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Genetic Predisposition to Symptomatic Lumbar Disk Herniation in Pediatric and Young Adult Patients

Theodore, Nicholas MD; Ahmed, Ali Karim BS; Fulton, Travis MS; Mousses, Spyro PhD; Yoo, Christopher PhD; Goodwin, Courtney Rory MD, PhD; Danielson, Jill RN; Sciubba, Daniel M. MD; Giers, Morgan B. PhD; Kalani, Mohammad Yashar S. MD, PhD

doi: 10.1097/BRS.0000000000002949

Study Design. Case-control whole-genome sequencing analysis of a highly select, young cohort with symptomatic lumbar disk herniation (LDH) compared with the standard variation in a large reference population.

Objective. To assess genetic influences predisposing pediatric and young adult patients to symptomatic LDH.

Summary of Background Data. LDH has traditionally been attributed to natural weakening or mechanical insult, but recent literature supports a potential genetic influence.

Methods. Young patients with symptomatic, clinically confirmed LDH who underwent surgical treatment were included. Patients were younger than the average age of presentation, limiting the influence of environmental risks. DNA collected from these patients was compared with a reference genome (1000 Genomes Project). A genome-wide association study using whole-genome sequencing was used to characterize genetic mutations potentially associated with LDH.

Results. Among the 61 candidate genes flagged, 20 had missense mutations in 2 or more LDH cases. Missense mutations in collagen-encoding genes were observed in 12 of 15 patients (80%). A potential association with clinical presentation was indicated by odds ratios of key single-nucleotide polymorphism (SNP) variants in genes that encode collagen. Relative to the reference population, the LDH cohort demonstrated two statistically significant SNP variants in the gene encoding for aggrecan, a protein that facilitates load-bearing properties in the cartilaginous end plate. Aggrecan genes SNPs rs3817428 and rs11638262 were significantly associated with decreased odds of symptomatic LDH: odds ratio 0.05 (0.02–0.11) and 0.04 (0–0.26), respectively (P < 1 × 10–7 for both).

Conclusion. These results suggest that collagen-encoding variants may be a genetic risk factor for LDH. They also shed new light on the role of variants that impact aggrecan, which sustains the cartilaginous end plate. Genetic predisposition to LDH may therefore be related to a multimodal combination of mutations that affect the nucleus pulposus, annulus fibrosus, and the cartilaginous end plates.

Level of Evidence: 4

Genomic sequencing from a highly selected young LDH population was compared to with an established reference population and demonstrated significant variants in the main proteoglycan-encoding gene and numerous missense mutations in the collagen-encoding genes. These results suggest that symptomatic LDH, especially in young patients, may be partly attributed to genetic predisposition.

Department of Neurosurgery, Barrow Neurological Institute, St. Joseph's Hospital and Medical Center, Phoenix, AZ

Department of Neurosurgery, Johns Hopkins University School of Medicine, Baltimore, MD

Systems Imagination, Inc, Phoenix, AZ.

Address correspondence and reprint requests to Nicholas Theodore, MD, Neuroscience Publications, Barrow Neurological Institute, St. Joseph's Hospital and Medical Center, 350 West Thomas Road, Phoenix, AZ 85013; E-mail:

Received 5 March, 2018

Revised 15 October, 2018

Accepted 8 November, 2018

The manuscript submitted does not contain information about medical device(s)/drug(s).

The Millard Seldin Laboratory, Barrow Neurological Institute, St. Joseph's Hospital and Medical Center, Phoenix, Arizona funds were received in support of this work.

Relevant financial activities outside the submitted work: consultancy, grants.

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