Alagille Syndrome Research

Physicians and scientists from The Children’s Hospital of Philadelphia have led and participated in significant, ground-breaking research into the causes of Alagille syndrome.

Our experienced team of clinicians and researchers from the Alagille Syndrome Clinical Care Program and the Fred and Suzanne Biesecker Pediatric Liver Center at CHOP have developed screening tests for Alagille syndrome — allowing us to confirm the diagnosis and create individualized care plans based on each child’s individual needs.


In 1997, clinicians and scientists from the Alagille Syndrome Clinical Care Program — in collaboration with others — discovered that mutations in the gene Jagged-1 on chromosome 20p12 cause Alagille syndrome. We were able to pinpoint the gene after finding multiple patients with Alagille syndrome had chromosomal abnormalities in and around chromosome 20.

The Jagged-1 gene causes protein to be manufactured on the surface of some cells. By interacting with proteins on other cell surfaces, the Jagged-1 protein helps cells choose what types of cells they will become (cell-fate decisions).

Our current screening methods detect Jagged-1 mutations in more than 90 percent of people with classic clinical Alagille syndrome features. Individuals with Jagged-1 mutations have a wide range of clinical findings, ranging from very mild (i.e. an isolated cardiac murmur, facial features or butterfly-shaped vertebrae) to very severe (i.e. cardiac or liver disease requiring transplantation).

We continue to study the full range of clinical features associated with a Jagged-1 mutation, and we are working to better understand the molecular basis for these differences.


In 2005, we discovered a small percentage of patients with Alagille syndrome had mutations in another gene, NOTCH2, which is known to interact with Jagged-1.

We are now working to search for NOTCH2 mutations in additional patients, and determine if there are differences in the clinical presentation associated with Jagged-1 and NOTCH2 mutations. We are also working to define the molecular basis of NOTCH2-mediated Alagille syndrome.

Current research

Currently, our research is focused on:

  • Improving the mutation detection rate for Alagille syndrome
  • Understanding what factors influence the variability of severity in Alagille syndrome (i.e. studying genetic modifiers)
  • Understanding the spectrum and nature of vascular anomalies in Alagille syndrome
  • Understanding how the Jagged-1 and NOTCH2 proteins interact with other cellular proteins and lead to the abnormalities seen in Alagille syndrome


The Children’s Hospital of Philadelphia is one of 14 clinical sites and a data-coordinating center, participating in the Childhood Liver Disease Research Network (ChiLDReN).

ChiLDReN is comprised of a collaborative team of physicians, nurses, research coordinators, and patient support organizations in North America working together to improve the lives of children and families dealing with rare liver diseases. The ChiLDReN consortium represents the merger of two previous networks, the Biliary Atresia Research Consortium (BARC) and the Cholestatic Liver Disease Consortium (CLiC).

Bench to bedside

Under the leadership of Nancy Spinner, PhD, the Alagille Syndrome Clinical Care Program has performed molecular analysis for more than 250 children with Alagille syndrome and their families.

We have published landmark studies on the mutation spectrum and frequency in Alagille syndrome, and on the implications of carrying a mutation in Jagged-1. More than 20 physicians and scientists work collaboratively in the Alagille Program to provide the best possible care for all children with the disorder and their families.

We continue investigating, looking for answers to help us better understand, diagnose, treat, and perhaps eventually to prevent Alagille syndrome.