Characterization of the Cystic Phenotype Associated with Monoallelic ALG8 and ALG9 Pathogenic Variants.
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Jawaid Tabinda, Elbarougy Doaa E, Lavu Sravanthi, Buia Guillaume, Senum Sarah R, Olinger Eric, Yang Hana, McDonnell Shannon K, Bublitz Joshua T, Ma Jun, Audrézet Marie-Pierre, Madsen Charles D, Schauer Rachel S, Baker Tracy A, Gregory Adriana V, Orr Sarah E, Barroso-Gil Miguel, Neatu Ruxandra, Joli Giancarlo, Dahl Neera K, Kline Timothy L, Gillion Valentine, Dahan Karin, Jouret Francois, Perrone Ronald D, Steinman Theodore I, Peters Dorien J M, Gitomer Berenice Y, Watnick Terry J, Coto Eliecer, Chebib Fouad T, Hogan Marie C, Olson Janet E, Larson Nicholas B, Ars Elisabet, Halbritter Jan, Demoulin Nathalie, Torres Vicente E, Sayer John A, Cornec-Le Gall Emilie, Harris Peter C, Genomics England Research Consortium, UK Biobank, HALT PKD, DIPAK, TAME PKD, Genkyst studies, Mayo Clinic Biobank, and Regeneron Genetics Center
Аннотация
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.