Unraveling the Genetic Contributions to Congenital Scoliosis and Vertebral Malformations

Idiopathic and congenital scoliosis (CS) are conditions that are frequently encountered by genetics professionals. Patients affected by these conditions are concerned about prognosis, associated health conditions and recurrence risks. Recent developmental genetic studies of the spine, genome-wide association studies, and whole exome/genome analysis aid in understanding the genetic etiology of idiopathic and congenital scoliosis. With the identification of mutations in TBX6 accounting for approximately 10% of CS, the genetic etiology for the vast majority of vertebral malformations (VMs) and CS awaits discovery. We hypothesize the existence of novel genes and phenotypes associated with these conditions. Fetal exposures such as anticonvulsants, hyperthermia, fumonisins, maternal diabetes and alcohol use have been reported to be associated with the development of VMs. Genetically mediated environmental exposures mediated by mutations in the NAD pathway have been shown to be a recent cause of VMs.

Understanding Environmental Contributions for Adolescent Idiopathic Scoliosis

We hypothesize that alterations in neighborhood-level factors, including social stressors and environmental exposures (e.g., air quality), play a contributing role in the occurrence of idiopathic scoliosis. Since social stressors and adverse environmental exposures co-occur in space and time, resulting in disproportionate patterns of exposure, it is important to consider the health impacts of these cumulating burdens. Access to care often varies spatially as well, with fewer treatment providers located in lower socioeconomic status or in racially isolated, predominantly non-Hispanic Black and Hispanic neighborhoods. In our studies, we aim to use geocoding to identify and link information regarding environmental exposures, link data on social stressors – including neighborhood deprivation index (NDI) and the Children’s Environmental Health Initiative’s (CEHI @ UIC) local, spatial measure of racial isolation – and determine the distribution of exposures of the potential source population using descriptive statistics and geospatial maps. Our team will delve into investigating this hypothesis further, examining its implications on structural birth defects and congenital scoliosis. Additionally, we’ll employ an animal model to bolster our research efforts.
Web article related to CEHI studies: https://today.uic.edu/using-maps-to-fight-inequities/

• Genomic Analysis in Patients with Vertebral Malformation, Congenital and/or Idiopathic Scoliosis: Our team is interested in learning more about possible genetic changes occurring in patients with vertebral malformations (VM), congenital scoliosis (CS), and adolescent idiopathic scoliosis (AIS). PI: Philip F. Giampietro; UIC
  Contact: Interested patients should contact study coordinator via UI Health Research Registry link for more information.

• Evaluation and comparison of optical chromosomal mapping and long-read DNA sequencing platforms with standard chromosomal microarray analysis for clinical application: Compare next-generation cytogenetics (NGC) technologies to standard technologies on clinical samples with an established diagnosis or normal findings.
  Sponsor: Ulrich Broeckel, MD, Medical College of Wisconsin.

• Shriners Hospitals for Children (Canada) R01 Clinical Grant, “EXPAND AMC: Expand the Phenotype and Advance Next generation sequencing Discovery in arthrogryposis multiplex congenita,” PI: Noemi Dahan-Oliel, OT, PhD: Phenotypic and genetic characterization of patients with arthrogryposis enrolled in Shriners Registry.
  Web article related to study

• Shriners Hospitals for Children Genomics Institute: Collaboration with Shriners Hospital to investigate genetic markers linked to both congenital and idiopathic scoliosis.
• American College of Medical Genetics and Genomics (ACMG): ACMG Working Group: Autism Spectrum Disorder Evidence Based Guidelines.

• National Institutes of Health 1 R03 HD099516, “Functional Analysis of Whole Exome Sequence Variants Identified in Patients with Vertebral Malformations”
  The purpose of this grant was to use zebrafish as a model system to evaluate pathogenicity of DNA sequence variants obtained from whole exome sequence analysis in patients with vertebral malformations.

• Shriners Hospitals for Children (Canada), “Registry for Arthrogryposis: Epidemiology, Etiology, Intervention and Genomics”
  The purpose of this grant was to phenotypically characterize patients with arthrogryposis multiplex congenital and perform whole genome sequence analysis on a cohort of 50 patients with distal arthrogryposis.

• Genetics Division Translational Research Portfolio

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• Rebello D, Wohler E, Erfani V, Li G, Aguilera AN, Santiago-Cornier A, Zhao S, Hwang SW, Steiner RD, Zhang TJ, Gurnett CA, Raggio C, Wu N, Sobreira N, Giampietro PF, Ciruna B. COL11A2 as a candidate gene for vertebral malformations and congenital scoliosis. Hum Mol Genet. 2023 Jul 18;. doi: 10.1093/hmg/ddad117. [Epub ahead of print] PubMed PMID: 37462524.