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Original article
Distal chromosome 16p11.2 duplications containing SH2B1 in patients with scoliosis
  1. Brooke Sadler1,
  2. Gabe Haller2,
  3. Lilian Antunes1,
  4. Xavier Bledsoe1,
  5. Jose Morcuende3,
  6. Philip Giampietro4,
  7. Cathleen Raggio5,
  8. Nancy Miller6,
  9. Yared Kidane7,
  10. Carol A Wise7,
  11. Ina Amarillo8,
  12. Nephi Walton9,
  13. Mark Seeley9,
  14. Darren Johnson9,
  15. Conner Jenkins9,
  16. Troy Jenkins9,
  17. Matthew Oetjens9,
  18. R Spencer Tong10,
  19. Todd E Druley10,
  20. Matthew B Dobbs2,
  21. Christina A Gurnett11
  1. 1 Department of Neurology, Washington University in Saint Louis School of Medicine, St. Louis, Missouri, USA
  2. 2 Department of Orthopedic Surgery, Washington University in Saint Louis School of Medicine, St. Louis, Missouri, USA
  3. 3 Department of Orthopaedic Surgery and Rehabilitation, University of Iowa Roy J and Lucille A Carver College of Medicine, Iowa City, Iowa, USA
  4. 4 Department of Genetics, St. Christopher’s Hospital for Children, Philadelphia, Pennsylvania, USA
  5. 5 Orthopedic Surgery, Pediatrics, Hospital for Special Surgery, New York City, New York, USA
  6. 6 Department of Orthopedics, University of Colorado at Denver - Anschutz Medical Campus, Aurora, Colorado, USA
  7. 7 Sarah M. and Charles E. Seay Center for Musculoskeletal Research, Texas Scottish Rite Hospital for Children, Dallas, Texas, USA
  8. 8 Department of Pathology and Immunology, Washington University in Saint Louis School of Medicine, St. Louis, Missouri, USA
  9. 9 Genomic Medicine, Geisinger Health System, Danville, Pennsylvania, USA
  10. 10 Department of Pediatrics, Washington University in Saint Louis School of Medicine, St. Louis, Missouri, USA
  11. 11 Department of Neurology, Division of Pediatric Neurology, Washington University in St. Louis School of Medicine, St. Louis, Missouri, USA
  1. Correspondence to Dr Christina A Gurnett, Department of Neurology, Division of Pediatric Neurology, Washington University in St. Louis School of Medicine, St. Louis MO USA; gurnettc{at}


Introduction Adolescent idiopathic scoliosis (AIS) is a common musculoskeletal disorder with strong evidence for a genetic contribution. CNVs play an important role in congenital scoliosis, but their role in idiopathic scoliosis has been largely unexplored.

Methods Exome sequence data from 1197 AIS cases and 1664 in-house controls was analysed using coverage data to identify rare CNVs. CNV calls were filtered to include only highly confident CNVs with >10 average reads per region and mean log-ratio of coverage consistent with single-copy duplication or deletion. The frequency of 55 common recurrent CNVs was determined and correlated with clinical characteristics.

Results Distal chromosome 16p11.2 microduplications containing the gene SH2B1 were found in 0.7% of AIS cases (8/1197). We replicated this finding in two additional AIS cohorts (8/1097 and 2/433), resulting in 0.7% (18/2727) of all AIS cases harbouring a chromosome 16p11.2 microduplication, compared with 0.06% of local controls (1/1664) and 0.04% of published controls (8/19584) (p=2.28×10−11, OR=16.15). Furthermore, examination of electronic health records of 92 455 patients from the Geisinger health system showed scoliosis in 30% (20/66) patients with chromosome 16p11.2 microduplications containing SH2B1 compared with 7.6% (10/132) of controls (p=5.6×10−4, OR=3.9).

Conclusions Recurrent distal chromosome 16p11.2 duplications explain nearly 1% of AIS. Distal chromosome 16p11.2 duplications may contribute to scoliosis pathogenesis by directly impairing growth or by altering expression of nearby genes, such as TBX6. Individuals with distal chromosome 16p11.2 microduplications should be screened for scoliosis to facilitate early treatment.

  • scoliosis
  • copy-number
  • 16p11.2

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Scoliosis is defined as a spinal deformity consisting of a 10° or greater lateral curvature of the spine using the Cobb measurement method on a standing radiograph.1 Known causes of scoliosis include congenital abnormalities, neuromuscular and connective tissue disorders. However, the majority of scoliosis cases are idiopathic (~80%). Adolescent idiopathic scoliosis (AIS) develops during late childhood and affects up to 3% of the population, with females disproportionately experiencing more severe scoliosis than males.2 Twin studies show high rates of concordance for AIS and increased risk in first-degree relatives.3 Genetic studies of common variants have shed important insight into the aetiology of AIS and include associations with variants near basonuclin-2,4 adherens junctions-associated protein 1, BCL2 apoptosis regulator, ladybird homeobox 1 antisense RNA 1,5 ladybird homeobox 1,6 neural cell adhesion molecules,7 paired homeobox 18 and G-protein-coupled receptor 126,9 but these variants explain only a small fraction of the heritability of AIS. With the advances of sequencing technology, rare genetic variants are also being shown to contribute to AIS risk. Rare variants in FBN1 and FBN2, which underlie Marfan syndrome and congenital contractural arachnodactyly, along with musculoskeletal collagen genes, were recently shown to be enriched in AIS cases and contribute to scoliosis severity.10 11

In addition to single nucleotide variants, CNVs resulting in large-scale duplications or deletions can also influence disease risk through alteration of gene dosage.12 CNVs contribute to a wide range of disorders, including autism, schizophrenia and neuropsychiatric disorders13 14 and influence bone mineral density15 and numerous Mendelian and complex traits.16 Scoliosis and other skeletal abnormalities were observed among patients with proximal chromosome 16p11.2 CNVs ascertained during evaluation for developmental disabilities.17 18 Furthermore, proximal chromosome 16p11.2 deletions containing TBX6 are strongly associated with congenital scoliosis.19–21

In the single prior study of CNVs in AIS, recurrent CNVs were identified in several of the 143 cases studied, suggesting a possible role in AIS pathogenesis.22 However, this study was too small to determine a role for CNVs in AIS. In the current study, we performed a comprehensive, large-scale study to determine the contribution of recurrent CNVs to AIS risk by analysing exome sequence data from 1197 AIS cases and 1664 controls.

Materials and methods

Cohort description

Patients with juvenile or AIS were recruited from St. Louis Children’s Hospital, St. Louis Shriners Hospital for Children, University of Iowa, University of Colorado, Hospital for Special Surgery and University of Wisconsin-Madison. All patients and/or parents provided informed consent. Inclusion criteria was spinal curve of >10°, although most patients had severe scoliosis with a mean curve of 50°. Patients with developmental delay, multiple congenital anomalies or known or suspected underlying disorders, including Marfan syndrome or Ehlers-Danlos syndrome, were excluded from the study.

Exome sequencing

Sequencing data for 1197 AIS samples was generated at the McDonnell Genome Institute (MGI) using IDT xGen Exome Panel V1 capture on Illumina HiSeq 4000 paired-end reads. The St Louis replication cohort of 443 AIS samples were captured using Agilent reagents and sequenced on HiSeq 1500/2000. For controls, we used MGI in-house control data from 1664 samples that included 860 male infertility cases, which were captured and sequenced using the identical IDT platform from AIS cases, and 637 amyotrophic lateral sclerosis cases and 167 multiple congenital anomaly cases captured using Agilent reagents and sequenced on HiSeq 1500/2000 (dbGAP accession number: phs001677).

Exome alignment and BAM file processing

The sequencing reads (ie, fastq files) from all AIS cases and controls samples were aligned to the human genome reference (GRCh37) using BWA-MEM (V.0.7.15). The resulting BAM files were sorted, and duplicates were marked using Picard MarkDuplicates (V.2.9.0). Realignment intervals for each BAM file was determined using GATK (V.3.5) RealignerTargetCreator using a list of known indel sites (Mills and 1 kg indels data from the GATK resource bundle ), and local realignment and base quality recalibration were then performed by GATK (V.3.5) IndelRealigner and BaseRecalibrator, respectively.

Exome CNV analysis

Copy number analysis was performed on AIS cases and control samples using the software package FishingCNV23 that is designed to identify rare CNVs from exome-sequencing data without the need for a paired control. This program uses an algorithm to prioritise rare variants and compares coverage depth in a test sample against the background distribution, as well as principle components analysis (PCA) to remove batch effects. The program extracts coverage information from GATK processed BAM files,24 then normalises read depth information at each exon25 into reads per kilobase per million mapped reads (RPKM) files. To identify only the most confident CNV calls, we included only CNVs with an average RPKM of at least 10, the mean log-ratio coverage between background and sample of −1.2 to −0.8 (consistent with a deletion) or 0.4 to 0.8 (consistent with a duplication) and Holm-Bonferroni adjusted p value less than 10−3.

To systematically assess our samples for known recurrent CNVs, we used a size overlap threshold of 40% to call known recurrent CNVs. This lower threshold was used because the exome sequence often does not cover the entire CNV and because FishingCNV occasionally breaks a CNV into smaller segments, particularly for larger CNVs. Data were also manually reviewed to identify CNVs that were broken into smaller segments and therefore removed by the above filter.

CNV analysis in replication cohort

Raw intensity data were obtained from 1390 subjects using the Illumina HumanCoreExome-24 V.1.0 BeadChip. CNVs were called using PennCNV.26 B allele frequency (BAF) and log R ratio (LRR) values were computed in Genome Studio. Data were exported out and processed using the ‘’ script in PennCNV to obtain BAF and LRR values per SNP per subject. Population frequency of B allele (PFB) and Gcmodel data sets were derived using the ‘compile_pfb’ and ‘cal_gc_snp’ Perl modules in PennCNV, respectively.

After CNV calling, we merged CNVs if the gap between adjacent calls was ≤50% of the combined length. Then, we performed initial quality control checks as recommended by PennCNV. Subjects were excluded from downstream analysis if they had a LRR SD of >0.28, a BAF drift of >0.01 or an absolute waviness factor of >0.05. Then, we excluded spurious CNV calls pertaining to telomeric and centromeric regions. CNVs that overlapped with immunoglobulin encoding regions were also removed. We retained 1339 subjects for further analysis after quality control. Of these, 1097 were unique from the original dataset.

CNV validation

For validation of CNVs using qPCR, we designed three primer pairs to exonic sequence within the CNV. Primers were tested for quality and efficiency using PCR and RT-qPCR standard curves, respectively. Quality control (QC) was performed on the tested DNA using the Qubit Fluorimeter (Invitrogen). qPCR is performed on a 96-well high-sided low-profile PCR plates (Thermo Scientific) on the Applied Biosystems StepOne Real-Time PCR System. Positive and negative controls with known gains or losses in the gene of interest were included in each run. The RPL27 housekeeping gene was used as a reference.

Geisinger dataset

We assessed the exome sequencing data of 92 445 participants in the MyCode program, data that was generated as part of the Geisinger-Regeneron DiscovEHR project.27 We used copy number estimation using Lattice-Aligned Mixture Models software for calling CNVs from the exome data.28 We identified all individuals in the DiscovEHR cohort with duplications of the chromosome 16p11.2 region that contained the SH2B1 gene. Manual chart review was performed on all the patients with SH2B1 duplications to assess for scoliosis. All images were reviewed by an orthopaedic surgeon who assessed them for scoliosis and calculated Cobb angles. Patients were identified as having scoliosis if they met any of the following criteria: (1) mention of significant scoliosis in notes or in an imaging report, (2) scoliosis was identified on the problem list or (3) imaging of the spine that showed a Cobb angle >10°.


To systematically identify the frequency of 55 clinically relevant recurrent CNVs described in Coe et al 29 in AIS, the discovery cohort data consisting of 1197 AIS cases and 1664 in-house controls was assessed for CNVs with >40% overlap in size with known recurrent CNVs (table 1).

Table 1

Recurrent microdeletions and microduplications seen in our adolescent idiopathic scoliosis (AIS) cases

A total of 8 AIS cases with distal chromosome 16p11.2 duplications were detected (online supplementary table S1). The smallest duplication was detected by manual review, because it did not pass the initial filter criteria due to minimal overlap with the known CNV (only 11%). Other than the distal chromosome 16p11.2 duplication, there were no other recurrent CNVs that were statistically enriched in the AIS cohort. Identical analysis of our in-house control samples revealed only one distal chromosome 16p11.2 duplication out of 1664 controls (table 2).

Table 2

Enrichment of distal chromosome 16p11.2 duplication in adolescent idiopathic scoliosis (AIS) cases

All distal chromosome 16p11.2 duplications were validated by qPCR. A large published study of CNVs identified this distal chromosome 16p11.2 duplication in only 8 of 19 584 controls.29 Therefore, the distal chromosome 16p11.2 duplication was significantly enriched in our cases compared with both in-house controls (p=0.005, OR=8.55) and published controls (p=1.05×10−6, OR=16.34) even after Bonferonni correction for multiple tests.

Replication of chromosome 16p11.2 duplications in AIS

Two replication cohorts were assayed for chromosome 16p11.2 duplications containing the SH2B1 gene to replicate the discovery cohort results. Replication cohort 1 consisted of 1097 AIS cases who were genotyped using the Illumina HumanCoreExome-24 V.1.0 BeadChip and had CNVs called using PennCNV.26 Replication cohort 2 consisted of 433 AIS cases with exome data that were generated using Agilent reagents and were analysed for the presence of CNVs separately from the discovery cohort, which was captured using IDT probes. Eight AIS cases with the distal chromosome 16p11.2 duplication were identified in replication cohort 1 (n=1097). Two additional cases were identified in replication cohort 2 (n=433). When the discovery and replication cohorts were combined, the distal chromosome 16p11.2 duplication was present in 0.7% cases (18/2727) compared with 0.04% (8/19584) controls (p=2.28×10−11, OR=16.15) (table 2).

The locations of the distal chromosome 16p11.2 duplications that included SH2B1 were mapped onto the genome (figure 1). The chromosome 16p11.2 region is highly enriched for segmental microduplications and microdeletions with known breakpoints defining these regions (figure 1). The proximal 600 kb region (29.5–31.1 Mb) is defined by BP4-BP5 and has previously been associated with congenital scoliosis,19 while the distal BP2-BP3 region (28.7–28.9 Mb) has not previously been associated with a skeletal phenotype. The duplications ranged from 80 to 340 exons in length and were consistent in size with known CNVs mediated by segmental duplications in this region. One duplication was slightly smaller than the typical BP2-BP3 CNV and involved only 80 exons in four genes, including SH2B1. These duplications were near, but did not include, the proximal chromosome 16p11.2 deletion (BP4-BP5). The proximal deletion was seen only once in the AIS cohort, shown in red on figure 1; however, further review revealed a subtle vertebral segmentation anomaly consistent with congenital scoliosis. Therefore, if we exclude this case, there were no AIS cases with proximal chromosome 16p11.2 deletions, suggesting no or minimal overlap with this genetic cause of congenital scoliosis. While the eight duplications identified in the replication cohort 1 appear slightly larger, their size was determined based on genotype data, rather than exome data.

Figure 1

Locations of distal chromosome 16p11.2 duplications. Legend: locations of distal chromosome 16p11.2 duplications containing SH2B1 (blue) and proximal chromosome 16p11.2 deletions containing TBX6 (red) in our AIS cohort of 1197 patients and in replication cohort 1 (1097 AIS cases) and replication cohort 2 (433 AIS cases). Previously discovered locations of segmental duplications (orange) are shown along with locations of break points (BPs) resulting in recurrent proximal and distal CNV locations (purple). AIS, adolescent idiopathic scoliosis.

Clinical phenotypes associated with chromosome 16p11.2 duplications

Clinical evaluations of the AIS cases with the distal chromosome 16p11.2 duplication revealed that all but two are women, which is consistent with the strong gender bias in severe AIS cases. The mean body mass index (BMI) of cases with the chromosome 16p11.2 duplication was lower than those without the duplication but the difference was not significant (21.1 vs 22.2) (p=0.17) (online supplementary table S2). The mean maximum curve severity in individuals with and without the chromosome 16p11.2 duplication was not different. As developmental disability was an exclusion for the study, all of the cases had normal neurodevelopment. One case had ADHD. Beighton scores of joint hypermobility30 and Ghent systemic feature scores31 were unremarkable in four cases but were not measured in others.

Analysis of scoliosis in chromosome 16p11.2 duplication carriers in Geisinger dataset

Finally, we examined a dataset of 92 445 patients from Geisinger Health System with exome data and discovered 66 patients with microduplications that include SH2B1. Of these 66 patients, 20 had evidence for scoliosis by imaging and/or report, suggesting a 30% lifetime risk of scoliosis. Their mean age was 58 years and 16 (80%) were women. Nineteen of the 20 patients had healthcare visits specifically for back pain and three out of 20 had back surgery for scoliosis. Of the 46 patients who were not classified as having scoliosis, 31 had imaging that included at least a section of the spine and showed no scoliosis or minor scoliosis (Cobb angle <10°) and 15 patients did not have any imaging that included the spine. One patient reported having scoliosis when younger but showed no scoliosis on current imaging, and two other patients had mild scoliosis on an imaging report from an outside hospital, but images were not available for assessment; therefore, all three were classified as not having scoliosis using the diagnostic criteria. In comparison, evaluation of 132 age-matched and sex-matched controls from the Geisinger dataset using the same criteria revealed that 7.6% controls (10/132) had scoliosis, suggesting an approximately fourfold increase in lifetime scoliosis risk in patients with the distal chromosome 16p11.2 duplication (p=5.6×10−4, OR=3.9).


Here we describe the occurrence of distal chromosome 16p11.2 duplications in nearly 1% of patients with AIS, a common paediatric musculoskeletal disorder whose aetiology is largely unexplained. The chromosome 16p11.2 region was previously proposed as a candidate locus for AIS based on linkage data.32 33 This complex chromosomal region has undergone a recent, rapid integration of segmental duplications followed by adaptive evolution that has occurred since the split between the human/great ape lineage and orangutans, approximately 12 million years ago.34 This region’s richness in segmental duplications predisposes it to recurrent rearrangements.35 The proximal 600 kb region (29.5–30.1 Mb) defined by breakpoints 4–5 (BP4-BP5; OMIM #611913) harbours the TBX6 gene and has been previously associated with congenital scoliosis,19 while the distal 220 kb BP2-BP3 region (28.7–28.9 Mb) reported here in AIS has not been previously associated with any skeletal phenotype. Deletion of the proximal region is associated with autism spectrum disorder, obesity and macrocephaly,36 and deletion of the distal region has similarly associated phenotypes.37 Developmental delay is associated with the distal chromosome 16p11.2 deletion and, to a lesser degree, with the duplication.38 39 Distal chromosome 16p11.2 duplication (OMIM #614671) carriers also have lower BMI and reduced head circumference.37 This distal region includes the SH2B1 gene, which is involved in leptin and insulin signalling. Variants in SH2B1 are associated with behavioural abnormalities and obesity40 and deletion of which is associated with severe obesity, hyperphagia and insulin resistance,41 suggesting that SH2B1 is the major gene driving these growth phenotypes.

The complex relationship between the proximal and distal chromosome 16p11.2 regions is exemplified by data demonstrating that perturbation of the distal region may impact expression of genes in the proximal region, including TBX6.37 The two regions are reciprocally engaged in complex chromatin looping, bringing together regulatory elements and genes, which is disturbed in carriers of the proximal CNV. The observed duplication could also be affecting nearby topologically associated domains and, as such, have an effect on expression and coregulation of more distant genes in the region. Thus, duplications of distal chromosome 16p11.2 may influence scoliosis risk by indirectly altering TBX6 expression. However, a role for TBX6 is considered less likely because none of the AIS cases with the distal chromosome 16p11.2 duplication had evidence for structural vertebral anomalies that are hallmarks of congenital scoliosis associated with TBX6 dysregulation.19 Likewise, we detected only one proximal chromosome 16p11.2 deletion that includes TBX6 in our large cohort, and this patient should have been excluded from our study as he had subtle congenital scoliosis on closer review. Additional support against a role for TBX6 in AIS pathogenesis is also provided by prior work showing the lack of segregating TBX6 coding variants in idiopathic scoliosis families.42

While the distal chromosome 16p11.2 duplication may influence scoliosis risk by indirectly altering nearby genes such as TBX6, direct involvement of single genes within the interval may also be causative. The smallest duplication interval in our AIS cases included only ATXN2L, Tu translation elongation factor, mitochondrial (TUFM), SH2B1 and ATPase sarcoplasmic/endoplasmic reticulum Ca2+ transporting 1 (ATP2A1). SH2B1 is a strong candidate due to its previous associations with growth, obesity and BMI. The distal duplication is also associated with low BMI.37 When combined with the observation that patients with AIS are significantly more likely be underweight than healthy controls,43 the enrichment of this duplication in our sample is intriguing and suggests the possibility that genetic abnormalities that alter growth, such as the distal chromosome 16p11.2 duplication, directly influence either susceptibility to scoliosis or its progression. Notably, SH2B1 is one of only two genes in this particular CNV with a probability of loss intolerance (pLI) score of greater than 0.9,44 indicating a strong dependence on gene dosage. The other gene with a high pLI score is ATXN2L (ataxin 2 like), which encodes a protein of unknown function. Other genes in the region include TUFM , which is associated with human combined oxidative phosphorylation deficiency, and ATP2A1, an enzyme involved in muscular excitation and contraction. Delineation of the exact mechanism by which the chromosome 16p11.2 microduplication influences scoliosis risk will require additional study.

To grossly estimate the penetrance of scoliosis associated with this distal chromosome 16p11.2 microduplication, we used a genotype-first approach to analyse a very large cohort of patients in the Geisinger Health System database with paired exome data and found a 30% overall lifetime risk of scoliosis, which represents a >4-fold lifetime risk of scoliosis compared with controls from the same healthcare system. In comparison, prior studies determined that this microduplication is mildly associated with cognitive impairment, with penetrance estimates of only ~11%.45 Incomplete penetrance of CNVs associated with neuropsychiatric disorders and cognitive impairment is well established, and we have confirmed this is also true for scoliosis. However, chromosome 16p11.2 microduplications appear to be more strongly associated with scoliosis than any other phenotype.

Limitations of the present study include the propensity of the program to fragment large CNVs into many smaller CNVs, as well as potential coverage biases, both of which relate to the use of exome sequence data to call CNVs rather than whole genome or chromosomal microarray data. The size of our cohort is relatively small compared with association studies of autism and other neuropsychiatric disorders, which often used ~20 000 samples to identify associations due to the low frequency of these CNVs. Of note, the distal chromosome 16p11.2 duplication is a significant risk factor that has an OR that is much higher than any other previously described for AIS, which explains why we were able to detect it with this relatively modest sample size. In addition to the distal chromosome 16p11.2 duplication, we also identified a small number of other recurrent CNVs in AIS cases (online supplementary table S3), although due to their rarity, the numbers are too small to statistically confirm enrichment in AIS. Our numbers are also likely too small to determine whether the distal chromosome 16p11.2 duplication influences clinical factors such as curve severity. While we did not detect a difference in scoliosis curve severity in cases with and without the distal chromosome 16p11.2 duplication, our cohort consists predominantly of severe AIS cases, and therefore, future studies with a broader representation of curve severity in cases are needed to determine if this CNV has any prognostic role in predicting curve progression.

While it is not yet standard of care to perform genetic testing in otherwise healthy patients with AIS, discovery of this distal chromosome 16p11.2 duplication as an AIS risk factor in nearly 1% of patients will add to the benefits of genetic testing for this patient population, which may also include identifying associated aortic aneurysm disease gene variants,11 anaesthesia and surgical bleeding risk factors and determination of recurrence risk in family members. For now, the results of this study support scoliosis screening for individuals identified with distal chromosome 16p11.2 microduplications in order to increase the utilisation and effectiveness of early treatment interventions such as bracing.


We would like to thank the Genome Technology Access Center in the Department of Genetics at Washington University School of Medicine for help with genomic analysis. The Center is partially supported by National Cancer Institute (NCI) Cancer Center Support Grant #P30 CA91842 to the Siteman Cancer Center and by the Institute for Clinical and Translational Sciences (ICTS) / Clinical and Translational Science Awards Program (CTSA) Grant #UL1RR024992 from the National Center for Research Resources, a component of the National Institutes of Health (NIH) and NIH Roadmap for Medical Research. Funded with support from University of Missouri Spinal Cord Injury Research Program, Shriners Hospital for Children and the Children’s Discovery Institute of Washington University and St. Louis Children’s Hospital, and Hope Center DNA/RNA Purification Core at Washington University School of Medicine. Computations were performed using the facilities of the Washington University Center for High Performance Computing, which were partially funded by NIH grants 1S10RR022984-01A1 and 1S10OD018091-01. We would like to thank the patients and their families for their participation, as well as Drs Munish Gupta, Keith Bridwell, Mike Kelly, Scott Luhmann, Brian Kelly, Luke Zebala, Lawrence Lenke and Christi Abeln.



  • Contributors BS, GH, MD and CAG conceived of the study; BS and GH carried out statistical analyses, LA compiled exome data; XB compiled supplemental table data; CAW, YK, JM, PG, CR and NM compiled and provided additional exome data from University of Iowa, University of Colorado and University of Texas; IA provided additional advice on CNV location methods; NW, MS, DJ, CJ, TJ and MO provided and analysed Geisinger dataset for CNVs and phenotypic data, and ST and TD validated CNVs. All authors edited the manuscript.

  • Funding Research reported in this publication was supported by National Institute of Arthritis and Musculoskeletal and Skin Diseases under Award Number R01AR067715, Eunice Kennedy Shriver National Institutes of Child Health and Human Development of the National Institutes of Health under the Award Number P01HD084387, the Marfan Foundation Faculty Grant award #81831, Washington University Institute of Clinical and Translational Sciences grant UL1 TR002345 from the National Center for Advancing Translational Sciences of the National Institutes of Health, Washington University Musculoskeletal Research Center (NIH/NIAMS P30 AR057235) and the Eunice Kennedy Shriver National Institute of Child Health & Human Development of the National Institutes of Health under Award Number U54 HD087011 to the Intellectual and Developmental Disabilities Research Center at Washington University.

  • Disclaimer The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

  • Competing interests None declared.

  • Ethics approval The institutional review board at each institution approved this study.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Author note Accession number for the AIS exome data reported in this paper are dbGAP: phs001677.