Rare LRRFIP1 variants contribute to pathophysiology of severe early-onset scoliosis and common scoliotic phenotypes

Tanja Frey; Elena M. Cabello; Gabriele Siegel; Carla Bello; Rike Schiller; Martina A. Trippel; Neguin Ranjbar; Paranchai Boonsawat; Stephanie E. van Gijn; Ivan Ivanovski; Michael Papik; Markus Zweier; Kan Min; Katharina Steindl; Anita Rauch

doi:10.1172/JCI202751

¹Institute of Medical Genetics, University of Zurich, Zurich, Switzerland

²University Children's Hospital Zurich, University of Zurich, Zurich, Switzerland

³Centre for Scoliosis and Spinal Surgery, Swiss Scoliosis, Zurich, Switzerland

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¹Institute of Medical Genetics, University of Zurich, Zurich, Switzerland

²University Children's Hospital Zurich, University of Zurich, Zurich, Switzerland

³Centre for Scoliosis and Spinal Surgery, Swiss Scoliosis, Zurich, Switzerland

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¹Institute of Medical Genetics, University of Zurich, Zurich, Switzerland

²University Children's Hospital Zurich, University of Zurich, Zurich, Switzerland

³Centre for Scoliosis and Spinal Surgery, Swiss Scoliosis, Zurich, Switzerland

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¹Institute of Medical Genetics, University of Zurich, Zurich, Switzerland

²University Children's Hospital Zurich, University of Zurich, Zurich, Switzerland

³Centre for Scoliosis and Spinal Surgery, Swiss Scoliosis, Zurich, Switzerland

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¹Institute of Medical Genetics, University of Zurich, Zurich, Switzerland

²University Children's Hospital Zurich, University of Zurich, Zurich, Switzerland

³Centre for Scoliosis and Spinal Surgery, Swiss Scoliosis, Zurich, Switzerland

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¹Institute of Medical Genetics, University of Zurich, Zurich, Switzerland

²University Children's Hospital Zurich, University of Zurich, Zurich, Switzerland

³Centre for Scoliosis and Spinal Surgery, Swiss Scoliosis, Zurich, Switzerland

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¹Institute of Medical Genetics, University of Zurich, Zurich, Switzerland

²University Children's Hospital Zurich, University of Zurich, Zurich, Switzerland

³Centre for Scoliosis and Spinal Surgery, Swiss Scoliosis, Zurich, Switzerland

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¹Institute of Medical Genetics, University of Zurich, Zurich, Switzerland

²University Children's Hospital Zurich, University of Zurich, Zurich, Switzerland

³Centre for Scoliosis and Spinal Surgery, Swiss Scoliosis, Zurich, Switzerland

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¹Institute of Medical Genetics, University of Zurich, Zurich, Switzerland

²University Children's Hospital Zurich, University of Zurich, Zurich, Switzerland

³Centre for Scoliosis and Spinal Surgery, Swiss Scoliosis, Zurich, Switzerland

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¹Institute of Medical Genetics, University of Zurich, Zurich, Switzerland

²University Children's Hospital Zurich, University of Zurich, Zurich, Switzerland

³Centre for Scoliosis and Spinal Surgery, Swiss Scoliosis, Zurich, Switzerland

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¹Institute of Medical Genetics, University of Zurich, Zurich, Switzerland

²University Children's Hospital Zurich, University of Zurich, Zurich, Switzerland

³Centre for Scoliosis and Spinal Surgery, Swiss Scoliosis, Zurich, Switzerland

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¹Institute of Medical Genetics, University of Zurich, Zurich, Switzerland

²University Children's Hospital Zurich, University of Zurich, Zurich, Switzerland

³Centre for Scoliosis and Spinal Surgery, Swiss Scoliosis, Zurich, Switzerland

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¹Institute of Medical Genetics, University of Zurich, Zurich, Switzerland

²University Children's Hospital Zurich, University of Zurich, Zurich, Switzerland

³Centre for Scoliosis and Spinal Surgery, Swiss Scoliosis, Zurich, Switzerland

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¹Institute of Medical Genetics, University of Zurich, Zurich, Switzerland

²University Children's Hospital Zurich, University of Zurich, Zurich, Switzerland

³Centre for Scoliosis and Spinal Surgery, Swiss Scoliosis, Zurich, Switzerland

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¹Institute of Medical Genetics, University of Zurich, Zurich, Switzerland

²University Children's Hospital Zurich, University of Zurich, Zurich, Switzerland

³Centre for Scoliosis and Spinal Surgery, Swiss Scoliosis, Zurich, Switzerland

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J Clin Invest. https://doi.org/10.1172/JCI202751.
Copyright © 2026, Frey et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

Published September 29, 2026 - Version history

Despite enormous advances in clinical genomics, idiopathic scoliosis remains an enigmatic condition with poorly understood genetic and pathophysiological underpinnings impeding molecular diagnosis and the development of targeted treatments. We performed linkage analysis, exome, genome and short- and long-read RNA sequencing in a multigenerational family affected by autosomal dominant early-onset scoliosis (EOS) with a unique pattern of spondylodysplastic elements and progressive endplate erosion and identified the LRR binding FLII interacting protein 1 gene (LRRFIP1) as the disease-causing gene. The underlying cause is a rare noncoding variant altering transcription factor binding of NR3C1 (glucocorticoid receptor) leading to changes in LRRFIP1-isoform expression. Transcriptomic changes in fibroblasts of affected individuals indicated a combination of disturbed Wnt-signaling during somitogenesis, planar cell polarity signaling and postnatal inflammatory dysregulation with clinical and molecular overlaps with Ankylosing Spondylitis and Scheuermann kyphosis. We conducted a rare variant enrichment analysis using genome data from 484,903 UK Biobank participants and found an enrichment of rare risk-increasing LRRFIP1-variants in individuals with scoliosis. Our analysis of an Lrrfip1^{tm1.1(KOMP)Wtsi} KO mouse model showed increased prevalence of idiopathic kyphoscoliosis in Lrrfip1-deficient mice. Our work provides insights into the pathophysiology of rare and common spinal disorders and hints to potential future therapeutic approaches with selective NR3C1-inhibitors.

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Rare LRRFIP1 variants contribute to pathophysiology of severe early-onset scoliosis and common scoliotic phenotypes

Tanja Frey,¹ Elena M. Cabello,¹ Gabriele Siegel,¹ Carla Bello,¹ Rike Schiller,² Martina A. Trippel,¹ Neguin Ranjbar,¹ Paranchai Boonsawat,¹ Stephanie E. van Gijn,¹ Ivan Ivanovski,¹ Michael Papik,¹ Markus Zweier,¹ Kan Min,³ Katharina Steindl,¹ and Anita Rauch¹

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Rare LRRFIP1 variants contribute to pathophysiology of severe early-onset scoliosis and common scoliotic phenotypes

Tanja Frey,1 Elena M. Cabello,1 Gabriele Siegel,1 Carla Bello,1 Rike Schiller,2 Martina A. Trippel,1 Neguin Ranjbar,1 Paranchai Boonsawat,1 Stephanie E. van Gijn,1 Ivan Ivanovski,1 Michael Papik,1 Markus Zweier,1 Kan Min,3 Katharina Steindl,1 and Anita Rauch1

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Tanja Frey,¹ Elena M. Cabello,¹ Gabriele Siegel,¹ Carla Bello,¹ Rike Schiller,² Martina A. Trippel,¹ Neguin Ranjbar,¹ Paranchai Boonsawat,¹ Stephanie E. van Gijn,¹ Ivan Ivanovski,¹ Michael Papik,¹ Markus Zweier,¹ Kan Min,³ Katharina Steindl,¹ and Anita Rauch¹