Scientists can now better diagnose diseases with multiple genetic causes

Scientists at Baylor College of Medicine, Baylor Genetics, the University of Texas Health Science Center at Houston and Texas Children’s Hospital are combining descriptions of patients’ clinical features with their complex genetic information in a unified analysis to obtain more precise diagnoses of complex diseases, particularly those that involve more than one gene causing the condition.
The researchers anticipate that improved clinical and genetic diagnoses could lead to patients receiving more effective treatments and families benefiting from needed counselling.
“One of the main interests of our lab is to better understand the impact of genetic variation on human health and disease,” said co-first author Dr. Jennifer Posey, assistant professor of molecular and human genetics at Baylor.
“Traditionally, physicians have spoken of a unifying diagnosis, meaning that genetic conditions are due to mutations in only one gene,” said co-first author Dr. Tamar Harel, who was a genetics fellow at Baylor when she was working on this study and currently is a geneticist at Hadassah Medical Center in Israel. “Yet, we see here that two or more genes can be involved in a disease and produce a complex clinical picture. For many in the field, this is a revolutionary idea.”

The challenge of diagnosing diseases with multiple genetic causes
The researchers used whole exome sequencing to analyse all the genes in the genomes of nearly 7,400 unrelated patients with the goal of identifying the genetic cause of their conditions. They found a genetic cause in 2,076 of the 7,374 patients (28 percent); among these patients, 101 (approximately 5 percent) had two or more disease genes involved. If an individual has multiple defective genes, he or she may present with a complex set of clinical features that may lead to an imprecise diagnosis.
“Clinically, multiple genetic causes can be missed because a patient may present with characteristics that overlap those of two different conditions, so the patient can be diagnosed with one or the other,” said Posey. “Alternatively, a patient’s clinical characteristics may not match those of any described condition, so the patient may be diagnosed with what is thought to be a new condition.”
“In these situations, we, as physicians, have to think of the possibility that more than one gene might be involved in the patient’s disease,” said senior author Dr. James R. Lupski, Cullen Professor of Molecular and Human Genetics at Baylor. “Our study shows the limitations of defining a disease according to what we see in the clinic alone. Our work shows the need to consider that a patient may have two or more genetic diseases, not one, and to send for a genomic test to help sort out the patient’s condition and causes of it.”

Paving a future toward more precise multiple genetic diagnoses
“One of the contributions of our work involves utilization of a structured phenotype ontology,” said Posey. “This computational tool allows us to model complex clinical features (phenotypes) that can result when more than one gene is involved, in order to better understand, from the perspective of the physician, how such cases may present in the clinic.”
Furthermore, Dr. Regis James, now at Regeneron Pharmaceuticals, previously created OMIM Explorer while training as a graduate student at BCM. OMIM Explorer is a tool that helps analyse genomic data in the context of the clinical characteristics of the patient. Both James and his thesis advisor and mentor, Dr. Chad Shaw, director of bioinformatics at Baylor Genetics and associate professor of molecular and human genetics at Baylor, were contributors to this work.
“It provides a more complete perspective of how genes and physical traits relate to each other,” said Lupski.
“My colleagues and I anticipate that in the future, geneticists, clinicians and mathematicians will work together using genetic and clinical information to make diagnostic and therapeutic decisions,” said Harel.

Baylor College of Medicine http://tinyurl.com/jm44mr5