Boston Children's Hospital announces international genomics competition winner

Boston Children's Hospital announces international genomics competition winner

PR Newswire

SAN FRANCISCO, Nov. 7, 2012

Results will inform "best practices" for field where standards are lacking

SAN FRANCISCO, Nov. 7, 2012 /PRNewswire-USNewswire/ -- 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, the Division of Clinical Genetics at Brigham and Women's
Hospital, Boston, 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 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 (Tubingen) 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's design

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. 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 Corporationand 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 Adam 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.

Eight of the 23 CLARITY contestants identified alterations in a gene called
titin as the cause of Adam'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, Ph.D., director of the Manton Center for
Orphan Disease Researchat Boston Children's, had independently identified
titin mutations in four other patients with centronuclear myopathy by using
whole-exome sequencing. "Even if we had suspected titin mutations in Adam,
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, Adam'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, Ph.D., 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, and see:

  oThirty teams compete to interpret three families' genomes (press release)
  oBoston Children's Hospital launches CLARITY challenge (press release)
  oSeeking CLARITY: Genomics sleuths set out for the prize
  oThree families, three mysteries: Results soon to come from genomic
  oWhole-genome sequencing in medicine: New knowledge, new responsibilities

Boston Children's Hospitalis 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:

Keri Stedman
Boston Children's Hospital
(cell 774-244-6490 at ASHG meeting)

Cathy Yarbrough

SOURCE Boston Children's Hospital

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