Dr. Robert Gish: I would state that my greatest difficulties in this PFIC world were the first 10 cases because I had no idea what I was doing. I didn't know what to do with VUS or indeterminate. And it was difficult because I had to search out one of my pediatric hepatology colleagues, present the case, make it clear I didn't know what to do with this information, I didn't know what was next. But after 10 cases and reading and looking at the literature, doing my searches, I really gained a lot of confidence.

Dr. Richard Thomson: There are clues early on which can make us think about genetic testing and hopefully speed it up for the adult patients. I think the ones that stand out are patients with a strong family history of liver disease, patients with low gamma-GT cholestasis, patients who've got a sclerosing cholangitis, they've got bile duct injury, but in the absence of any autoimmunity or any IBD, or patients who are all auto-antibody negative, AMA negative PBC, for instance. These are all alarm bells that should be making genetic testing much earlier in the diagnostic algorithm.

For the last few years, we've been using panels of NGS or next-generation sequencing, where a small or maybe dozens or even 100 genes are being interrogated. Increasingly, we're switching those to using whole exome or whole genome sequencing, where potentially all genes or the entire genome are being sequenced. We are finding variants which are consequential and causing contribution to phenotype in a very similar proportion of the adults and children. It's about 30% in both cases. There's lots of variants in all these genes, and we find novel ones all the time. I think reading genetic reports is daunting, and there's often a lot of information.

Dr. Robert Gish: You may see a genetic report that says VUS, Variant of Unknown Significance. You may see another one that says indeterminate. What those two things mean on the genetic report means that the company doing the sequencing doesn't have enough information to provide a clinical assessment or a clinical tool to help you. It's our job to take VUS and convert that to clinical correlation. We're seeing the patient. We have all the liver biochemistries. We have the imaging. We now have the genetic testing.

It's a new world. This is really fantastic to be able to use genetic testing. And I realized I had 50, 60, 70 patients with unexplained liver disease, and now I've done over 80 genetics panels. Out of 80, 74 patients have a clear explanation for their liver disease. So it's a new world. I think we are great resources, and I have people that I turn to for resources. Let's work as a community.