A competition to identify and explain genetic mutations using genome sequencing has solved an 11-year mystery for the family of a boy with centronuclear myopathy
Update (Oct. 1, 2013): For more about the titin gene and CNM, see Titin Mutations Can Cause CNM, posted Sept. 23, 2013.
Update (Dec. 4, 2012): This story was updated to reflect that the 13 previously identified genes that were tested as potentially associated with Adam Foye's disease were genes for various disorders that cause muscle weakness, not just centronuclear myopathy. Including titin, there are five genes now known to be associated with CNM.
A unique international contest organized by Boston Children’s Hospital has solved a genetic mystery for the family of a boy diagnosed with centronuclear myopathy (CNM).
|From left: A 2007 photo shows Elizabeth DeChene, research coordinator and genetic counselor in Beggs' lab; researcher Alan Beggs; and Patrick and Sarah Foye with son Adam who has CNM.|
Adam Foy, 11, of Pinebrook, N.J., received a CNM diagnosis at 13 months of age, based on a muscle biopsy. However, Adam — who has muscle weakness and fatigue that severely limit his activities — does not have abnormalities in any of 13 genes previously associated with muscle weakness. Neither his parents nor his extended family have a history of muscle weakness.
The mystery was solved through a contest designed to further the burgeoning science of genome sequencing — CLARITY (Children’s Leadership Award for the Reliable Interpretation and appropriate Transmission of Your genomic information).
Genome sequencing — analyzing an individual’s entire genetic code or “genome” — is rapidly becoming faster, cheaper and more readily available to consumers. But the field has not advanced as quickly in understanding how to apply the findings from genome sequencing to everyday patient care. The CLARITY Challenge was designed to answer such questions as:
CLARITY was won by a multi-institution team led by the Brigham and Women’s Hospital Division of Genetics in Boston, Mass., one of 23 research groups from around the world that submitted complete entries.
But the real winners are the families of three children with rare conditions who now have a clearer understanding of the likely genetic culprits — including the Foye family.
The winning team identified alterations in the gene for a protein called titin as the likely cause of Adam’s muscle weakness. Adam’s disorder is recessive, meaning that both of his parents are carriers for a mutation in the titin gene, but do not have symptoms of the disorder. The titin gene encodes a spring-like protein that is part of the main contractile structure in skeletal and heart muscle tissue.
Since titin gene mutations have previously been associated with heart problems, the finding suggests that Adam should be monitored more regularly with cardiac testing. The Foyes also could have prenatal testing for titin mutations should they decide to have another child.
Alan Beggs, CLARITY co-organizer and director of the Manton Center for Orphan Disease Research at Boston Children’s Hospital, notes that even if titin mutations had been suspected previously, sequencing the gene individually in Adam’s family would have taken nine months, because of its enormous size. (Sequencing the entire genome at once, and ignoring everything except the gene of interest, is actually faster and cheaper.)
Beggs, who holds a current MDA grant for research in congenital myopathies (including CNM), now plans a research project to model the titin defect in zebrafish, allowing large-scale testing of drugs that might help compensate for the defect.
The competition also identified a probable genetic cause for heart rhythm disturbances in a second family, whose son died 12 days after birth.
The genetic cause of a third child’s neuromuscular disorder, nemaline myopathy (NM), was narrowed down, but remains unclear. Seven genetic variants were cited by two or more CLARITY contestants, of which four variants were judged worthy of further investigation. This includes variants of two genes never before associated with NM. The Manton Center plans to explore these variants further to see if they are causative for the disease.
The Foye family is “thrilled” that this diagnostic milestone has been passed — although it doesn’t mark the end of Adam’s journey with CNM. Adam currently is an above-average sixth-grade student whose significant muscle weakness prevents him from carrying his own school books, makes him vulnerable to respiratory infections and requires him to use assisted ventilation at night. He can walk for limited distances (up to four city blocks) and uses a stroller or scooter for longer distances.
“We’ve been celebrating, we’ve been waiting for an answer for 11 years,” Sarah Foye, Adam’s mother, said in a press release. “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.”
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