Researchers at Johns Hopkins have discovered that two clinically different inherited syndromes are in fact variations of the same disorder. The team suggests that at least for this class of disorders, the total number and “strength” of genetic alterations an individual carries throughout the genome can generate a range of symptoms wide enough to appear like different conditions.

“We’re finally beginning to blur the boundaries encompassing some of these diseases by showing that they share the same molecular underpinnings,” says Nicholas Katsanis, Ph.D., an associate professor of ophthalmology at the McKusick-Nathans Institute of Genetic Medicine at Hopkins. “This is important progress for several reasons. First, knowing what’s going on molecularly and being able to integrate rarer conditions under common mechanisms allows us to potentially help more people at once. Second, clinicians can finally begin to offer more accurate diagnoses based on what really matters: the state of affairs at the cellular/biochemical level. In time, this will empower genetic counseling and much improved patient management.”

Katsanis’s team studies Bardet-Biedl syndrome (BBS), a rare so-called ciliopathy that is characterized by a combination of vision loss, obesity, diabetes, extra digits and mental defects and caused by faulty cilia, tiny hairlike projections found on almost every cell of the body. Recently they started looking at another disease, Meckel-Gruber syndrome (MKS), which also shows cilia dysfunction but is clinically distinct from BBS and generally associated with prenatal or newborn death.

“While these two groups of patients exhibit such different clinical outcomes, the genes associated with both syndromes all seemed to be pointing at the same culprit: cilia,” says Katsanis. “So we wondered if BBS and MKS might actually represent different flavors of the same disease.”

The researchers sequenced the MKS genes from 200 BBS patients and found six families that, in addition to carrying BBS genetic mutations, also carried mutations in MKS genes. To figure out what, if any, effect these MKS mutations have on BBS, the team used a system they previously developed in zebrafish.

Knocking out BBS genes in zebrafish generates short fish with even shorter tails, among other malformations. Injecting normal BBS genes into these fish rescues them, resulting in normal looking fish.

The researchers reasoned that if MKS and BBS are indeed the same condition, then fish with the MKS genes knocked out should mimic the BBS knockout fish. They did. The team then went on to test mutant versions of MKS genes in BBS fish and found that three genes originally attributed to MKS do indeed cause BBS or render the BBS defects more pronounced, increasing the number of BBS genes to 14 in total.

“From a clinical perspective, these two syndromes look nothing alike, but molecularly, the genes involved clearly participate in the same fundamental processes,” says Katsanis. “This means that Meckel-Gruber and Bardet-Biedel actually represent a continuum of one disease. This never would have been discovered in the clinic-only molecular analysis can reveal these things.”

But what does this mean for clinicians and the diagnosis and treatment of these syndromes" Katsanis hopes that the growing body of molecular data will help move medicine away from symptom-defined syndromes, which can leave clinicians struggling with ambiguous diagnoses, to approaching disorders from a molecular standpoint. “We now have the possibility of merging several rare disorders,” he says. “And their gross sum now turns out to be fairly common; hopefully this will now put them on the radar for drug development and other therapies.”

The research was funded by the National Institutes of Health, National Institute of Child Health and Development, the National Institute of Diabetes, Digestive and Kidney Disorders, the Polycystic Kidney Disease Foundation, Medical Research Council, Research to Prevent Blindness and the Wellcome Trust.

Authors on the paper are Carmen Leitch, Norann Zaghloul, Erica Davis and Katsanis, all of Hopkins; Corrine Stoetzel and Helene Dollfus of Université Louis Pasteur, Strasbourg, France; Anna Diaz-Font, Suzanne Rix and Philip Beales of University College London, UK; Majid Al-Fadhel and Wafaa Eyaid of King Fahad Hospital, Riyadh, Saudi Arabia; Richard Alan Lewis of Baylor College of Medicine, Houston, Texas.; Eyal Banin of Hadassah-Hebrew University Hospital, Jerusalem, Israel; and Jose Badano, previously of Hopkins and now at the Institut Pasteur de Montevideo, Uruguay.