4 , Miguel Barroso-Gil  4 , Ruxandra Neatu  4 , Giancarlo Joli  1   8 , Neera K Dahl  1 , Timothy L Kline  9 , Valentine Gillion  10   11   12 , Karin Dahan  12   13 , Francois Jouret  14 , Ronald D Perrone  15 , Theodore I Steinman  16 , Dorien J M Peters  17 , Berenice Y Gitomer  18 , Terry J Watnick  19 , Eliecer Coto  20 , Fouad T Chebib  21 , Marie C Hogan  1 , Janet E Olson  22 , Nicholas B Larson  6 , Elisabet Ars  23 , Jan Halbritter  24   25 , Nathalie Demoulin  10   11   12 , Vicente E Torres  1 , John A Sayer  4   26 , Emilie Cornec-Le Gall  2   3 , Peter C Harris  1   27 ; Genomics England Research Consortium, UK Biobank, HALT PKD, DIPAK, TAME PKD, Genkyst studies, Mayo Clinic Biobank, and Regeneron Genetics Center
Collaborators, Affiliations

Characterization of the Cystic Phenotype Associated with Monoallelic ALG8 and ALG9 Pathogenic Variants

Tabinda Jawaid et al. J Am Soc Nephrol. .

Abstract

Key Points:

  1. Loss-of-function ALG8 and ALG9 variants were enriched in polycystic kidney/liver groups and International Classification of Diseases–coded cystic individuals in population cohorts.

  2. The ALG8 and ALG9 kidney phenotypes were usually mild to moderate, and lower eGFR or kidney failure was rare.

  3. ALG8 pathogenic variants sometimes resulted in severe polycystic liver disease.

Background: Autosomal dominant polycystic kidney disease (ADPKD) is a common, inherited nephropathy often resulting in kidney failure. It is genetically heterogeneous; along with the major genes, PKD1 and PKD2, at least eight others have been suggested. ALG8 pathogenic variants have been associated with autosomal dominant polycystic liver disease and implicated in ADPKD, while ALG9 has been suggested as an ADPKD gene, but details of the phenotypes and penetrance are unclear.

Methods: We screened >3900 families with cystic kidneys and/or livers using global approaches to detect ALG8 or ALG9 pathogenic variants. In addition, population cohorts with sequence data (Genomics England 100K Genomics Project, UK Biobank, and Mayo Clinic Biobank [MCBB]) were screened for ALG8/ALG9 pathogenic variants.

Results: Multicenter screening of individuals with polycystic kidney and/or liver disease identified 51 (1.3%) ALG8 (7 multiplex) and 23 (0.6%) ALG9 (5 multiplex) families—frequencies that were approximately 10× and approximately 24× greater than nonpolycystic kidney disease controls. Analysis of individuals with polycystic kidney disease phenotypes in 100K Genomics Project, UK Biobank, and MCBB identified nine ALG8 (0.39%) and nine ALG9 (0.39%) families, an enriched frequency over controls. Two individuals had PKD1 and ALG8 pathogenic changes. Eighty-nine percent of individuals with ALG8 mutations with imaging in the entire MCBB had kidney cysts (50%, >10 cysts), with greater median kidney and liver cyst numbers than controls. For ALG9, 78% had kidney cysts (27%, >10 cysts). Individuals with ALG8 mutations typically had mild cystic kidneys with limited enlargement. Liver cysts were common (71%), with enlarged livers (>2L) found in 11 of 62 patients, although surgical intervention was rare. The ALG9 kidney phenotype was also of mild cystic kidneys, but enlarged livers were rare; for both genes, CKD or kidney failure were rare.

Conclusions: ALG8 and ALG9 are defined as cystic kidney/liver genes but with limited penetrance for lower eGFR.

Keywords: ADPKD; genetic diseases and development; nephropathy; polycystic kidney disease.

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Conflict of interest statement

Disclosure forms, as provided by each author, are available with the online version of the article at http://links.lww.com/JSN/F62.

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References

    1. Torres VE, Harris PC, Pirson Y. Autosomal dominant polycystic kidney disease. Lancet. 2007;369(9569):1287–1301. doi: 10.1016/S0140-6736(07)60601-1 - DOI - PubMed
    1. Bergmann C, Guay-Woodford LM, Harris PC, Horie S, Peters DJM, Torres VE. Polycystic kidney disease. Nat Rev Dis Primers. 2018;4(1):50. doi: 10.1038/s41572-018-0047-y - DOI - PMC - PubMed
    1. Cornec-Le Gall E, Alam A, Perrone RD. Autosomal dominant polycystic kidney disease. Lancet. 2019;393(10174):919–935. doi: 10.1016/S0140-6736(18)32782-X - DOI - PubMed
    1. Pei Y Obaji J Dupuis A, et al. Unified criteria for ultrasonographic diagnosis of ADPKD. J Am Soc Nephrol. 2009;20(1):205–212. doi: 10.1681/ASN.2008050507 - DOI - PMC - PubMed
    1. Pei Y Hwang YH Conklin J, et al. Imaging-based diagnosis of autosomal dominant polycystic kidney disease. J Am Soc Nephrol. 2015;26(3):746–753. doi: 10.1681/ASN.2014030297 - DOI - PMC - PubMed

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