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Study Reveals Distinct Genetic Conditions May Have Common Origin

NEW YORK (GenomeWeb News) – A new genetic study suggests that two inherited, clinical syndromes — previously presumed to be distinct — may be different manifestations of the same underlying condition.
An international team of researchers used sequencing and genetic interaction analysis to show that two seemingly separate syndromes — Bardel-Biedl and Meckel-Gruber — are actually caused by interacting and overlapping genes. These findings, published online in Nature Genetics this week, could broaden researchers’ view of a group of diseases called ciliopathies and, perhaps, shed new light on complex genetic diseases in general.
Bardet-Biedl syndrome is characterized by symptoms such as vision loss, obesity, diabetes, mental defects, and extra digits. Meckel-Gruber syndrome, on the other hand, is a genetic condition associated with neonatal malformations, particularly in neural tube development, that lead to prenatal or newborn death.
Though they appear to be very different syndromes, both are ciliopathies — genetic disorders that lead to defects in cilia, which are tiny, microtubule-based, hair-like projections found on almost every type of cell. Since cilia influence some cells’ motility as well as several key signaling pathways, ciliopathies can affect both developmental and normal cellular functions, though their exact functions are tissue dependent.
Consequently, senior author Nicholas Katsanis, a researcher at Johns Hopkins University’s McKusick-Nathans Institute of Genetic Medicine, and his colleagues suspected that Meckel-Gruber syndrome might actually be a more severe form of Bardet-Biedl syndrome. To test this, they sequenced a Meckel-Gruber risk gene called MKS1 in individuals from 155 BBS-affected families. Within that group, they found six families with potentially deleterious MKS1 mutations that were absent in 192 ethnically matched control chromosomes.
These mutations seemed to exacerbate Bardet-Biedl symptoms. For instance, five of the six individuals with Bardel-Biedl who carried MKS1 mutations were also prone to seizures, something not normally associated with the syndrome. To a lesser extent, the team also detected mutations in the Meckel-Gruber gene MKS3, and CEP290 in Bardet-Biedl patients. They also found a number of genetic interactions between Meckel-Gruber and Bardet-Biedl genes in a zebrafish model system.
“These data extend the genetic stratification of ciliopathies and suggest that BBS and MKS, although distinct clinically, are allelic forms of the same molecular spectrum,” the authors wrote.
This expands the list of genes linked to Bardet-Biedl, previously pegged at about a dozen. But it’s too early to say whether these findings will affect the way these and similar conditions are diagnosed and treated. “That’s the million dollar question,” Katsanis told GenomeWeb Daily News.
At this point, Katsanis said, a very small subset of ciliopathies are diagnosed genetically. That’s partly because testing ten or fifteen different genes for a rare and so-far untreatable condition such as Bardet-Biedl is unrealistic. Even with the advent of more rapid and affordable sequencing techniques, he added, there is also insufficient knowledge about how to assess risk.
As more and more interactions are detected between disease risk genes and the rest of the genome, Katsanis said, the challenge will be developing physiological assays that integrate the data in a meaningful way. This awareness of a “genome-context dependent morphology” may influence everything from researchers’ understanding of the disease biology to diagnostics and treatment targets.
For his part, Katsanis advocates molecular diagnoses whenever possible, rather than classifying and diagnosing diseases based purely on symptoms, an approach that misses cases that don’t fit neatly into a disease category. “We have too many patients who fall through the cracks because of that,” Katsanis said. “We have to start redefining genetic disorders [based on biochemistry].”

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