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SOX6 belongs to a family of 20 SRY-related HMG-box-containing (SOX) genes that encode transcription factors controlling cell fate and differentiation in many developmental and adult processes. For SOX6, these processes include, but are not limited to, neurogenesis and skeletogenesis. Variants in half of the SOX genes have been shown to cause severe developmental and adult syndromes, referred to as SOXopathies. We here provide evidence that SOX6 variants also cause a SOXopathy. Using clinical and genetic data, we identify 19 individuals harboring various types of SOX6 alterations and exhibiting developmental delay and/or intellectual disability; the individuals are from 17 unrelated families. Additional, inconstant features include attention-deficit/hyperactivity disorder (ADHD), autism, mild facial dysmorphism, craniosynostosis, and multiple osteochondromas. All variants are heterozygous. Fourteen are de novo, one is inherited from a mosaic father, and four offspring from two families have a paternally inherited variant. Intragenic microdeletions, balanced structural rearrangements, frameshifts, and nonsense variants are predicted to inactivate the SOX6 variant allele. Four missense variants occur in residues and protein regions highly conserved evolutionarily. These variants are not detected in the gnomAD control cohort, and the amino acid substitutions are predicted to be damaging. Two of these variants are located in the HMG domain and abolish SOX6 transcriptional activity in vitro. No clear genotype-phenotype correlations are found. Taken together, these findings concur that SOX6 haploinsufficiency leads to a neurodevelopmental SOXopathy that often includes ADHD and abnormal skeletal and other features. Copyright © 2020 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.


Dara Tolchin, Jessica P Yeager, Priya Prasad, Naghmeh Dorrani, Alvaro Serrano Russi, Julian A Martinez-Agosto, Abdul Haseeb, Marco Angelozzi, G W E Santen, Claudia Ruivenkamp, Saadet Mercimek-Andrews, Christel Depienne, Alma Kuechler, Barbara Mikat, Hermann-Josef Ludecke, Frederic Bilan, Gwenael Le Guyader, Brigitte Gilbert-Dussardier, Boris Keren, Solveig Heide, Damien Haye, Hilde Van Esch, Liesbeth Keldermans, Damara Ortiz, Emily Lancaster, Ian D Krantz, Bryan L Krock, Kieran B Pechter, Alexandre Arkader, Livija Medne, Elizabeth T DeChene, Eduardo Calpena, Giada Melistaccio, Andrew O M Wilkie, Mohnish Suri, Nicola Foulds, Genomics England Research Consortium, Amber Begtrup, Lindsay B Henderson, Cara Forster, Patrick Reed, Marie T McDonald, Allyn McConkie-Rosell, Julien Thevenon, Pauline Le Tanno, Charles Coutton, Anne C H Tsai, Sarah Stewart, Ales Maver, Rudolf Gorazd, Olivier Pichon, Mathilde Nizon, Benjamin Cogné, Bertrand Isidor, Dominique Martin-Coignard, Radka Stoeva, Véronique Lefebvre, Cédric Le Caignec. De Novo SOX6 Variants Cause a Neurodevelopmental Syndrome Associated with ADHD, Craniosynostosis, and Osteochondromas. American journal of human genetics. 2020 Jun 04;106(6):830-845

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PMID: 32442410

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