Research Grant Award Information
Despite the challenges of rare disease research, PFIC Network is committed to improving treatment options, slowing disease progression, and ultimately finding a cure for PFIC diseases. Our grants are designed to contribute to this mission by funding research that leads to improvements in the lives of PFIC patients and their caretakers. By supporting innovative, patient-focused projects, we aim to close knowledge gaps, accelerate scientific discovery, and bring hope to families around the world.
Project Name: Undiagnosed PFIC
Award Period: July 2025-July 2026
Awardees: Dr. Laura Bull and Dr. Richard Thompson
Laura Bull, Ph.D, RDN is a Professor at the University of California San Francisco. Her research has focused upon understanding the genetic causes and manifestations of pediatric and pregnancy-related cholestasis. Richard Thompson, MRCP, MRCPCH, specialises in pediatric liver disease and is a Professor of Molecular Hepatology at King’s College London. In particular he is interested in genetic disease, both in children and adults. Both awardees serve on PFIC Network’s Scientific-Medical Advisory Board and their research has helped to identify several disease genes, and establish important genotype/phenotype correlations.
Project Background & Lay Summary
by Dr. Laura Bull
Progressive Familial Intrahepatic Cholestasis (PFIC) is actually a group of related disorders, with the commonality of abnormal bile production. In the majority of children with PFIC we can find underlying genetic changes. However, in approximately 1/3rd of children clinically diagnosed with PFIC, a clear genetic diagnosis is not currently able to be made. Understanding the genetic cause(s) of cholestasis can help the care team and family to develop a better understanding of the expected course and outcomes of a patient’s condition and may allow treatment better tailored to individual needs. Some possible future treatments, such as gene therapy, typically rely upon detailed understanding of the genetic cause of disease in a patient.
The purpose of our research study is to identify genetic causes of cholestasis in children for whom that cause has not yet been found. This study is currently focusing on participants already enrolled in research studies.
We will focus on 2 categories of patients:
The 1st category are patients in whom no clear genetic cause has been identified, despite having had DNA sequencing undertaken, whether that focused either on known cholestasis genes, or on the whole exome (protein-coding sequence of the human genome). DNA from these patients will undergo either whole-exome sequencing (WES), if not previously done, or whole-genome sequencing (WGS). We anticipate being able to identify genetic causes of disease in some of these children. These causes may include genes not previously identified as cholestasis genes, as well as mutations in already-known cholestasis genes that have eluded routine diagnostic methods.
The 2nd category are patients for whom previous sequencing has only identified 1 copy of a known cholestasis gene as defective, although the condition is expected to require both gene copies to be abnormal. DNA from these patients will undergo WGS. Again, we anticipate identifying some mutations that may have been missed using more commonly employed techniques.
Sometimes, genetic variants are found in a single patient in a gene not currently associated with cholestasis, but it is very difficult to tell whether they are disease-causing. If more than 1 patient has variants in the same gene, that gene becomes a stronger candidate disease gene. To increase our chances of finding multiple patients with mutation in novel disease genes, the genetic data from this study will be analyzed in combination with existing WES data from other cholestasis patients who are as yet genetically undiagnosed.
The number of genes on cholestasis diagnostic panels has increased dramatically in recent years as a result of research by ourselves and others, but we know that the panels still do not include all cholestasis-causing genes. Genes identified through this study will be added to diagnostic panels in the future. Consistent with participating families’ consent, deidentified results will be shared with the PFIC Network and disseminated through academic meetings, scientific publications and publicly available databases.