May 15, 2015
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Genetic testing can influence treatment aid, discovery of endocrine disorders

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NASHVILLE, Tenn. — The study of human genetics  either through exome sequencing or through targeted sequencing — can have both immediate and long-term impact on endocrine practice, leading to the diagnosis of unrecognized single-gene disorders and allowing clinicians to implement more successful treatment therapies.

According to a presenter at the 24th annual American Association of Clinical Endocrinologists Scientific & Clinical Congress, identifying patients with Mendelian or non-Mendelian disorders through genetic screening can provide much-needed insight into various endocrine cancers and diseases.

Once a particular genetic mutation is discovered, some patients should actually get treated differently than those without the genetic mutation but the same disorder, said Joel Hirschhorn, MD, PhD, a professor of pediatrics at Harvard Medical School in Boston. “There’s good evidence for a few of these [genetic] diseases that the treatment plan should be altered from the diagnosis.”

Joel Hirschhorn

Joel Hirschhorn

Speaking during a conference presentation, Hirschhorn said a genetic diagnosis could have multiple benefits for both the clinician and the patient. Hirschhorn pointed to examples like maturity onset diabetes of the young, or MODY, a form of monogenic diabetes caused by mutations in different genes. MODY, Hirschhorn said, is often underdiagnosed in patients, and a particular genetic variation of MODY can influence the type of treatment that will work most effectively.

There are also hundreds of genetic disorders associated with short stature, Hirschhorn said, as well as many rare genetic mutations that can lead to severe obesity, where a diagnosis can be made that influences treatment.

“This serves as a very potent reminder that in fact … what may appear to be a behavior phenotype can be profoundly influenced by endocrine physiology,” Hirschhorn said.

“There are really two main impacts of genetics on endocrinology,” Hirschhorn told Endocrine Today. “One is a short-term impact, in that many patients have single-gene disorders that go unrecognized and can be discovered by genetic testing. The other is that genetic studies of human disease, in the longer term, are going to help us understand the biology and hopefully help lead to better therapies.”

Because genetic disorders are often highly penetrant within families, Hirschhorn said, a diagnosis could lead to needed counseling for the patient’s relatives. A diagnosis can also have a positive psychological impact on the patient, he said, ending what he called a “diagnostic odyssey” of countless tests to discover what may be causing their illness.

Exome sequencing, Hirschhorn said, has revolutionized genetic discovery, allowing geneticists to sequence entire exomes for less than it used to cost to screen for one gene. Approximately 20% to 50% of patients with high suspicion of a genetic disorder can receive a diagnosis from exome sequencing, Hirschhorn said.

Exome sequencing is not perfect, Hirschhorn said. Interpreting sequences can be difficult, though growing reference databases are improving outcomes. There is also the potential for discovering incidental findings and how those discoveries can impact patients and their families.

Targeted genetic testing, Hirschhorn said, may be more sensitive and have fewer incidental findings. Exome sequencing, however, is more comprehensive and “does not rely on guessing the correct gene.

“Understanding the genetic basis of a patient’s symptoms should affect clinical management,” Hirschhorn said. “The only way to know that is to be able to identify those patients in the first place.” – by Regina Schaffer

Reference:

Hirschhorn J. Oral presentation FGS2. Presented at: AACE 24th Annual Scientific & Clinical Congress; May 13-17, 2014; Nashville, Tenn.

Disclosure: Hirschhorn reports receiving a research grant from Pfizer in pharmacogenetics research.