A Rare Case of Polycystic Kidney Disease due to Pathogenic Variants in the ALG9 and TTC21B Genes
- Genetic Diseases: Cystic - Genetic Analysis and Extrarenal Manifestations
November 04, 2023 | Location: Exhibit Hall, Pennsylvania Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Genetic Diseases of the Kidneys
- 1201 Genetic Diseases of the Kidneys: Cystic
- Graham, Garry Anthony, Albert Einstein College of Medicine, Bronx, New York, United States
- Cunningham, Khyra, Albert Einstein College of Medicine, Bronx, New York, United States
- Chen, Wei, Albert Einstein College of Medicine, Bronx, New York, United States
- Fisher, Molly, Albert Einstein College of Medicine, Bronx, New York, United States
ALG9 is a novel disease gene that accounts for <1% of cases on the polycystic kidney disease (PKD) spectrum. Pathogenic mutations of the TTC21B gene are associated with nephronophthisis, characterized by tubulointerstitial disease and kidney cysts. Animal studies suggest that TTC21B modifies the phenotype of PKD due to the PKD gene mutation. Whether ALG9 interacts with TTC21B is unknown. We present a rare case of PKD due to heterozygosity for pathogenic variants in ALG9 and TTC21B.
A 65-year-old Hispanic woman with well-controlled human immunodeficiency virus, osteoporosis and nephrolithiasis presented for evaluation of chronic kidney disease, proteinuria, and bilateral kidney cysts. Serum creatinine fluctuated between 1.1-1.3 mg/dL (eGFR 44-54 ml/min/1.73m2) with no hematuria. Urine protein-creatinine ratio was 442 mg/g. Replacing tenofovir in her antiretroviral regimen did not improve kidney function. Kidney ultrasound revealed slightly enlarged kidneys of 12.4 cm on the left and 11.5 cm on the right, increased parenchymal echogenicity as well as numerous bilateral cysts, some of which were complex. A CT abdomen showed 4 cysts in the left kidney and 3 cysts in the right kidney that were >8 mm in diameter, as well as innumerable bilateral cysts that were too small to count. There were no liver cysts. She reported had no known family history of cystic kidney disease. Genetic test revealed a heterozygous ALG9 nonsense, loss of function mutation (c.1219C>T, p.Arg407*) and a heterozygous TTC21B variant that resulted in a frame-shift (c.2913dup, p.Val972Serf*11). Using UCSC Genome Browser, we found evidence that ALG9 and TTC21B both interact with ubiquitin C.
ALG9 encodes a-1,2-mannosyltrasnsferase, which adds specific mannose molecules to a N-glycan precursor in the endoplasmic reticulum lumen. ALG9 mutation is associated with a milder phenotype than PKD mutations. TTC21B encodes a retrograde intraflagellar transport protein. A previous case reported that TTC21B heterozygous variants exacerbated the phenotype of PKD due to PKD1 mutation. The interactions between PKD genes and TTC21B were validated in animal studies. However, whether ALG9 interacts with TTC21B is unknown. Addressing this knowledge gap will help define the prognosis and guide treatment therapy in patients like ours.