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Abstract: TH-PO372

Reduced Penetrance of ALG9-Associated Cystic Kidney Disease in a Real-World Cohort

Session Information

Category: Genetic Diseases of the Kidneys

  • 1101 Genetic Diseases of the Kidneys: Cystic

Authors

  • Beretich, Lauren, Natera, Inc., Austin, Texas, United States
  • Abdullatif, Umayma, CLS Health, Webster, Texas, United States
  • Alrejjal, Kenan Mohd Rashad Said, CLS Health, Webster, Texas, United States
  • Hendricks, Emily, Natera, Inc., Austin, Texas, United States
  • Raible, Darbey, Natera, Inc., Austin, Texas, United States
  • Clark, Dinah, Natera, Inc., Austin, Texas, United States
  • Punj, Sumit, Natera, Inc., Austin, Texas, United States
  • Abdellatif, Abdul A., Baylor College of Medicine, Houston, Texas, United States
Background

Recently, heterozygous loss-of-function variants in ALG9 have been associated with autosomal dominant polycystic kidney and liver disease. Variable expressivity and reduced penetrance were reported in the limited cohorts studied with these conditions. The goal of this study was to assess the frequency of polycystic kidney and/or liver disease in individuals with heterozygous loss-of-function variants in ALG9 from a real-world cohort of patients referred for clinical genetic testing.

Methods

A retrospective review of laboratory data and clinical information from test requisition forms was conducted. Participants with a clinically ordered genetic panel for kidney disease (the RenasightTM test) between May 2020 and April 2022 and a heterozygous pathogenic (P) or likely pathogenic (LP) variant in ALG9 were included in this study.

Results

Among the 15 patients that met inclusion criteria, patients were predominantly female (10/15) and Caucasian (6/15). The median age at the time of genetic testing was 51 years (range 23-62 years). Patients were most often referred for genetic testing due to chronic kidney disease (8/15) and/or cystic kidney disease (7/15). All of the reported ALG9 variants were classified as LP and were predominantly nonsense variants (8/15). In this cohort, 47% (7/15) patients were reported to have cystic or polycystic kidneys and one patient (1/7) was reported to have liver cysts. Only one patient (1/15) was reported to have a relevant family history.

Conclusion

In this real-world cohort, reduced penetrance was observed in ALG9 heterozygotes, consistent with previous literature. These results may underrepresent the prevalence of autosomal dominant polycystic kidney and liver disease in ALG9 heterozygotes as complete clinical information is not always provided on the test order form. In addition, 43% (3/7) of patients with a cystic phenotype and an ALG9 variant also had a variant of uncertain significance (VUS) in separate genes related to cystic disease, for which additional data are needed to understand the impact on their phenotype. Future research can help further our understanding of the association between ALG9 variants and cystic phenotypes.