I was drawn to genetic counseling due to an interest in lifelong learning. This served me well during my stint in general genetics, where within a given week, I saw everything from routine cancer or cardiac indications, to obscure referrals like “peg-shaped teeth”. When I transitioned to industry and began focusing on renal genetics, I imagined my learning would consist of knowing finite test details, navigating the twisted tunnels of the kidneys, and cultivating a deeper understanding of the conditions that impact them. One scenario I had not considered was an updated gene-disease association that changed our understanding of the most common hereditary kidney disorder.
A publication broke ground in early 2022, suggesting that loss-of-function variants in IFT140 were associated with Autosomal Dominant Polycystic Kidney Disease (ADPKD) (Senum, 2022). Months later, another publication confirmed this association (Chang, 2022). Unlike the most common causes of ADPKD (PKD1, PKD2), those with ADPKD-IFT140 tend to have fewer kidney and liver cysts and better kidney function over a longer period of time, meaning they are less likely to require dialysis and transplant.
Prior to this, IFT140 was only associated with two recessive conditions: Short-Rib Thoracic Dysplasia (SRTD9) and non-syndromic Retinitis Pigmentosa (RP80). SRTD9 is characterized by progressive kidney disease, bone abnormalities (like constricted ribcage or polydactyly), and vision loss. Interestingly, some individuals have been reported with cystic kidney disease, an observation also seen in knockout mouse models. Perhaps it was these observations that made researchers query IFT140 in various ADPKD databases.
Regardless, research has the most impact when it influences reporting. Initially, I saw IFT140 wear the “limited evidence” label, something I struggled to discuss in clinic because I never liked the feeling of maybe. However, my confidence that this label would be updated increased as I spoke with several patients carrying IFT140 who had cysts. Eventually, I saw GeneReviews update its ADPKD entry to reflect the newest research. In early 2023, I was thrilled to see some labs begin reporting the ADPKD-IFT140 association as a positive finding. I also helped patients and providers navigate the impact of these updated reports (which often involved confusion and surprise, but mostly relief).
Many individuals who previously carried a clinical diagnosis but lacked genetic confirmation have been able to receive a supporting molecular diagnosis. Not only does this better inform patients of their prognosis, it allows for informed familial testing, aids reproductive decision-making, assists proper living donor identification when transplant is needed, opens the door for research to better characterize this condition, and allows for updated testing. For these reasons among others, it is exciting to witness an update like this for a well-known condition. I suspect IFT140 will be one of many stories that proves the interpretation of test results is not static. While this may cause us to sit with uncertainty more than we would like, I think we should embrace the opportunity to keep learning.
- Chang, A. R., Moore, B. S., Luo, J. Z., et al. (2022). Exome Sequencing of a Clinical Population for Autosomal Dominant Polycystic Kidney Disease. JAMA, 328(24), 2412–2421. https://doi.org/10.1001/jama.2022.22847
- Senum, S. R., Li, Y. S. M., Benson, K. A., et al. (2022). Monoallelic IFT140 pathogenic variants are an important cause of the autosomal dominant polycystic kidney-spectrum phenotype. American journal of human genetics, 109(1), 136–156. https://doi.org/10.1016/j.ajhg.2021.11.016.
Meg Hager, MS, MPH, CGC is passionate about kidney genetics, which is reflected in her work as a lab genetic counselor for Natera's Renasight panel and service as the Vice-Chair for the Renal SIG. When she is not thinking of #BeanGenes, she spends time knitting, long-distance running and listening to a copious amount of true crime