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Exome Sequencing Uncovers Gene Linked to Idiopathic Scoliosis

NEW YORK (GenomeWeb) – In a study appearing online today in the Journal of Clinical Investigation, an international team described ties between a gene called POC5 and idiopathic scoliosis in French Canadian families.

"To date, many genes have been suspected of causing scoliosis amongst different populations, but the gene that causes the familial form of the disease remained unknown," Florina Moldovan, a researcher affiliated with CHU Sainte Justine research hospital and the University of Montreal, said in a statement. Moldovan co-led the study with Patrick Edery from the Civil Hospice of Lyon. 

Moldovan, Edery, and colleagues first came across a rare, scoliosis-associated variant in POC5, a centriolar protein-coding gene, when they used genetic linkage mapping and exome sequencing to assess members of a French Canadian family frequently affected by the vertebral column deformation condition. They subsequently unearthed the same POC5 variant — and two more rare, missense changes in the gene — in patients with or without a family history of the condition.

"This crucial first step will open the door to future studies that will identify the complementary genes and pathways that play a role in scoliosis in other populations," co-author Pierre Drapeau, a neuroscience researcher at the University of Montreal Hospital Research Centre (CRCHUM), said in a statement. "[A] full portrait of genetic events would enable the perfecting of effective preventative methods and strategies for understanding scoliosis."

A copy number analysis-based study published in the New England Journal of Medicine last month linked compound mutations in a gene called TBX6 to congenital scoliosis in individuals from the Han Chinese population.

For the current study, researchers tapped into samples from hundreds of individuals belonging to 41 idiopathic scoliosis-prone families and from 150 unrelated individuals with the condition. 

Genetic mapping experiments on a dozen members of one of the French Canadian families led them to suspicious stretches of chromosome 3 and chromosome 5.

To get a more comprehensive look at potential risk factors, collaborators at McGill University and the Genome Quebec Innovation Center used the Illumina HiSeq 2000 to sequence the protein-coding portions of the genome in three affected family members, generating 134-fold average coverage of each exome.

When they sifted through the exome sequence data, the investigators detected a rare missense glitch in the chromosome 5 gene POC5 that was found in those with scoliosis but not in unaffected family members.

The team subsequently saw the original variant, along with two more missense POC5 variants, in other scoliosis-prone families and in unrelated individuals affected by idiopathic scoliosis, suggesting several different glitches in the gene may contribute to the spine deformation condition.

In a series of follow-up experiments, the researchers found evidence for a POC5 role in normal spine development as well. For example, zebrafish embryos expressing versions of POC5 that contained one of the three newly detected variants went on to develop spinal deformations.

The study's authors noted that additional alleles may modify the effect of the POC5 variants in one or more of the families considered for the study — a possibility they are continuing to investigate.

"Further studies of large cohorts of various ethnicities are needed to determine the contribution of POC5 genetic variants to [idiopathic scoliosis] in other populations," they wrote, "and to establish the prevalence of these variants in the general population."