the AJMG SEQUENCE
Rasopathy diagnosis advances
Quick, accurate diagnoses are now commonplace
With multigene chips now common in identification of RASopathies and whole exome sequencing (WES) emerging in diagnosis of these disorders, clinicians and laboratorians say pinpointing their molecular cause has gotten much easier.
Symptoms of Noonan syndrome, cardo-facio-cutaneous syndrome (CFC), Costello syndrome, neurofibromatosis 1, and Noonan syndrome with multiple lentigines (formerly known as LEOPARD syndrome) often overlap and make these RASopathies difficult to diagnose, especially in young children. While each disorder has a distinct phenotype, all of them involve facial dysmorphism, a wide spectrum of cardiac disease, reduced postnatal growth, and ectodermal and skeletal defects. The disorders are collectively called RASopathies because they result from germ line mutations in genes that encode protein components of the RAS-MAPK pathway. Their incidence ranges from a few hundred cases worldwide to about 1 in 2,000.
With genetic testing, identifying the cause of symptoms, and the right course of care, has become easier and has shortened families' diagnostic odysseys, say RASopathy specialists.
Research and testing advances have made this possible. The 2001 discovery of PTPN11, which causes Noonan syndrome, kicked off the discovery of causative genes. Today, 12 genes are known to cause RASopathies. Molecular diagnosis began in the mid-2000s with single gene tests that helped confirm diagnoses and sometimes quicken them. Families sometimes had to wait for results of multiple gene tests before one identified a cause. By 2007, some labs had begun multigene panels and expanded them as new causative mutations were discovered, says Katherine Rauen, MD, PhD, Associate Adjunct Professor of Medicine and Director of the NF/Ras Pathway Clinic at the University of California, San Francisco, Helen Diller Family Comprehensive Cancer Center.
For example, with a Costello syndrome diagnosis, Dr. Rauen knows to watch for signs of certain cancers that aren't features of Noonan syndrome or CFC. If a child has CFC caused by a mutation in the v-raf murine sarcoma viral oncogene homolog B1 gene (BRAF), it is less likely that parents are carriers. However, a Noonan syndrome diagnosis has family planning implications for parents. That disorder may be inherited from parents, but their carrier status “doesn't come to their attention until the child is examined,” Dr. Rauen says.
Gene panels for RASopathy tests will give way to genomic sequencing in a few years, Dr. Rauen predicts, and as WES becomes cheaper and reveals more information, using it will make more sense.
Sherri Bale, PhD, and Managing Director of GeneDx, has had WES orders from physicians who suspect a RASopathy in children. “Clinicians are ordering WES for two reasons. They have been working up a child for years and this is a last-ditch effort, or they are considering 20 or 30 possible genes, so it's cheaper to do whole exome sequencing up front,” she says.
“If I had a patient whom I thought had a RASopathy, but a comprehensive panel didn't diagnose one, I'd do whole exome sequencing,” explains Karen Gripp, MD, Chief of the Division of Genetics and Director of the MAP Program for Genetic Disorders at Nemours/Alfred I. duPont Hospital for Children in Wilmington, Delaware.
Both approaches have strengths and weaknesses. A panel will provide more reliable, detailed information about a particular RASopathy, notes Dr. Gripp who discovered a rare H-ras gene mutation through a panel. But, WES is very sensitive to single nucleotide polymorphisms and missense changes and can pick up rare mutations in genes not included in a limited panel approach, Drs. Gripp and Bale add.
Dr. Bale points out that WES captures all of a child's genomic data at once and can be re-mined bioinformatically in the future. However, WES requires several steps beforehand, including genetic counseling and insurance approval, and requires more time for analysis and interpretation, Dr. Gripp says.
Parent Advocates' view
Whether by WES or panel, a molecular diagnosis is a boon for patients and families, says Lisa Schill, a parent advocate with the RASopathies Foundation in Wheaton, Illinois. A panel test found the PTPN 11 mutation causing Noonan syndrome in her son, Max, when he was 18 months old. The diagnosis allowed her to anticipate problems caused by her son's condition and address them.
Colin Stone, founder of the International Costello Syndrome Support Group in the U.K., values molecular tests, but places great faith in geneticists' clinical skills. His 18-year-old daughter, Helaina, was diagnosed with the condition— without such assays—at 3 months old.