When the Genes Don't Fit: A Genetic Mystery of Mosaicism in Tuberous Sclerosis and PKD

Introduction: Autosomal Dominant Polycystic Kidney Disease (ADPKD) and Tuberous Sclerosis (TSC) are conditions with culprit genes located adjacent on chromosome 16. ADPKD is marked by numerous cysts on bilateral kidneys that can lead to progressive kidney damage and end-stage renal disease. TSC can also cause kidney problems, with cysts and angiomyolipomas (AML), but predominant features are skin and neurologic disorders. In less than 2% of cases, a rare overlap between TSC and ADPKD may occur. Case Description: A 39-year-old male with chronic kidney disease (CKD) stage 3b and multiple renal cysts with a notable history of TSC, diagnosed clinically based on a history of facial angiofibromas and AMLs of the brain and left kidney. Routine imaging also showed numerous bilateral renal cysts and given this there was concern for ADPKD. Family history was significant for his son with CKD stage 5 and TSC, with a confirmed multi-exon deletion in the TSC2 gene, possibly involving the PKD1 gene. Therefore, he was sent for genetic testing. However, the Natera Renasight Kidney gene panel returned negative for mutations in TSC and ADPKD genes. Though this result is puzzling based on family and clinical history, one explanation may be genetic mosaicism. Discussion: This case presented an unexpected result and highlights the challenges practitioners may face with genetic testing. Mosaicism, a rare occurrence with as low as 0.5%-3% incidence, refers to the presence of a distinct cell population within an organism. As germline mosaicism are isolated to gonadal cells the organism does not typically exhibit phenotypical findings. It is possible if the event leading to mosaicism occurred during development that both somatic and germ line cells can become mosaic, leading to symptoms as well as the ability to pass the mutation to offspring. Next steps include blood sampling for microarray testing of the patient and son for more information about the extent of the genetic deletion and its involvement of the PKD1 gene. Given the patient’s history, the diagnosis of TSC is certain, however it remains unclear whether ADPKD is also present. A confirmed diagnosis will help both provider and patient make the best-informed decision possible on treatment.