Researchers have found that two clinically different inherited syndromes are in fact, variations of the same disorder.
The research team, led by Nicholas Katsanis, Ph.D., an associate professor of ophthalmology at the McKusick-Nathans Institute of Genetic Medicine at Hopkins, studies Bardet-Biedl syndrome (BBS), a rare so-called ciliopathy.
BBS 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.
The group, recently 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. So we wondered if BBS and MKS might actually represent different flavors of the same disease," Nature quoted Katsanis, as saying.
For reaching their conclusions, 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 and 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. 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," Katsanis said.
The study 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.
The study is published in the journal Nature Genetics.