Results will inform “best practices” for field where standards are lacking
November 7, 2012
San Francisco—A first-of-its-kind international contest organized by Boston Children’s Hospital, known as CLARITY, solves at least one family’s genetic mystery while taking the first steps toward establishing “best practices” for using genomic sequencing in patient care safely, responsibly and in a meaningful way.
The contest winner, a multi-institution team led by Brigham and Women's Hospital's (BWH) Division of Genetics (Boston, Mass.), was one of 23 research groups competing to provide the best interpretation and communication of DNA sequencing results. Results were announced today at the American Society of Human Genetics (ASHG) annual meeting (Moscone Convention Center, hashtag #CLARITYDNA) and will be detailed in a forthcoming paper.
As testing costs go down, genomic sequencing is increasingly offered to patients, sometimes direct to consumer. Yet there haven’t been standards for interpreting the voluminous DNA data, identifying actionable findings, communicating them to doctors and patients and dealing with unexpected, incidental findings.
“The community took this challenge very seriously, and we had tremendous participation,” says CLARITY co-organizer David Margulies, MD, executive director of the Gene Partnership at Boston Children’s Hospital. “We got the best thinking from around the world, and it has moved us toward a consensus on how to report sequencing data for use in the clinic.”
The winning team--led by the BWH Division of Genetics with members from Massachusetts General Hospital (Boston), Partners Laboratory for Molecular Medicine (Boston), Brown University (Providence, RI) and Utrecht University (Netherlands)--was awarded $15,000. Two finalist teams were awarded $5,000 each: the University of Iowa and a German team comprised of Genomatix (Munich), CeGaT (Tübingen) and the Institute of Pathology at University Hospital of Bonn (Bonn).
Five additional teams received Special Mention for their contributions: the Clinical Institute of Medical Genetics (Ljubljana, Slovenia); The Research Institute at Nationwide Children's Hospital (Columbus, Ohio); Science for Life Laboratory (SciLifeLab) of the Karolinska Institute (Solna, Sweden); Scripps Genomic Medicine, Scripps Translational Science Institute (San Diego, Calif.); and a team comprised of SimulConsult (Chestnut Hill, Mass.) and Geisinger Health System (Danville, Pa.).
CLARITY (Children’s Leadership Award for the Reliable Interpretation and appropriate Transmission of Your genomic information) was launched in January 2012. It challenged contestants to interpret DNA sequences from three children with rare conditions for which no genetic cause had been identified, selected by the Manton Center for Orphan Disease Research at Boston Children’s Hospital. The children’s identities were kept anonymous.
Of 40 research groups that submitted applications, 30 were selected to compete (see backgrounder for a complete list). Each received medical data for the three children and their parents, along with whole-genome and whole-exome sequences generated by contest sponsors Life Technologies Corporation and Complete Genomics.
Twenty-three teams went on to submit complete entries, reviewed by an independent panel of judges using predefined criteria. While many entries got high marks, the Brigham and Women's team was judged to have the best combination of cutting-edge bioinformatic analysis, clarity and utility of its clinical reports for the three families, and appropriate identification of the families’ likely genetic defects. The two finalist teams were judged unique and outstanding in one or more areas; the Genomatix team was the only group to correctly flag every likely genetic mutation in all three families, while the University of Iowa team took unique approaches to returning unexpected genetic results based on patient preferences and indicating regions of low coverage or low confidence in their reports.
Answers for families
For one of the three families, CLARITY solved a mystery more than a decade old. Sixth-grader AJ Foye had undergone testing for every gene known to explain his type of muscle weakness, a condition called centronuclear myopathy, always with negative findings. He also has hearing impairment. (See backgrounder on the participating families.)
Eight of the 23 CLARITY contestants identified alterations in a gene called titin as the cause of AJ’s muscle weakness, and six teams identified mutations in a gene called GJB2 as the likely cause of his hearing loss. These results were judged to be correct, and three teams made both identifications.
CLARITY co-organizer Alan Beggs, PhD, director of the Manton Center for Orphan Disease Research at Boston Children’s, had independently identifiedtitin mutations in four other patients with centronuclear myopathy by using whole-exome sequencing. “Even if we had suspected titin mutations in AJ, it’s an enormous gene, and to sequence it individually, by hand, would have taken nine months in the lab, at a prohibitive cost,” Beggs says. “That’s why genomic sequencing is such a revolutionary technology.”
Titin’s involvement makes biological sense, Beggs adds, since its protein makes up part of the contractile structure in muscles. Beggs now plans to model the titin defect in zebrafish, allowing his team to do large-scale testing of potential drugs that might correct it.
“We’ve been celebrating, we’ve been waiting for an answer for 11 years,” says Sarah Foye, AJ’s mother. “It doesn’t mean we know the treatment now, but it’s pointing us in the right direction and we can cross other possibilities off the list.”
The contest also identified a probable cause for heart rhythm disturbances in the second family, whose son Liam Burns died 12 days after birth: mutation of a gene called TRPM4, cited by seven teams as likely to be causative. In addition to rhythm disturbances, Liam and several other family members had structural heart defects that remain unexplained by CLARITY; Boston Children’s researchers at The Manton Center are investigating whether the TRPM4 alterations are involved.
The genetic cause of the third child’s disorder, another muscle-weakening disease known as nemaline myopathy, remains unclear. In all, seven genetic variants were cited by two or more contestants; four were judged worthy of further investigation, including variants of two genes never before associated with nemaline myopathy. The Manton Center at Boston Children’s plans to explore these genes further to see if the variants are causative.
Guidance for best practices
There was considerable variability among the contestants’ techniques and findings, to be described in the forthcoming paper. However, the teams that were finalists had methods and results that were sound and substantially similar, says Margulies.
“When these best practices are disseminated, skilled practitioners around the world will be able to benchmark themselves against them,” he says.“Through CLARITY, we’ve learned that the best teams in the world, when given raw sequence data, agree fairly closely on results, the meaning of the results and how to deliver them. The best teams were able to elucidate a precise cause for previously unexplained genetic disorders.”
“The contestants have demonstrated that genomics, bioinformatics and biotechnology can now have routine relevance in clinical care,” says Isaac Kohane, MD, PhD, chair of the Children’s Hospital Informatics Program and CLARITY’s third co-organizer. “They also demonstrate the range of disciplines required to safely and rapidly interpret the millions of variants that are present in all of our genomes.”
The CLARITY team plans a second challenge around interpretation of cancer genomes, and will lead a Clinical Bioinformatics Summit in Boston next spring to hammer out the details.
“It is essential that families are cared for by practitioners who are trained in the use of genomic analysis,” notes Margulies. “Training of care providers will be the next challenge.”
For further background, visit www.childrenshospital.org/CLARITY, and see:
(cell 774-244-6490 at ASHG meeting)
Boston Children’s Hospital is home to the world’s largest research enterprise based at a pediatric medical center, where its discoveries have benefited both children and adults since 1869. More than 1,100 scientists, including nine members of the National Academy of Sciences, 11 members of the Institute of Medicine and nine members of the Howard Hughes Medical Institute comprise Boston Children’s research community. Founded as a 20-bed hospital for children, Boston Children’s today is a 395-bed comprehensive center for pediatric and adolescent health care grounded in the values of excellence in patient care and sensitivity to the complex needs and diversity of children and families. Boston Children’s also is a teaching affiliate of Harvard Medical School. For more information about research and clinical innovation at Boston Children’s, visit: http://vectorblog.org/.