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Genotype-phenotype correlations
Short report
Pathogenic SATB2 missense variants affecting p.Gly392 have variable functional implications and result in diverse clinical phenotypes
  1. Joery den Hoed1,
  2. Hirokazu Hashimoto2,3,
  3. Mubeen Khan1,
  4. Fleur Semmekrot1,
  5. Katherine A Bosanko4,
  6. Chihiro Abe-Hatano5,
  7. Eiji Nakagawa6,
  8. Hanka Venselaar7,
  9. Nada Quercia8,9,
  10. Lauren Chad8,10,
  11. Hiroshi Kurosaka11,
  12. Stephane Rondeau12,
  13. Simon E Fisher1,13,
  14. Shinya Yamamoto2,3,
  15. Yuri A Zarate14,15
  1. 1Language and Genetics Department, Max Planck Institute for Psycholinguistics, Nijmegen, Netherlands
  2. 2Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA
  3. 3Jan and Dan Duncan Neurological Research Institute,Texas Children's Hospital, Houston, Texas, USA
  4. 4Section of Genetics and Metabolism, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA
  5. 5Medical Genome Center, National Center of Neurology and Psychiatry, Tokyo, Japan
  6. 6Department of Child Neurology, National Center Hospital, National Center of Neurology and Psychiatry, Tokyo, Japan
  7. 7Center for Molecular and Biomolecular Informatics, Radboud University Medical Center, Nijmegen, Netherlands
  8. 8Division of Clinical and Metabolic Genetics, The Hospital for Sick Children, Toronto, Ontario, Canada
  9. 9Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada
  10. 10Department of Paediatrics, University of Toronto, Toronto, Ontario, Canada
  11. 11Department of Orthodontics and Dentofacial Orthopedics, Osaka University Graduate School of Dentistry, Suita, Japan
  12. 12Department of Early Medico-Social Action, CHU de Rouen, Rouen, France
  13. 13Donders Institute for Brain, Cognition and Behaviour, Radboud University, Nijmegen, Netherlands
  14. 14University of Kentucky, Lexington, Kentucky, USA
  15. 15University of Arkansas for Medical Sciences College of Medicine, Little Rock, Arkansas, USA
  1. Correspondence to Dr Yuri A Zarate; yuri.zarate{at}uky.edu; Dr Shinya Yamamoto; yamamoto{at}bcm.edu

Abstract

SATB2-associated syndrome (SAS) is caused by pathogenic variants in SATB2, which encodes an evolutionarily conserved transcription factor. Despite the broad range of phenotypic manifestations and variable severity related to this syndrome, haploinsufficiency has been assumed to be the primary molecular explanation.

In this study, we describe eight individuals with SATB2 variants that affect p.Gly392 (four women, age range 2–16 years; p.Gly392Arg, p.Gly392Glu and p.Gly392Val). Of these, individuals with p.Gly392Arg substitutions were found to have more severe neurodevelopmental phenotypes based on an established rubric scoring system when compared with individuals with p.Gly392Glu, p.Gly392Val and other previously reported causative SATB2 missense variants. Consistent with the observations at the phenotypic level, using human cell-based and model organism functional data, we documented that while all three described p.Gly392 variants affect the same residue and seem to all have a partial loss-of-function effect, some effects on SATB2 protein function appear to be variant-specific. Our results indicate that genotype–phenotype correlations in SAS are more complex than originally thought, and variant-specific genotype–phenotype correlations are needed.

  • Genetics, Medical
  • Genotyping Techniques
  • Loss of Function Mutation
  • Phenotype

https://doi.org/10.1136/jmg-2024-110015

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    Footnotes

    • Contributors Study concept and design, collection and assembly of data: JdH, HH, SEF, SY, YAZ. Functional studies: JdH, HH, MK, FS, HV, SEF, SY. Medical care to patients: KB, CA-H. EN, NQ, LC, HK, SR, YAZ. Data interpretation: JdH, HH, MK, HV, FS, SEF, SY, YAZ. Manuscript writing: JdH, HH, SEF, SY, YAZ. Manuscript review and approval: all authors.

    • Funding This work was financially supported by research grants from the SATB2 Gene Foundation (Drs. Fisher, den Hoed and Yamamoto) and institutional funds from the Max Planck Society (Drs. Fisher and den Hoed) and Baylor College of Medicine (Dr. Yamamoto).

    • Competing interests YZ is a medical advisor to the SATB2 Gene Foundation. YZ and SY received grants from the SATB2 Gene Foundation. SY serves as a member of the Scientific Advisory Board for SATB2 Europe. No other authors declare any conflict of interest.

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

    • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.