What gene discovery means for families and physicians seeking answers to medical mysteries

At Lucile Packard Children’s Hospital Stanford, families and physicians who are seeking answers to the medically unknown turn to genomics experts to unlock secrets hidden in genes. The human genome is defined as the complete set of genes present in a human being. Genomics explores the structure, function, evolution and mapping of genomes.

Alejandra, now age 12, came to Packard Children’s in 2006 when she was 1 year old. She had end-stage liver cirrhosis of an unknown cause and needed a liver transplant to survive. Her brother Adrian, now age 4, was born in 2013 and started presenting symptoms of the same disease when he was just 2 weeks old. He also needed a liver transplant, which he received that same year. Both children did very well after their transplants, but their blood work often showed abnormalities that required biopsies (a procedure to remove a small sample of liver tissue) for their care teams to rule out the possibility of organ rejection. The biopsies were always negative for rejection, which puzzled their physicians.

In the time between each sibling’s transplants came the rise of clinical genetic sequencing. In 2015, with the siblings’ two complete sets of genetic data to compare along with their parents’, whole-exome sequencing revealed a single-gene mutation that proved to be the cause of the children’s liver disease.

The diagnosis indicated a genetic cause for what is known as progressive familial intrahepatic cholestasis (PFIC) in neonates. PFIC is a disorder in which the liver fails to secrete bile acids normally, which progressively injures the liver and eventually leads to liver failure. For Alejandra and Adrian, the discovery also meant that their transplanted livers were in fact healthy.

“Once we learned about the affected gene, it became clear how the lack of this protein resulted in the clinical symptoms, and it provided an explanation for the abnormal lab values we kept seeing. The protein was also lacking in the intestine, and the normal cross-talk between the liver and intestine was not happening normally,” explained the sibling’s geneticist Natalia Gomez-Ospina, PhD, MD. She was the lead author on a paper highlighting the discovery in Nature Communications. The gene mutation is now part of the gene panel that is tested for in other babies who present symptoms of liver disease.

“This is a brand-new condition, so we are learning how it impacts other tissues in their bodies, and we can potentially identify new therapies that can treat them,” said William Berquist, MD, pediatric gastroenterologist. “We can also add another diagnosis to help other families and doctors, hopefully saving time in future investigations and allowing providers to better tailor their treatment plans.”

“That is the power of whole-exome sequencing,” remarked Louanne Hudgins, MD, co-medical director of the new collaborative Clinical Genomics Program launched on February 28, 2018, at Stanford Health Care and Stanford Medicine Children’s Health. “It allows us to make accurate diagnoses in 25 to 30 percent of cases. This has been a total boon to what we do clinically. And it has been a total boon for gene discovery.”

In addition to conducting the initial whole-exome sequencing, every year specialists at the Clinical Genomics Program will consider reanalyzing the sequencing data from patients for who a genetic cause was not initially identified. New genes and new mutations in existing genes are continually being identified “With yearly reanalysis, we can continue to make diagnoses for years,” stated Hudgins.

According to Hudgins, by performing the interpretation of the sequencing data in house, this improves coordination between the doctor requesting the test and the team performing the genetic analysis. This helps pinpoint more precise diagnoses for patients.

While the long-term impact of their condition remains to be known, today both Alejandra and Adrian are doing well. Alejandra is in eighth grade and enjoys running and reading. Adrian is active and playful.

In light of the children’s diagnoses, Berquist acknowledges that the care team feels comfortable not doing as many biopsies. That means less time in the hospital for the kids, which their mother, Socorro Ayala-Paredes, is grateful for.

“Nothing makes me happier than seeing my children feeling healthy and just getting to be kids.”