Clinical Genetics Branch Discovery: RTEL1 Founder Mutation Among Ashkenazi Jews

February 22, 2016, by DCEG Staff

by Victoria A. Fisher, M.P.H.

For over 15 years, researchers in the Clinical Genetics Branch (CGB) have made great strides in understanding the clinical and laboratory features of dyskeratosis congenita (DC). They’ve been at the forefront of gene discovery for this disorder, utilizing the latest methods and technologies to identify a number of new genes. Led by Branch Chief Sharon Savage, M.D., their work has reached beyond the clinic to directly improve the lives of patients and families with DC. Recently, investigators identified a rare founder mutation in a DC susceptibility gene that will be included in future genetic carrier screening panels for Ashkenazi Jews.

DC is a rare inherited bone marrow failure and cancer predisposition syndrome caused by abnormal telomere biology. Telomeres are specialized structures at the ends of chromosomes that are essential for maintaining chromosomal integrity. DC is often diagnosed in childhood, but individuals can develop features of DC at any age. Families who have one child with DC are at high risk for having future children with the disorder.

Through family-based genetic linkage studies and more recent exome sequencing studies, Dr. Savage and colleagues have discovered several genes in which mutations cause DC, including TINF2, WRAP53, RTEL1, ACD, and PARN. Germline mutations in these genes plus six others are present in approximately 70 percent of DC patients. The remaining patients await new genes to be discovered.

In 2013, Dr. Savage and colleagues identified a homozygous recessive founder mutation in RTEL1 that causes Hoyeraal-Hreidarsson syndrome, a clinically severe variant of DC among Ashkenazi Jews (Ballew, 2013). The first major finding from DCEG’s whole-exome sequencing efforts, the RTEL1 discovery has led to a direct benefit for at least one DC family. The story has been covered in the popular press.

“It’s extremely rewarding to see the work of our exome sequencing studies lead to a family’s happy ending,” Dr. Savage said. “Patients and families are an important component of this research; family advocacy can really make a difference.”

Moving from the study housed at the NIH Clinical Center to the arena of population genetics, investigators collaborated with the Center for Rare Jewish Genetic Disorders and the Mount Sinai genetic testing laboratory to evaluate the frequency of the RTEL1 founder mutation among Ashkenazi Orthodox and the general Ashkenazi Jewish population. They found the mutation at a high-enough frequency (0.5 to 1% carrier frequency) to suggest its inclusion in future screening panels for this population (Fedick, 2014).

“The carrier frequency of this mutation was certainly higher than expected,” Dr. Savage said. “Eventually, we want to look at this variant in a larger number of samples to get an even more refined estimate of the population prevalence.”

In addition, questions about the specific action of RTEL1 mutations remain, and the known spectrum of disease caused by its variants is growing. The gene is recognized to be involved in telomere biology, but it encodes a multi-faceted protein that also has DNA helicase functions (important in DNA replication). “We’re still learning about this gene,” Dr. Savage said. “For example, there are variants associated with brain tumors and certain dominant mutations that cause pulmonary fibrosis, which is part of the DC phenotype. This particular RTEL1 variant found in Ashkenazi Jews—we don’t know if it can act in an autosomal dominant way, or if it is only recessive. This needs to be explored in the future.”

As chair of the medical board of the advocacy group Dyskeratosis Congenita Outreach, Inc., Dr. Savage recognizes the importance of this research to both clinicians and families. Many patients with DC still do not yet have an identified causative mutation.

“Finding these genes gives DC families an added identity and helps them to better understand their disease,” Dr. Savage said. “Even if finding the gene doesn’t necessarily mean that we can fix it, knowing the cause of disease makes a difference in the lives of our patients and families.”