Unsatisfied, Rienhoff went back to Illumina in 2009 to ask for more help. He proposed exome sequencing, which captures the whole protein-encoding portion of the genome, and is in some ways more comprehensive than transcriptome sequencing. At the time, Illumina was developing its exome-sequencing technology, and the company again took on the Rienhoff family as a test group.
The analysis pulled up a mutation in one copy of the gene that encodes TGF-β3 — just in Bea. In cell culture and experiments in frog eggs, the faulty gene seems to produce a non-functional protein that reduces TGF-β signaling. This mechanism would differ from what many suspect is going on in Marfan and Loeys–Dietz syndromes, in which mutations paradoxically amp up TGF-β signaling. A collaborator of Rienhoff is now engineering a mouse that shares Bea’s gene variant, which could help to clarify whether the mutation revs up signaling or suppresses it.
The latest study does not define a new ‘Rienhoff syndrome’. For that, Rienhoff and his collaborators would need to find other patients who share Bea’s features and genetic markers. Rienhoff says that he would be relieved if he found an older person with similar symptoms who seems as vivacious as his daughter, who recently earned an orange belt in karate; it would tell him that cardiovascular complications are not pre-ordained. “If I saw a single case, I might say, ‘Hallelujah’,” he says.