title: Genomic Analyses of Patients With Unexplained Early-Onset Scoliosis.
abstract: METHODS
  To test for rare genetic mutations, a cohort of patients with unexplained early-onset scoliosis (EOS) was screened using high-density microarray genotyping. A cohort of patients with adolescent idiopathic scoliosis (AIS) was similarly screened and the results were compared.
  
  
  BACKGROUND
  Patients with scoliosis in infancy or early childhood (EOS) are at high risk for progressive deformity and associated problems including respiratory compromise. Early-onset scoliosis is frequently associated with genetic disorders but many patients present with nonspecific clinical features and without an associated diagnosis. The authors hypothesized that EOS in these patients may be caused by rare genetic mutations detectable by next-generation genomic methods.
  
  
  METHODS
  The researchers identified 24 patients with unexplained EOS from pediatric orthopedic clinics. They genotyped them, along with 39 connecting family members, using the Illumina OmniExpress-12, version 1.0 beadchip. Resulting genotypes were analyzed for chromosomal changes, specifically copy number variation and absence of heterozygosity. They screened 482 adolescent idiopathic scoliosis (AIS) patients and 744 healthy controls, who were similarly genotyped with the same beadchip, for chromosomal changes identified in the EOS cohort.
  
  
  RESULTS
  Copy number variation and absence of heterozygosity analyses revealed a genetic diagnosis of chromosome 15q24 microdeletion syndrome in 1 patient and maternal uniparental disomy of chromosome 14 in a second one. Prior genetic testing and clinical evaluations had been negative in both cases. A large novel chromosome 10 deletion was likely causal in a third EOS patient. These mutations identified in the EOS patients were absent in AIS patients and controls, and thus were not associated with AIS or found in asymptomatic individuals.
  
  
  CONCLUSIONS
  These data underscore the usefulness of updated genetic evaluations including high-density microarray-based genotyping and other next-generation methods in patients with unexplained EOS, even when prior genetic studies were negative. These data also suggest the intriguing possibility that other mutations detectable by whole genome sequencing, as well as epigenetic effects, await discovery in the EOS population.
authors.affiliation: Sarah M. and Charles E. Seay Center for Musculoskeletal Research, Texas Scottish Rite Hospital for Children, 2222 Welborn St., Dallas, TX 75219, USA.
authors.forename: Xiaochong
authors.initials: X
authors.lastname: Gao
authors.affiliation: Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, TX, USA.
authors.forename: Garrett
authors.initials: G
authors.lastname: Gotway
authors.affiliation: Department of Orthopedic Surgery, Texas Scottish Rite Hospital for Children, Dallas, TX, USA; Department of Orthopaedic Surgery, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, Texas 75390, USA.
authors.forename: Karl
authors.initials: K
authors.lastname: Rathjen
authors.affiliation: Department of Orthopedic Surgery, Texas Scottish Rite Hospital for Children, Dallas, TX, USA; Department of Orthopaedic Surgery, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, Texas 75390, USA.
authors.forename: Charles
authors.initials: C
authors.lastname: Johnston
authors.affiliation: Department of Neurology, Texas Scottish Rite Hospital for Children, Dallas, TX, USA; Department of Neurology and Neurotherapeutics, University of Texas Southwestern Medical Center, Dallas, TX, USA.
authors.forename: Steven
authors.initials: S
authors.lastname: Sparagana
authors.affiliation: Sarah M. and Charles E. Seay Center for Musculoskeletal Research, Texas Scottish Rite Hospital for Children, 2222 Welborn St., Dallas, TX 75219, USA; Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, TX, USA; Department of Orthopaedic Surgery, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, Texas 75390, USA; McDermott Center for Human Growth and Development, University of Texas Southwestern Medical Center, Dallas, TX, USA. Electronic address: Carol.Wise@tsrh.org.
authors.forename: Carol A
authors.initials: CA
authors.lastname: Wise
keywords: Copy number variation; Early-onset scoliosis; Genotyping; Microarray