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. 2014 Jul 9;472(10):3216–3225. doi: 10.1007/s11999-014-3766-8

Are Copy Number Variants Associated With Adolescent Idiopathic Scoliosis?

Jillian G Buchan 1, David M Alvarado 2, Gabe Haller 2, Hyuliya Aferol 2, Nancy H Miller 4, Matthew B Dobbs 2,5, Christina A Gurnett 1,2,3,✉
PMCID: PMC4160470  PMID: 25005481

Abstract

Background

Adolescent idiopathic scoliosis (AIS) is a complex genetic disorder that causes spinal deformity in approximately 3% of the population. Candidate gene, linkage, and genome-wide association studies have sought to identify genetic variation that predisposes individuals to AIS, but the genetic basis remains unclear. Copy number variants are associated with several isolated skeletal phenotypes, but their role in AIS, to our knowledge, has not been assessed.

Questions/Purposes

We determined the frequency of recurrent copy number rearrangements, chromosome aneuploidy, and rare copy number variants in patients with AIS.

Methods

Between January 2010 and August 2014, we evaluated 150 patients with isolated AIS and spinal curvatures measuring 10° or greater, and 148 agreed to participate. Genomic copy number analysis was performed on patients and 1079 control subjects using the Affymetrix® Genome-wide Human SNP Array 6.0. After removing poor quality samples, 143 (97%) patients with AIS were evaluated for copy number variation.

Results

We identified a duplication of chromosome 1q21.1 in 2.1% (N = 3/143) of patients with AIS, which was enriched compared with 0.09% (N = 1/1079) of control subjects (p = 0.0057) and 0.07% (N = 6/8329) of a large published control cohort (p = 0.0004). Other notable findings include trisomy X, which was identified in 1.8% (N = 2/114) of female patients with AIS, and rearrangements of chromosome 15q11.2 and 16p11.2 that previously have been associated with spinal phenotypes. Finally, we report rare copy number variants that will be useful in future studies investigating candidate genes for AIS.

Conclusions

Copy number variation and chromosomal aneuploidy may contribute to the pathogenesis of adolescent idiopathic scoliosis.

Clinical Relevance

Chromosomal microarray may reveal clinically useful abnormalities in some patients with AIS.

Electronic supplementary material

The online version of this article (doi:10.1007/s11999-014-3766-8) contains supplementary material, which is available to authorized users.

Introduction

Scoliosis is a common spine deformity that is defined as a 10° or greater lateral curvature of the spine measured by the Cobb method on a standing radiograph [12]. Although scoliosis may result from congenital abnormalities, neuromuscular disorders or other conditions, the majority (approximately 80%) are idiopathic. Adolescent idiopathic scoliosis (AIS) develops during late childhood in otherwise healthy individuals and affects up to 3% of the population. In patients with mild scoliosis (spinal curves measuring 10°–25°), AIS affects males and females equally, but severe spinal curves (> 40°) affect adolescent females at a ratio of 10:1 [29]. While patients with mild scoliosis typically are not treated, approximately 10% of patients with AIS have a progressive deformity develop [33], and bracing or surgery may be indicated to mitigate negative physical and psychologic morbidities. Risk factors for progressive AIS include skeletal immaturity, female gender, and larger spinal curvature at initial diagnosis [43].

Monozygotic twins have higher concordance for AIS (73%) compared with dizygotic twins (36%) [23], suggesting that there are genetic factors contributing to AIS. Additionally, the incidence of AIS is greater among family members of affected patients, with 6% to 11% of first-degree relatives also affected [44, 61]. Most affected families have complex, non-Mendelian inheritance, and emerging views of AIS heritably favor a complex genetic model with large genetic heterogeneity [26, 27, 34, 35, 60]. Numerous candidate genes and linkage associations have been reported in AIS [17, 26, 58], but the importance of these loci remain unclear. Genome-wide association studies have uncovered common polymorphisms associated with AIS [25, 48, 55]. However, common polymorphisms account for only a small amount of AIS heritability, suggesting that other forms of genetic variation also play a role in AIS etiology.

Copy number variant analysis has been used successfully for patients with intellectual disability, neuropsychiatric disorders, and multiple congenital abnormalities, revealing multiple genes and genomic regions contributing to disease susceptibility [13, 38, 54]. In comparison, relatively few copy number variant studies have assessed patients with isolated skeletal phenotypes, although copy number variants have been associated with idiopathic short stature [57, 62], idiopathic clubfoot [4–6], adult-onset degenerative lumbar scoliosis [52], and bone mineral density [11]. Moreover, a recent study showed that recurrent rearrangements of chromosome 16p11.2 are risk factors for nonidiopathic scoliosis and vertebral abnormalities in children with additional developmental, neurologic, and congenital abnormalities [2]. These results show the potential for recurrent and other rare copy number variants to affected skeletal phenotypes, like scoliosis, and warrant evaluation in patients with AIS.

In this study, we determine the frequency of copy number rearrangements, chromosome aneuploidy, and rare copy number variants from a genome-wide copy number variant screen of 143 patients with AIS and report a role for copy number variants in AIS pathogenesis.

Materials and Methods

Patient Samples

Between January 2010 and August 2014, we evaluated 150 patients with isolated AIS and spinal curvatures measuring 10° or greater using the Cobb method [12], and 148 agreed to participate. The AIS cohort included primarily familial AIS with moderate to severe scoliosis (> 25°) resulting in treatment and 92% were of European-American ancestry. The average spinal curve (Cobb angle) for patients in this cohort was 49° and 80% were female (Table 1). Patients with known or suspected scoliosis etiologies (eg, Marfan syndrome, congenital abnormalities) were excluded. Growth parameters were calculated based on data from the National Center for Health Statistics [10]. Blood or saliva samples were collected for probands and available relatives after obtaining informed consent. DNA isolations were performed using the DNA Isolation Kit for Mammalian Blood (Roche, Indianapolis, IN, USA) or the Oragene® Purifier (DNA Genotek, Kanata, ON, Canada) according to the manufacturer’s instructions. Replication cohorts for chromosome 1q21.1 (N = 120) and trisomy X (N = 172) included patients with AIS recruited from St. Louis Children’s Hospital, St. Louis Shriners Hospital for Children, and the University of Colorado using identical inclusion criteria. Human Subjects Committees at all three institutions approved this study.

Table 1.

Demographics of 143 AIS probands analyzed for copy number variation

Variable Familial Nonfamilial Total
Patients with AIS 134 (94%) 9 (6%) 143
 Males 29 (100%) 0 (0%) 29 (20%)
 Females 105 (92%) 9 (8%) 114 (80%)
Cobb angle
 Mean 49° (N = 122) 50° (N = 9) 49° (N = 131)
 Range 10°–97° (N = 122) 26°–74° (N = 9) 10°–97° (N = 131)
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AIS = adolescent idiopathic scoliosis.

Control subjects of European-American ancestry (N = 1079) were analyzed concurrently. Control subjects were described previously and included 666 healthy subjects from a bipolar disorder study [15] and 413 patients with idiopathic clubfoot [5]. Copy number variation data from 8329 published control subjects previously described in a study of developmental delay [14] were included as an additional control cohort in a subset of analyses.

Copy Number Variant Analysis

Copy number analysis was performed for 148 AIS probands and 1079 control subjects using the Genome-wide Human SNP Array 6.0 (Affymetrix®, Santa Clara, CA, USA). Copy number calls were generated with the Genotyping Console software (Affymetrix®) using a reference set of 270 HapMap controls [56]. AIS samples with contrast quality control less than 0.04 and median absolute pairwise difference greater than 0.35 or total copy number variants greater than two standard deviations more than the average were excluded (N = 5). Analysis of the remaining 143 AIS samples and 1079 control subjects was limited to copy number variants of 125 kb or greater with 50 or more markers and 10 kb or less average distance between markers to enrich our dataset with high confidence copy number variants. Copy number variants with more than 50% overlap with assembly gaps were removed. We identified rare and novel copy number variants by limiting our analysis to those that had less than 50% overlap with copy number variants at greater than 1% frequency or with all copy number variants, respectively, in the Database of Genomic Variants [32] when 100 or more individuals were evaluated. To evaluate known, clinically significant copy number disorders in patients with AIS, we identified copy number variants that overlapped genomic regions associated with recurrent copy number disorders, including 45 recurrent genomic disorder regions (< 10 Mb) examined in 8329 published controls [14]. Copy number variants in published controls were identified as previously described [14]. Quantitative PCR (qPCR) using three or more PCR primer pairs validated selected copy number variants. All sequence coordinates are reported using National Center for Biotechnology Information (NCBI) assembly build 36 (hg18) [39].

Results

Recurrent Copy Number Rearrangements

Recurrent rearrangements of chromosome 16p11.2 are associated with scoliosis and other abnormalities [2], but this locus, to our knowledge, has not been evaluated for copy number variants in a patient cohort with isolated scoliosis, and the role of 16p11.2 and other recurrent copy number variants in AIS remains unknown. Therefore, we identified patients with AIS with copy number variants overlapping 45 loci associated with recurrent copy number disorders that contribute to a broad range of phenotypes [14]. Seven patients (4.9%; N = 7/143) in our AIS cohort had copy number variants overlapping one of the recurrent genomic disorder regions. These copy number variants caused rearrangements of chromosome 1q21.1 (N = 3), chromosome 2q13 (N = 1), chromosome 15q11.2 (N = 2), and chromosome 16p11.2 (N = 1) (Table 2).

Table 2.

Frequency of 45 genomic copy number disorder regions in patients with AIS

Abnormality Genomic disorder region (Mb) Size (kb) Patients with AIS (this study) Control subjects (this study) Control subjects (published) [16]
Patient(s) Phenotype(s) CNV (Mb) Size (kb) Frequency Frequency p value Frequency p value
1q21.1
duplication
(proximal)		 chr1:
144–144.34		 340 6041-001 AIS chr1:142.72–144.97 2241 2.10%
(N = 3/143)		 0.09%
(N = 1/1079)		 0.0057 0.07%
(N = 6/8329)		 0.0004
6267-001 AIS chr1:144.08–144.50 420
6035-004 AIS chr1:144.08–144.46 379
2q13
duplication		 chr2:
110.18–110.34		 160 6126-001 AIS chr2:110.13–110.52 394 0.70%
(N = 1/143)		 0.65%
(N = 7/1079)		 0.6316 0.38%
(N = 32/8329)		 0.4304
15q11.2
deletion		 chr15:
20.35–20.64		 290 6053-001 AIS chr15:19.09–21.04 1949 0.70%
(N = 1/143)		 0.37%
(N = 4/1079)		 0.4639 0.23%
(N = 19/8329)		 0.2888
15q11.2 duplication chr15:
20.35–20.64		 290 6036-001 AIS chr15:20.22–20.97 744 0.70%
(N = 1/143)		 0.46%
(N = 5/1079)		 0.5269 0.43%
(N = 36/8329)		 0.4681
16p11.2 duplication chr16:
29.56–30.11		 550 6032-001 AIS, spina
bifida occulta		 chr16:29.50–30.09 587 0.70%
(N = 1/143)		 0.19%
(N = 2/1079)		 0.3118 0.02%
(N = 2/8329)		 0.0498
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Genomic coordinates are reported using NCBI assembly build 36 (hg18); AIS = adolescent idiopathic scoliosis; CNV = copy number variant; chr = chromosome.

A duplication of chromosome 1q21.1 was the most frequent finding and was present in 2.1% (N = 3/143) of patients with AIS compared with 0.09% (N = 1/1079) of control subjects (p = 0.0057, one-tailed Fisher’s exact test) and 0.07% (N = 6/8329) of published control subjects (p = 0.0004, one-tailed Fisher’s exact test) [14]. After Bonferroni correction for 45 tests, the enrichment of chromosome 1q21.1 duplications in AIS remained significant compared with that of published control subjects (p < 0.001). Large segmental duplication blocks mediate four recurrent breakpoints in chromosome 1q21.1 copy number variants and define distinct proximal and distal regions, but only the proximal region was duplicated in all three patients (Fig. 1A). To test segregation of the proximal 1q21.1 duplication with AIS, available family members were evaluated for the presence of the copy number variant using qPCR. The proximal 1q21.1 duplication segregated with reduced penetrance in all three pedigrees (Fig. 1B). AIS ranged in severity from mild to severe in the five affected individuals with the duplication (Table 3). Two carriers of the duplication were unaffected, although this was not confirmed radiographically. Clinical information and family histories did not reveal evidence for intellectual or developmental disability or other significant comorbidities in the individuals with the duplication.

Fig. 1A–B.

Fig. 1A–B

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Duplications of the proximal region of chromosome 1q21.1 segregate with AIS. (A) Log2 ratios show duplications (shaded) of chromosome 1q21.1 in three AIS probands. The four recurrent breakpoints (BP1-BP4) and approximate locations of the proximal and distal regions are shown, but only duplications of the proximal region were common to all three patients with AIS. (Image modified from Genome Browser [http://genome.ucsc.edu]). All genomic coordinates are shown for the NCBI assembly build 36 (hg18). (B) The proximal chromosome 1q21.1 duplication identified in AIS probands (arrow) segregated with affected family members with reduced penetrance. Some individuals, including 001 in Family 6035 did not have DNA available to test. Dup = duplication; − = wild type.

Table 3.

Clinical information for individuals identified with chromosome 1q21.1 duplications

Family Individual Sex 1q21.1 status Affected (Cobb angle) Curve type Treatment
6035 004* F Dup/− Yes (15°) NA None
002 F Dup/− Yes, mild NA None
001 F NA Yes (56°) Right thoracic Surgery
6041 001* M Dup/− Yes (31°) Right thoracic Brace
002 F Dup/− Yes NA Surgery
003 F Dup/− No Not affected Not affected
6267 001* M Dup/− Yes (44°) Right thoracic Surgery
002 F −/− No Not affected Not affected
003 M Dup/− No Not affected Not affected
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NA = not available; Dup = duplication; − = wild type; *proband.

To screen for additional patients with AIS with copy number variants in chromosome 1q21.1, we used qPCR to identify proximal 1q21.copy number variants in an independent replication cohort (N = 120), but no additional chromosome 1q21.1 duplications were identified. However, even combined with the Affymetrix® Genome-wide Human SNP Array 6.0 results, the frequency of proximal 1q21.1 duplications in patients with AIS was enriched compared with that of control subjects from this study (N = 3/263 versus N = 1/1079; p = 0.0255, one-tailed Fisher’s exact test) and published control subjects (N = 3/263 versus N = 6/8329; p = 0.0021, one-tailed Fisher’s exact test) [14].

Trisomy X

We identified chromosomal aneuploidy in 1.4% (N = 2/143) of patients with AIS. Both patients were female with trisomy of the X chromosome (47, XXX). Trisomy X therefore was present in 1.75% (N = 2/114) of female patients with AIS and was confirmed by qPCR. Both patients had tall stature (> 99th percentile), but no additional physical or developmental comorbidities, and neither previously had been diagnosed with this condition. Only one of 529 females (0.19%) in our control cohort was identified with trisomy X, similar to the 0.11% frequency observed by Nielsen and Wohlert [40] in a large study of 17,038 newborn females. We screened an additional 172 female patients with AIS for trisomy X by qPCR and no additional patients were identified. Thus, the overall frequency of trisomy X in females with AIS was 0.7% (N = 2/286).

Rare Copy Number Variants in Patients with AIS

To determine if the overall burden of rare copy number variants differs between patients with AIS and control subjects, we identified variants that occurred at less than 1% in the Database of Genomic Variants. We identified 177 rare copy number variants in 92 patients with AIS (Table 4). Of these variants, 118 were duplications, 59 were deletions, and the average variant size was 328 kb (Appendix 1. Supplemental material is available with the online version of CORR [21]). The frequency of large (> 750 kb), autosomal copy number variants was similar between patients with AIS (4.90%; N = 7/143) and control subjects (5.65%; N = 61/1079).

Table 4.

Summary of rare copy number variants (< 1% frequency in DGV) identified in patients with AIS

Variable Number
Patients with AIS 143
Patients with AIS with rare copy number variants 92
Total rare copy number variants 177
Rare copy number variants containing Refseq genes 130
Average copy number variant size 328 kb
Median copy number variant size 217 kb
Duplications 118
Deletions 59
Large autosomal copy number variants (> 750 kb) 7
Patients with AIS with large copy number variants 4.90%
In-house control subjects with large copy number variants 5.65%
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AIS = adolescent idiopathic scoliosis; DGV = Database of Genomic Variants.

Discussion

AIS affects up to 3% of children but its genetic basis remains poorly understood. Copy number variation has been associated with isolated skeletal phenotypes such as idiopathic clubfoot [4–6], suggesting that they may be associated with additional skeletal phenotypes, such as AIS. Here, we report rare and recurrent copy number variation in a cohort of patients with AIS. In this study, 6.3% (N = 9/143) of patients with AIS were identified with a clinically relevant copy number rearrangement that previously was associated with a known condition, including trisomy X (N = 2/143) or a copy number variant affecting a region previously associated with a recurrent genomic disorder (N = 7/143). Our findings illustrate how frequently clinically relevant copy number variants will be encountered during microarray testing of patients with isolated scoliosis. Although several of the clinically important copy number variants identified in this study are unlikely to be related to AIS, others may have a role in AIS pathogenesis or contribute more generally to multiple spinal phenotypes.

There are several limitations to our study, including the relatively small sample size. For the rare copy number variants discussed here, a larger sample size would have improved frequency estimates and provided more statistical power. Moreover, in many patients, additional family members were unavailable for testing and limited our ability to provide additional support for causality. Second, control subjects used in this study included a large number of patients with idiopathic clubfoot and copy number variants already have been associated with this phenotype [4–6]. However, we also reference the frequency of recurrent copy number variants in an even larger published independent control dataset [14] and these frequencies are similar to our control dataset. Third, although the majority of patients with AIS were of European-American ancestry, including patients of other ancestral backgrounds could lead to population stratification. Finally, because our study cohort was ascertained in an orthopaedic clinic population and because patients with obvious developmental and intellectual impairment were excluded from the study, the frequency of copy number variation likely would have been greater if patients with additional comorbidities were included.

Proximal chromosome 1q21.1 duplications were the most frequently observed chromosomal abnormality identified in patients with AIS. Duplications of 1q21.1 were present in 2.1% of AIS probands but were found in only 0.07% to 0.08% of healthy control subjects [14, 46]. The distal region of chromosome 1q21.1 is associated with many phenotypes, whereas there are far fewer disease associations with the proximal region. The strongest association is with thrombocytopenia with absent radii (TAR) syndrome [24], which frequently is caused by compound inheritance of proximal 1q21.1 deletion and a rare single nucleotide variant in RBM8A [3], although 1q21.1 duplications and deletions of varying sizes have been noted to include congenital heart defects [9, 20, 59], Mayer-Rokitansky-Küster-Hauser syndrome [28], autism [50], fetal urogenital abnormalities [30], and additional diverse phenotypes [22, 46]. Although the three patients with AIS in our cohort had different chromosome 1q21.1 duplication breakpoints, only the proximal region was common to all three individuals and no individuals had additional phenotypes previously associated with chromosome 1q21.1 rearrangements. Scoliosis has not been described in patients with proximal chromosome 1q21.1 duplications, although the overall number of patients with this genomic abnormality is relatively small. Scoliosis was not reported in 17 patients with proximal duplications, although two had other spine phenotypes (lumbar lordosis and lumbosacral hyperlordosis) [46]. Of 34 patients with proximal deletions, three had a spinal phenotype (scoliosis, kyphosis, and C6-C7 vertebral fusion) [46]. Although some studies [30, 46] suggest that scoliosis is not a commonly associated phenotype, scoliosis often is not detected until adolescence and therefore is likely to be underreported in younger patient cohorts. Furthermore, mild scoliosis may be underreported in children with multiple congenital anomalies whose other major medical problems are of greater concern. Duplications of 1q21.1 segregated with AIS in small families with incomplete penetrance, but incomplete penetrance has also been noted in TAR syndrome [24] and other phenotypes [45, 46]. Because additional chromosome 1q21.1 duplications were not detected after screening an additional 120 patient samples, proximal duplications are likely rarer in AIS than estimated from our original cohort of 143 patients. Nevertheless, the combined dataset of 263 patients still showed a significant enrichment of proximal 1q21.1 duplications in AIS. Additional larger studies are needed to determine the importance of proximal chromosome 1q21.1 duplications in the etiology of AIS.

Several recurrent copy number variants identified in our patient cohort with AIS primarily are associated with cognitive impairment or other related phenotypes, but also may contribute to scoliosis and other spinal phenotypes. Hemivertebrae were present in 20% (N = 2/10) of patients with chromosome 15q11.2 duplications, although none of 15 patients with the reciprocal deletion had vertebral abnormalities [1]. Two patients in our AIS cohort had chromosome 15q11.2 copy number variants. Chromosome 15q11.2 deletions are strongly associated with developmental delay [14], but the reciprocal duplication is not and the significance and associated phenotypes of 15q11.2 duplications, if any, are not well established. Neurocognitive or developmental phenotypes were not present in either of our patients with AIS with the 15q11.2 copy number variant.

Likewise, various spinal abnormalities, including hemivertebrae, syringomyelia, and scoliosis have been described in patients with rearrangements of chromosome 16p11.2 [2, 8, 16, 19, 47, 49, 51] and this locus was hypothesized to be a risk factor for idiopathic scoliosis [2]. We identified a chromosome 16p11.2 duplication in one patient with AIS with spina bifida occulta. This patient did not have intellectual or developmental disability, which is consistent with the large phenotypic variability and reduced penetrance observed in individuals with chromosome 16p11.2 duplications [53]. Interestingly, chromosome 16 previously was associated with idiopathic scoliosis by linkage analysis in 202 families [36], and fine-mapping linkage analysis of 544 individuals from an additional 95 families narrowed the association to two regions on chromosome 16, which included 16p11.2 [37], providing further support for an association of the 16p11.2 locus with AIS.

We identified trisomy of the X chromosome (47, XXX), also called triple X syndrome, in 0.7% (N = 2/286) female patients with AIS. Triple X syndrome is estimated to occur in one of 1000 female births and generally causes mild phenotypes, such as premature ovarian failure and learning disabilities, which results in many patients being undiagnosed [18]. Scoliosis is known to occur more frequently in patients with triple X syndrome than in the general population [7, 41, 42]. Specifically, Olanders described scoliosis in 15.2% (N = 5/33) of patients with triple X syndrome [41]. Patients with triple X syndrome also typically are taller than average, with the average height being greater than the 80th percentile by the age of 14 years [31]. Both patients with AIS with trisomy X in our series were tall (> 99th percentile for height) but reported no additional phenotypes. Testing for triple X syndrome should be considered in tall females with AIS so that other associated phenotypes, such as premature ovarian failure and developmental delay, can be monitored.

Finally, we report a similar burden of rare copy number variants in patients with AIS compared with control subjects, which is in contrast to many other neurodevelopmental disorders. Unfortunately, most of the AIS families included in our study were small and relatively few family members were available for testing, so the role of individual rare copy number variants in the etiology of AIS remains unexplored. Although we did not have large families for segregation analysis, rare copy number variants identified in patients with AIS are ideal resources for identifying new candidate genes for AIS. None of the genes located in the rare or novel copy number variants has, to our knowledge, been associated with AIS previously, but this list of candidate genes will be a rich source of information for future investigations of AIS.

We analyzed copy number variation in a large cohort of patients with AIS. Our data show that more than 6% of patients with AIS harbor a clinically important copy number abnormality and many of these are possible risk factors for scoliosis and other spinal phenotypes. Our results suggest that microarray analysis for copy number variants may be a useful clinical test in this patient population. The rare number variants we provided will be useful for future studies evaluating candidate genes for AIS.

Electronic supplementary material

Supplementary material 1 (DOC 219 kb) (219.5KB, doc)

Acknowledgments

We thank Drs. Keith Bridwell, Lawrence Lenke, and Scott Luhmann for allowing us to recruit patients from their clinics. We thank the patients and their families for their role in this work. The Genome Technology Access Center in the Department of Genetics at Washington University School of Medicine processed the microarrays. The Center is partially supported by NCI Cancer Center Support Grant #P30 CA91842 to the Siteman Cancer Center and by ICTS/CTSA Grant #UL1RR024992 from the National Center for Research Resources (NCRR), a component of the NIH, and NIH Roadmap for Medical Research. The control dataset used for the analysis described in this manuscript was obtained from the database of Genotype and Phenotype (dbGaP) (http://www.ncbi.nlm.nih.gov/gap) through dbGaP accession number phs000017.v3.p1. Data for control samples were provided by John R Kelsoe and John Nurnberger as part of the NIMH Bipolar Genetics Collaborative. Control samples were genotyped through the Genetic Association Information Network (GAIN). This publication is solely the responsibility of the authors and does not necessarily represent the official view of NCRR or NIH.

Footnotes

Funding for this project was provided by National Institutes of Health (NIH, K12 HD001459-08), Shriners Hospital for Children, and the Children’s Discovery Institute of Washington University, and St. Louis Children’s Hospital.

Dr. Dobbs is a Senior Editor for Clinical Orthopaedics and Related Research.

The authors report no other conflicts of interest.

All ICMJE Conflict of Interest Forms for authors and Clinical Orthopaedics and Related Research editors and board members are on file with the publication and can be viewed on request.

Each author certifies that his or her institution approved the human protocol for this investigation, that all investigations were conducted in conformity with ethical principles of research, and that informed consent for participation in the study was obtained.

This work was performed at Washington University School of Medicine.

Contributor Information

Matthew B. Dobbs, Email: dobbsm@wudosis.wustl.edu.

Christina A. Gurnett, Email: gurnettc@neuro.wustl.edu.

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