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Exome Sequencing Identifies a Puzzling Disorder

Linda Seaton
| Nov 15, 2013

uniquenessChildren are cute, smart, funny, and energetic. Each is unique and that’s what makes them so special to us. Yet, when it comes to their health, a child who’s one of a kind isn’t necessarily a good thing.

That’s what Dr. Hugh Rienhoff found out soon after his daughter Bea was born. Bea is medically one of a kind, afflicted with a disorder so rare that it hasn’t even found its way into the medical literature yet. Her mix of symptoms has made it difficult to pinpoint the cause of her disorder. Her long, twiggy stature and flat feet are typical of Marfan syndrome, while joint contractures in her fingers and toes are similar to those seen in distal arthrogryposis, and her muscle weakness similar to Beals-Hecht syndrome. Yet, she doesn’t possess the complete list of hallmarks of any of these disorders

It’s been a long, tough journey for Bea and her Dad. She’s been examined by dozens of specialists, from orthopedists to geneticists and none have been able to diagnose her condition. In 2007, Dr. Rienhoff decided to start looking for the answer in Bea’s genome. He had bumped into Illumina CEO Jay Flatley at a meeting, and after hearing Bea’s story, Jay suggested that he contact Dr. Gary Schroth who leads the RNA research group at Illumina. Dr. Schroth and his team sequenced Bea’s transcriptome with Illumina next-generation sequencing (NGS). Nothing. Then they performed exome sequencing. Lo and behold they identified a mutation (TGF-β3G1226A) that could be the cause of Bea’s disorder.

The discovery hasn’t marked the end of Bea and her Dad’s journey. Dr. Rienhoff is now studying mice with Bea’s allele knocked in to determine the functional effects of the TGF-β3G1226A gene mutation. And he’s still looking for someone else with Bea’s disorder. As Dr. Rienhoff says, “I’d really like to find a bunch of octogenarians who have this mutation and who are just as cute as they were when they were eight years old.”