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Abstract: FR-PO707

Characterization of ADPKD-Like Patients Monoallelic for ALG8 Mutations

Session Information

Category: Genetic Diseases of the Kidneys

  • 1001 Genetic Diseases of the Kidneys: Cystic

Authors

  • Joli, Giancarlo, San Raffaele Scientific Institute, Milan, Italy
  • Senum, Sarah R., Mayo Clinic, Rochester, Minnesota, United States
  • Raj, Sonam, Mayo Clinic, Rochester, Minnesota, United States
  • Te paske, Iris B.a.w., Mayo Clinic, Rochester, Minnesota, United States
  • Cornec-Le Gall, Emilie, Centre Hospitalier Universitaire de Brest, Brest, France
  • Lavu, Sravanthi, Mayo Clinic, Rochester, Minnesota, United States
  • Coto, Eliecer, HUCA, Oviedo, Spain
  • Gitomer, Berenice Y., Div. Renal Diseases and Hypertension,, Aurora, Colorado, United States
  • Steinman, Theodore I., Beth Israel Deaconess Medical Center, Boston, Massachusetts, United States
  • Torres, Vicente E., Mayo Clinic, Rochester, Minnesota, United States
  • Harris, Peter C., Mayo Clinic, Rochester, Minnesota, United States
Background

Although PKD1 and PKD2 are the common ADPKD genes, recently monoallelic GANAB and DNAJB11 mutations have been associated with an ADPKD-like phenotype. These studies showed genic overlap between ADPKD and the related disorder, autosomal dominant polycystic liver disease (ADPLD). Our aim was to further determine the etiology of genetically unresolved ADPKD-like patients.

Methods

Here we screened 723 ADPKD-like patients without mutations in the known ADPKD genes employing a 137 gene panel of described ADPKD, ARPKD, ADPLD, ADTKD and ciliopathy genes, plus candidate loci. Identified families were characterized by segregation, imaging and analysis of the clinical phenotype.

Results

One gene, ALG8, stood out due to a high number of truncating variants across multiple families. ALG8 encodes a glucosyltransferase, and biallelic mutation have been associated with a congenital disorder of glycosylation, CDG1H, while monoallelic mutations have been described to cause ADPLD in 5 families. Nine families were identified with likely significant ALG8 pathogenic variants: 2 missense and 7 truncating, with 14 mutation proven cases. The kidney involvement was mild with normal function and small to medium sized cysts, predominantly in the left kidney, and few liver cysts. The presentation was often sporadic, but in one family two sibs had similar asymmetric disease. The relatively high frequency of ALG8 truncating changes in the normal population (gnomAD database) indicates that it may be a common cause of renal cysts, but additional modification may be required for clinically significant disease. Consistent with this, a patient with Stage 4 CKD also had a rare PKD1 missense variant, while his sister with only the ALG8 variant had just a few cysts. Further, in a described unlinked (PKD3) Spanish family, significantly affected individuals had splicing variants to one or two known ciliopathy genes segregating with the ALG8 mutation.

Conclusion

ALG8 is a gene associated with multiple cyst development in the kidney and screening will likely explain a significant number of mildly affected cases. Oligogenic inheritance with additional gene variants may be required to trigger clinically significant PKD.

Funding

  • NIDDK Support