one else like Brian. Yet seven of the brothers—the seven who provided DeLisi with samples, including at least a few nondiagnosed brothers—all had this same mutation, in a gene that also figured prominently in other mental illnesses.
“Lynn was right,” McDonough said. Studying families with multiple occurrences of mental illness was, in the end, the study of a shared genetic issue—one that, depending on each person, manifests itself in a different way. “These are multiplex families, and it sure looks like the same genetic determinants can give rise to subtly different diseases.”
It’s possible that discoveries like the Galvin family’s mutation could point the way toward a completely new conception of mental illness. That could come sooner rather than later; in some corridors, it’s already happening. In 2010, the psychiatrist Thomas Insel, then director of NIMH, called for the research community to redefine schizophrenia as “a collection of neurodevelopmental disorders,” not one single disease. The end of schizophrenia as a monolithic diagnosis could mean the beginning of the end of the stigma surrounding the condition. What if schizophrenia wasn’t a disease at all, but a symptom?
“The metaphor I use is that years ago, clinicians used to look at ‘fever’ as one disease,” said John McGrath, an epidemiologist with Australia’s Queensland Centre for Mental Health Research and one of the world’s authorities on quantifying populations of mentally ill people. “Then they split it into different types of fevers. And then they realized it’s just a nonspecific reaction to various illnesses. Psychosis is just what the brain does when it’s not working very well.”
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THE SECOND SURPRISE was about Mimi. For decades, Mimi had insisted that the family illness came from Don’s side. As far as she was concerned, his history of depression proved it, and no one who researched the family ever had reason to disagree with her. “We were looking for something transmitted from the father,” McDonough said.
The SHANK2 mutation, however, came from the mother’s side of the family—suggesting that it could have been Mimi all along who was the carrier of the mutation responsible for the family illness. Another study of SHANK2 and schizophrenia, published at about the same time as McDonough and DeLisi’s study, noted several more instances of an unaffected mother passing along a mutation to a son who developed the disease. It should also be possible for a father to be an unaffected carrier—SHANK2 is not a sex-specific gene; it is not located on the X or Y chromosome, which determine sex, but on chromosome 11.
Why did six out of ten boys develop serious mental illness, but neither of the two girls? It might simply be chance—a roll of the dice working out for both sisters and four of the ten brothers. It could be that the Galvins’ SHANK2 issue points to, as DeLisi and her coauthors suggested in their study, an “as yet uncharacterized sex-dependent influence” on how the illness develops—though that would not account for the Galvin sons who didn’t get the disease.
Or it could be that the mutation on the mother’s side is mingling with something else on the father’s side—that the SHANK2 mutation does nothing by itself, but needs another mutation elsewhere to completely set the table for the disease. Such is the way, sometimes, with genetic mutations. The geneticist Kevin Mitchell has noted how specific mutations can manifest differently in different people: The same mutation can trigger epilepsy in some people while in others it triggers autism, schizophrenia, or nothing at all. And sometimes, a second rare mutation elsewhere in their genome suggests a combined effect.
It is possible, maybe even likely, that the genetic flaw that caused schizophrenia in the Galvin boys might not be Mimi’s fault or Don’s fault, but both of their faults together—an entirely original cocktail, powerful enough to change all of their lives.
CHAPTER 37
2016
University of Colorado Medical Center, Denver, Colorado
While DeLisi and her new partners at Amgen followed the trail of the SHANK2 gene in Cambridge, Robert Freedman was continuing his work in Denver. Like DeLisi, Freedman had experienced a long period of early promise, followed by a painful reversal of fortune—the excitement of isolating the first gene to play a confirmed role in schizophrenia, and the anguish of watching the drug trials to