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De Novo SOX6 Variants Cause a Neurodevelopmental Syndrome Associated with ADHD, Craniosynostosis, and Osteochondromas.

Publication ,  Journal Article
Tolchin, D; Yeager, JP; Prasad, P; Dorrani, N; Russi, AS; Martinez-Agosto, JA; Haseeb, A; Angelozzi, M; Santen, GWE; Ruivenkamp, C; Depienne, C ...
Published in: Am J Hum Genet
June 4, 2020

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.

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Published In

Am J Hum Genet

DOI

EISSN

1537-6605

Publication Date

June 4, 2020

Volume

106

Issue

6

Start / End Page

830 / 845

Location

United States

Related Subject Headings

  • Translocation, Genetic
  • Transcriptome
  • Transcription, Genetic
  • Syndrome
  • SOXD Transcription Factors
  • RNA-Seq
  • Osteochondroma
  • Neurodevelopmental Disorders
  • Mutation, Missense
  • Male
 

Citation

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Tolchin, D., Yeager, J. P., Prasad, P., Dorrani, N., Russi, A. S., Martinez-Agosto, J. A., … Le Caignec, C. (2020). De Novo SOX6 Variants Cause a Neurodevelopmental Syndrome Associated with ADHD, Craniosynostosis, and Osteochondromas. Am J Hum Genet, 106(6), 830–845. https://doi.org/10.1016/j.ajhg.2020.04.015
Tolchin, Dara, Jessica P. Yeager, Priya Prasad, Naghmeh Dorrani, Alvaro Serrano Russi, Julian A. Martinez-Agosto, Abdul Haseeb, et al. “De Novo SOX6 Variants Cause a Neurodevelopmental Syndrome Associated with ADHD, Craniosynostosis, and Osteochondromas.Am J Hum Genet 106, no. 6 (June 4, 2020): 830–45. https://doi.org/10.1016/j.ajhg.2020.04.015.
Tolchin D, Yeager JP, Prasad P, Dorrani N, Russi AS, Martinez-Agosto JA, et al. De Novo SOX6 Variants Cause a Neurodevelopmental Syndrome Associated with ADHD, Craniosynostosis, and Osteochondromas. Am J Hum Genet. 2020 Jun 4;106(6):830–45.
Tolchin, Dara, et al. “De Novo SOX6 Variants Cause a Neurodevelopmental Syndrome Associated with ADHD, Craniosynostosis, and Osteochondromas.Am J Hum Genet, vol. 106, no. 6, June 2020, pp. 830–45. Pubmed, doi:10.1016/j.ajhg.2020.04.015.
Tolchin D, Yeager JP, Prasad P, Dorrani N, Russi AS, Martinez-Agosto JA, Haseeb A, Angelozzi M, Santen GWE, Ruivenkamp C, Mercimek-Andrews S, Depienne C, Kuechler A, Mikat B, Ludecke H-J, Bilan F, Le Guyader G, Gilbert-Dussardier B, Keren B, Heide S, Haye D, Van Esch H, Keldermans L, Ortiz D, Lancaster E, Krantz ID, Krock BL, Pechter KB, Arkader A, Medne L, DeChene ET, Calpena E, Melistaccio G, Wilkie AOM, Suri M, Foulds N, Genomics England Research Consortium, Begtrup A, Henderson LB, Forster C, Reed P, McDonald MT, McConkie-Rosell A, Thevenon J, Le Tanno P, Coutton C, Tsai ACH, Stewart S, Maver A, Gorazd R, Pichon O, Nizon M, Cogné B, Isidor B, Martin-Coignard D, Stoeva R, Lefebvre V, Le Caignec C. De Novo SOX6 Variants Cause a Neurodevelopmental Syndrome Associated with ADHD, Craniosynostosis, and Osteochondromas. Am J Hum Genet. 2020 Jun 4;106(6):830–845.
Journal cover image

Published In

Am J Hum Genet

DOI

EISSN

1537-6605

Publication Date

June 4, 2020

Volume

106

Issue

6

Start / End Page

830 / 845

Location

United States

Related Subject Headings

  • Translocation, Genetic
  • Transcriptome
  • Transcription, Genetic
  • Syndrome
  • SOXD Transcription Factors
  • RNA-Seq
  • Osteochondroma
  • Neurodevelopmental Disorders
  • Mutation, Missense
  • Male