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October 31, 2017

Whole-Exome Sequencing Identified a Novel IGFBP6 Variant in a Disc Degeneration Pedigree

Disc Degeneration Is the Basis for Most Spinal Degeneration

Whole-Exome Sequencing Identified a Novel IGFBP6 Variant in a Disc Degeneration Pedigree

Source: American Academy of Orthopaedic Surgeons

  • Disc degeneration is the basis for most spinal degeneration, which can cause disc herniation, disc space narrowing, spinal segmental instability, osteophyte formation, and other secondary lesions. This pathological process also leads to lower back pain and sciatica (Zhang et al., 2008). Because of its high prevalence and heavy medical burden, disc degeneration is a hot topic in current orthopedics research.

    To date, the molecular mechanisms of disc degeneration remain unclear. Previous studies suggest that the risk of disc degeneration is affected by age, sex, occupation, smoking history, vehicle vibration exposure history, and other factors. Recent studies have found that genetic factors play an important role in the development of disc degeneration, gaining strong support from a study of identical twins of patients with lumbar disc herniation (Battié et al., 2007; Pelle et al., 2014). Several susceptibility genes have been reported to be associated with disc degeneration, such as COL9a2 and MMP-3 (Yuan et al., 2010). However, these susceptibility genes are associated with occupationally induced disc degeneration and not causal genes, which lead to degenerative disc disease (Sun et al., 2013). Therefore, the genetic basis of disc degeneration remains unclear, limiting effort to prevent and treat this disease.

    Disc degeneration is a pathological process leading to diseases of the spine, the most common being lumbar disc herniation. Therefore, we focused our investigation on lumbar disc herniation. Most patients with lumbar disc herniation are sporadic or exist in small pedigrees. This makes it difficult to identify genetic variants that cause disc degeneration. Exome sequencing is a relatively new technology that was first used to study Mendelian diseases (Ng et al., 2009). Exon regions contain the information needed for protein synthesis and cover most functional variants affecting individual phenotypes. Therefore, they allow us to annotate identified genetic variants for analysis of biological function. Because the exome accounts for only about 1% of the entire genome, exome sequencing is more economic and efficient than whole-genome sequencing (Ng et al., 2010). Furthermore, exome sequencing technology has been successfully used to screen causal genetic mutations of Mendelian diseases. To our knowledge, there have been no exome sequencing studies of disc degeneration conducted to date.

    Conventional, large, sample-based association or linkage analysis methods cannot be applied to identify rare causal genetic variants. In this study, we propose a potent genetic screening strategy based on pedigree. We hypothesize that there may be a rare variant in a potent gene that leads to familial disc degeneration (Sun et al., 2013). Within a large pedigree with a high frequency of degenerative disc disease, exome sequencing was applied to four family members with lumbar disc herniation to screen for causal genetic variants. After filtering against the 1000 Genomes Project and dbSNP database (build 132), detected candidate gene variants were further validated by Sanger sequencing of five healthy family members and 200 unrelated healthy subjects.

  • * Abstract

    Objective: To identify the likely causal mutation that results in disc degeneration in a pedigree with a high incidence of disc degeneration.

    Materials and Methods: A large pedigree with a high incidence of disc degeneration was recruited for this study. Exome sequencing was completed on four family members with disc degeneration to screen for potential causal gene variants. Detected variants were filtered against the 1000 Genomes Project, the Short Genetic Variations database (dbSNP), and the Beijing Genomics Institute (BGI) in-house database. After removing synonymous variants, Sanger sequencing was used to verify the lack of the candidate single nucleotide polymorphism (SNP) in five healthy subjects of the study family.

    Results: We identified a novel SNP variant, Chr12:g.53494591T>C. c.T430C (p.S144P) in the insulin-like growth factor binding protein-6 (IGFBP6) gene. This variant was shared by all four affected family members, but not by five unaffected members in the same pedigree. Furthermore, this variant was not detected in 200 unrelated healthy people.

    Conclusions: The c.T430C (p.S144P) variant of IGFBP6 was identified as the likely causal variant associated with increased risk of familial disc degeneration in the studied pedigree.

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