Skin Health: New Insights from a Rare Disease

Forehead of study participant with rare form of ichthyosis

Courtesy of Keith Choate, Yale University School of Medicine, New Haven, CT

Skin is the largest organ in the human body, yet we often take for granted all of the wonderful things that it does to keep us healthy. That’s not the case for people who suffer from a group of rare, scale-forming skin disorders known as ichthyoses, which are named after “ichthys,” the Greek word for fish.

Each year, more than 16,000 babies around the world are born with ichthyoses [1], and researchers have identified so far more than 50 gene mutations responsible for various types and subtypes of the disease. Now, an NIH-funded research team has found yet another genetic cause—and this one has important implications for treatment. The new discovery implicates misspellings in a gene that codes for an enzyme playing a critical role in building ceramide—fatty molecules that help keep the skin moist. Without healthy ceramide, the skin develops dry, scale-like plaques that can leave people vulnerable to infections and other health problems.

Two patients with this newly characterized form of ichthyosis were treated with isotretinoin (Accutane), a common prescription acne medication, and found that their symptoms resolved almost entirely. Together, the findings suggest that isotretinoin works not only by encouraging the rapid turnover of skin cells but also by spurring patients’ skin to boost ceramide production, albeit through a different biological pathway.

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International “Big Data” Study Offers Fresh Insights into T2D

World map

Caption: This international “Big Data” study involved hundreds of researchers in 22 countries (red).

It’s estimated that about 10 percent of the world’s population either has type 2 diabetes (T2D) or will develop the disease during their lives [1]. Type 2 diabetes (formerly called “adult-onset”) happens when the body doesn’t produce or use insulin properly, causing glucose levels to rise. While diet and exercise are critical contributory factors to this potentially devastating disease, genetic factors are also important. In fact, over the last decade alone, studies have turned up more than 80 genetic regions that contribute to T2D risk, with much more still to be discovered.

Now, a major international effort, which includes work from my own NIH intramural research laboratory, has published new data that accelerate understanding of how a person’s genetic background contributes to T2D risk. The new study, reported in Nature and unprecedented in its investigative scale and scope, pulled together the largest-ever inventory of DNA sequence changes involved in T2D, and compared their distribution in people from around the world [2]. This “Big Data” strategy has already yielded important new insights into the biology underlying the disease, some of which may yield novel approaches to diabetes treatment and prevention.

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Study Shows DNA Sequencing Brings Greater Precision to Childhood Cancer

Dr. Plon with a patient and her family

Caption: Baylor’s Sharon Plon consults with a family at the Texas Children’s Cancer Center in Houston.
Credit: Paul V. Kuntz/Texas Children’s Hospital

An impressive number of fundamental advances in our understanding of cancer have occurred over the past several decades. One of the most profound is the realization that cancer is a disease of the genome, driven by a wide array of changes in DNA—some in the germline and affecting all cells of the body, but most occurring in individual cells during life (so-called “somatic mutations”). As the technology for sequencing cancer genomes has advanced, we are learning that virtually all cancers carry a unique set of mutations. Most are DNA copying errors of no significance (we call those “passengers”), but a few of them occur in genes that regulate cell growth and contribute causatively to the cancer (we call those “drivers”). We are now learning that it may be far more important for treating cancer to figure out what driver mutations are present in a patient’s tumor than to identify in which organ it arose. And, as a new study shows, this approach even appears to have potential to help cancer’s littlest victims.

Using genomic technology to analyze both tumor and blood samples from a large number of children who’d been newly diagnosed with cancer, an NIH-funded research team uncovered genetic clues with the potential to refine diagnosis, identify inherited cancer susceptibility, or guide treatment for nearly 40 percent of the children [1]. The potential driver mutations spanned a broad spectrum of genes previously implicated not only in pediatric cancers, but also in adult cancers. While much more work remains to determine how genomic analyses can be used to devise precise, new strategies for treating kids with cancer, the study provides an excellent example of the kind of research that NIH hopes to accelerate under the nation’s new cancer “moonshot,”  a research initiative recently announced by the President and being led by the Vice President.

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Genome Sequencing: Exploring the Diagnostic Promise

Hanners Family

Caption: Whole genome sequencing revealed that sisters Addison and Trinity Hanners, ages 7 and 10, shown here with their mother Hanna, have a rare syndrome caused by a mutation in the MAGEL2 gene.
Credit: Courtesy of the Hanners family

At the time that we completed a draft of the 3 billion letters of the human genome about a decade ago, it would have cost about $100 million to sequence a second human genome. Today, thanks to advances in DNA sequencing technology, it will soon be possible to sequence your genome or mine for  $1,000 or less. All of this progress has made genome sequencing a far more realistic clinical option to consider for people, especially children, who suffer from baffling disorders that can’t be precisely diagnosed by other medical tests.

While researchers are still in the process of evaluating genome sequencing for routine clinical use, and data analysis continues to be a major challenge, one area of considerable promise centers on neurodevelopmental disorders. Such disorders—which affect about 3 percent of children—range from relatively common conditions like autism spectrum disorder to very rare conditions that impair the development of the brain or central nervous system. In the latest study, an NIH-funded research team reports that sequencing either a patient’s whole genome or whole exome (the 1.5 percent of the genome that encodes proteins) appears to be an effective—as well as a cost-effective—strategy for diagnosing neurodevelopmental disorders that have eluded diagnosis through standard means.

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