Journal article
Rare missense variants in FNDC1 are associated with severe adolescent idiopathic scoliosis
Journal of medical genetics, Vol.62(7), pp.427-435
07/2025
DOI: 10.1136/jmg-2024-110586
PMCID: PMC12187536
PMID: 40306904
Abstract
Scoliosis is the most common paediatric spinal deformity. More than 80% of scoliosis is idiopathic and appears during the adolescent growth spurt. Spinal fusion surgery is often required for patients with progressive adolescent idiopathic scoliosis (AIS), and the genetic risk factors for severe disease (defined here as curve >35 degrees) are largely unknown.
To explore the role of rare variants in severe AIS, exome sequence data from 1221 individuals with AIS were compared with both 1397 in-house European ancestry controls and 56885 gnomAD non-Finish European controls. Segregation analysis of variants in prioritised genes was performed in additional family members. A replication study was performed using the Geisinger MyCode cohort.
function was investigated in
null mutant zebrafish.
Rare variants were enriched in 84 genes, including
(Noonan syndrome),
(Marfan syndrome) and
in individuals with severe AIS.
, which had previously been associated with joint hypermobility, harboured missense variants in 4.0% of individuals with AIS compared with 2.3% of controls (p=0.00764, OR=1.78).
variants segregated with AIS in five multiplex families with incomplete penetrance. In addition,
rare variants were also associated with scoliosis in the Geisinger MyCode cohort (p=0.0002, OR=3.6). Disruption of the
locus in zebrafish resulted in increased bone mineral density.
We broadened the phenotype associated with
and
variants and identified
as a novel gene associated with severe AIS. Mechanistic alterations of bone mineral density or joint hypermobility may explain the association of
missense variants with AIS.
Details
- Title: Subtitle
- Rare missense variants in FNDC1 are associated with severe adolescent idiopathic scoliosis
- Creators
- Wu-Lin Charng - Washington University in St. Louis School of MedicineGabe Haller - Washington University in St. Louis School of MedicineJulia Whittle - Washington University in St. Louis School of MedicineMomchil Nikolov - Washington University in St. Louis School of MedicineAddison Avery - Washington University in St. Louis School of MedicineJose Morcuende - University of IowaPhilip Giampietro - University of Illinois Urbana-ChampaignCathy Raggio - Hospital for Special SurgeryNancy Miller - University of Colorado Anschutz Medical CampusAnne E Justice - Geisinger Health SystemNatasha T Strande - Geisinger Health SystemMark Seeley - Geisinger Health SystemDale L Bodian - Geisinger, North Bethesda, Maryland, USACarol A Wise - Scottish Rite HospitalDiane S Sepich - Washington University in St. Louis School of MedicineMatthew B Dobbs - The Spine InstituteChristina A Gurnett - Washington University in St. Louis School of Medicine
- Resource Type
- Journal article
- Publication Details
- Journal of medical genetics, Vol.62(7), pp.427-435
- DOI
- 10.1136/jmg-2024-110586
- PMID
- 40306904
- PMCID
- PMC12187536
- NLM abbreviation
- J Med Genet
- ISSN
- 1468-6244
- eISSN
- 1468-6244
- Publisher
- BMJ Publishing Group
- Grant note
- National Institute of Mental HealthArts & Sciences Electronic Theses and Dissertations: 2021 Lilian Antunes ('Genetics of Pediatric Musculoskeletal Disorders'): 2358
We thank the individuals with AIS and their families for their participation in this study. We also thank the members of the International Consortium for Spinal Genetics Development and Disease, and Drs Lilian Antunes Heck, Carlos Cruchaga, Matthew Harms, Don Conrad, Liliana Solnica-Krezel and Sanjay Jain for their collaboration and access to samples. We also thank Kevin McCall for his technical assistance. Research in this paper includes part of the thesis of Julia Whittle ('Generation, Characterization, and Treatment of Functional Zebrafish Models for Musculoskeletal Disorders' (2022). Arts & Sciences Electronic Theses and Dissertations. 2756) and Lilian Antunes ('Genetics of Pediatric Musculoskeletal Disorders' (2021). Arts & Sciences Electronic Theses and Dissertations. 2358). We thank all the participants of the Geisinger's MyCode Community Health Initiative (MyCode) study. We thank the members of the Geisinger-Regeneron DiscovEHR Collaboration who have been critical in the generation of the genetic data used in this study.
- Language
- English
- Electronic publication date
- 04/29/2025
- Date published
- 07/2025
- Academic Unit
- Stead Family Department of Pediatrics; Orthopedics and Rehabilitation
- Record Identifier
- 9984816010002771
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