For Gleeson, the search into this overlap is just one quarry in a broad hunt he began in 1999 to uncover genetic causes of rare childhood brain disorders—a mission that’s sent him across the Middle East, from the United Arab Emirates to Turkey. Gene hunting in that corner of the world offers rich bounty. It has become evident in recent years that autism arises from a tangled network of hundreds of genetic factors. Teasing apart that web has been a frustrating challenge for scientists in the U.S. and the U.K. because the populations there are genetically diverse, and autism usually results from changes in multiple genes. Yet each of those changes contributes only a small bit of risk, requiring large sample sizes to detect.

But in the Middle East, it’s common for first or second cousins to wed in “consanguineous” marriages, and families tend to be large. That raises the odds of spotting rare, high-impact causes of the condition: devastating “recessive” genetic disorders that crop up when children inherit two copies of one mutated gene in the family bloodline. In these individuals, autism can be severe and accompanied by problems such as epilepsy and intellectual disability. By studying such cases, it’s easier to find those single-gene culprits.

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The BCKDK detective story began in Istanbul, Turkey, with two sisters, Ceren and Seyma. Gleeson met them and the rest of “family 558” in 2006 at Istanbul University’s Faculty of Medicine hospital, not far from the famed Blue Mosque.

Steve McDonald / Spectrum

The hospital was equipped with the latest brain scanners and diagnostic labs, but lacked the cutting-edge genetic sequencing tools available in the U.S. The waiting room of the genetics department was crammed that day with families in line to see Gleeson, desperately seeking a full genetic evaluation of their children and their mysterious brain conditions.

Ceren and Seyma were teenagers then. “When they came in, the girls really could not be distinguished from any other case walking in with autism,” Gleeson says. They also had intellectual disability and a history of epilepsy; both were taking epilepsy drugs.

Because Ceren and Seyma’s parents are first cousins, Gleeson hoped that the two girls might hold the key to finding what he sought—a new genetic cause for autism, and one that might also offer clues about its link to epilepsy. Working with Hülya Kayserili and Rasim Ozgur Rosti, medical geneticists at the Istanbul hospital, he took blood samples from family 558 and many others, along with copies of relevant medical records. Back in the U.S., Gleeson and his team added the samples and data to a growing database of information from hundreds of Middle Eastern families—a trove of genetic secrets waiting to be mined.

Four years later, in 2010, the team began sending hundreds of DNA samples to the Broad Institute of Harvard and MIT in Cambridge, Massachusetts, to be sequenced. At the time, a quick sequencing method that decodes only the exome (the 1 percent of the genetic blueprint that codes for proteins) offered a major advance in speed and convenience, and scientists at the Broad Institute were well equipped to handle the analysis. But the detective work only began in earnest once the San Diego group got the data back. The researchers spent countless hours filtering through all the genetic mutations and variants in the exome sequences of children with both autism and epilepsy. For each child, the researchers identified a short list of possible disease-causing variants inherited from both sides of the family tree.