Families and Results
Participating Families in The Boston Childrenâ€™s Hospital CLARITY Challenge
Adam Foye (parents Sarah and Patrick Foye), is an 11-year-old currently in sixth grade. He was born with muscle weakness and was delayed in his motor development as an infant. Because of low muscle tone, he had difficulties with feeding as a baby, has curvature of the spine (treated with a brace) and is vulnerable to respiratory infections. He fatigues easily and requires breathing assistance at night with a nasal ventilator. He walks for limited distances (up to four city blocks) and uses a stroller or scooter for longer distances.
Adam was diagnosed with centronuclear myopathy, a rare muscle disease, based on a muscle biopsy at 13 months of age. Adam was also diagnosed with sensorineural hearing loss as an infant and wears hearing aids in both ears.
Adam appears to be the only member of his family with muscle weakness. He has tested negative for 13 genes previously associated with muscle weakness, including some discovered at Boston Childrenâ€™s Hospital.
The CLARITY Challenge identified alterations in a gene called titin (TTN) as the likely cause of Adamâ€™s muscle weakness, and six teams also identified mutations in a gene called GJB2 as the likely cause of Adamâ€™s hearing loss. Both of these are recessive mutations, meaning that both of Adamâ€™s parents are carriers for each of these genes, but are not themselves affected.
Since titin has previously been associated with heart problems, the finding suggests that Adam should be monitored more regularly with cardiac testing. The Foyes could also have prenatal testing for titin should they decide to have another child.
The titin gene encodes a spring-like protein that is part of the main contractile structure in muscles (known as the sarcomere).
Alan Beggs, PhD, CLARITY co-organizer and director of the Manton Center for Orphan Disease ResearchÂ at Boston Childrenâ€™s Hospital, notes that even if titin had been suspected previously, sequencing it individually in Adamâ€™s family would have taken nine months, because of the geneâ€™s enormous size. (Sequencing the entire genome at once, and ignoring everything except the gene of interest, is actually faster and cheaper.) Beggs now plans a research project to model the titin defect in zebrafish, allowing large-scale testing of drugs that might correct the defect.
The Burns family sought genetic testing after Liam Burns died 12 days after birth from multiple cardiac defects: an underdeveloped (hypoplastic) right heart, a narrowed artery to the lungs (pulmonary stenosis) and a block in electrical conduction (a type II atrioventricular block). Liamâ€™s sister Eloise, born two years later, is a healthy baby with no heart problem
Three other family members also have right-sided heart defects of lesser, varying severity:
- Liamâ€™s 6-year-old first cousin has an arrhythmia known as right bundle branch block (RBBB) that does not cause any symptoms (her sister, 4, is free of heart problems).
- Liamâ€™s maternal aunt (the cousinsâ€™ mother) has RBBB that does not cause symptoms. Liamâ€™s father Casey has a heart block and arrhythmia requiring a pacemaker, as well as structural defects (coarctation of the aorta and pulmonary stenosis).
- Liamâ€™s father and aunt (who are brother and sister) had a third sibling who died as a newborn from heart complications.
The CLARITY Challenge identified mutation of a gene called TRPM4 as the likely cause of the heart rhythm disturbances in the Burns family. It encodes a protein that acts as a gate, allowing electrical charges in and out of cells. Build-up and discharge of these charges is part of normal muscle function.
The cause of the familyâ€™s structural heart defects remains uncertain. They may also be caused by TRPM4, or the family may have an unrelated mutation in a different gene. The CLARITY team plans to investigate further in consultation with experts in cardiac genetics.
The third child, a 7-year-old boy, was diagnosed with nemaline myopathy, another rare muscle disorder. His case is relatively mild, so he can breathe independently and walk with a walker, occasionally using a stroller or scooter for longer distances. In addition to muscle weakness, he was born with clubbed feet, pectus excavatum (sunken chest), osteoporosis and a dislocated elbow. His parents are unaffected.
The CLARITY Challenge did not lead to any firm gene identifications for this family. Mutations in seven different genes were cited as plausible possible causes, and the case was especially strong for four genes. Of these four, two genes have been linked with nemaline myopathy in the past, and two have not but were flagged by multiple teams. Whether those genes are actually connected to the disease remains to be seen with further research.