De Novo SOX6 Variants Cause a Neurodevelopmental Syndrome Associated with ADHD, Craniosynostosis, and Osteochondromas - Sorbonne Université Access content directly
Journal Articles American Journal of Human Genetics Year : 2020

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

Dara Tolchin (1) , Jessica Yeager (1) , Priya Prasad (2) , Naghmeh Dorrani (3) , Alvaro Serrano Russi (4) , Julian Martinez-Agosto (3) , Abdul Haseeb (1) , Marco Angelozzi (1) , G.W.E. Santen (5) , Claudia Ruivenkamp (5) , Saadet Mercimek-Andrews (6) , Christel Depienne (7, 8) , Alma Kuechler (8) , Barbara Mikat (8) , Hermann-Josef Ludecke (9) , Frederic Bilan (10) , Gwenael Le Guyader (10) , Brigitte Gilbert-Dussardier (10) , Boris Keren (11) , Solveig Heide (11) , Damien Haye , Hilde van Esch , Liesbeth Keldermans , Damara Ortiz , Emily Lancaster , Ian Krantz , Bryan Krock , Kieran Pechter , Alexandre Arkader (1) , Livija Medne , Elizabeth Dechene , Eduardo Calpena , Giada Melistaccio , Andrew O.M. Wilkie , Mohnish Suri , Nicola Foulds , Amber Begtrup , Lindsay Henderson , Cara Forster , Patrick Reed , Marie 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 (1) , Cédric Le Caignec (12, 13) , J.C. Ambrose , M. Bleda , F. Boardman-Pretty , J.M. Boissiere , C.R. Boustred , M.J. Caulfield , G.C. Chan , C.E.H. Craig , L.C. Daugherty , A. de Burca , A. Devereau , G. Elgar , R.E. Foulger , T. Fowler , P. Furió-Tarí , J.M. Hackett , D. Halai , J.E. Holman , T.J.P. Hubbard , D. Kasperaviciute , M. Kayikci , L. Lahnstein , K. Lawson , S.E.A. Leigh , I.U.S. Leong , F.J. Lopez , F. Maleady-Crowe , J. Mason , E.M. Mcdonagh , L. Moutsianas , M. Mueller , A.C. Need , C.A. Odhams , C. Patch , D. Perez-Gil , D. Polychronopoulos , J. Pullinger , T. Rahim , A. Rendon , T. Rogers , M. Ryten , K. Savage , R.H. Scott , A. Siddiq , A. Sieghart , D. Smedley , K.R. Smith , A. Sosinsky , W. Spooner , H.E. Stevens , A. Stuckey , E.R.A. Thomas , S.R. Thompson , C. Tregidgo , A. Tucci , E. Walsh , S.A. Watters , M.J. Welland , E. Williams , K. Witkowska , S.M. Wood , M. Zarowiecki
Damien Haye
  • Function : Author
Hilde van Esch
  • Function : Author
Liesbeth Keldermans
  • Function : Author
Damara Ortiz
  • Function : Author
Emily Lancaster
  • Function : Author
Ian Krantz
  • Function : Author
Bryan Krock
  • Function : Author
Kieran Pechter
  • Function : Author
Livija Medne
  • Function : Author
Elizabeth Dechene
  • Function : Author
Eduardo Calpena
  • Function : Author
Giada Melistaccio
  • Function : Author
Andrew O.M. Wilkie
  • Function : Author
Mohnish Suri
  • Function : Author
Nicola Foulds
  • Function : Author
Amber Begtrup
  • Function : Author
Lindsay Henderson
  • Function : Author
Cara Forster
  • Function : Author
Patrick Reed
  • Function : Author
Marie Mcdonald
  • Function : Author
Allyn Mcconkie-Rosell
  • Function : Author
Julien Thevenon
  • Function : Author
Pauline Le Tanno
  • Function : Author
Charles Coutton
  • Function : Author
Anne C.H. Tsai
  • Function : Author
Sarah Stewart
  • Function : Author
Ales Maver
  • Function : Author
Rudolf Gorazd
  • Function : Author
Olivier Pichon
  • Function : Author
Mathilde Nizon
  • Function : Author
Benjamin Cogné
  • Function : Author
Bertrand Isidor
  • Function : Author
Dominique Martin-Coignard
  • Function : Author
Radka Stoeva
  • Function : Author
J.C. Ambrose
  • Function : Author
M. Bleda
  • Function : Author
F. Boardman-Pretty
  • Function : Author
J.M. Boissiere
  • Function : Author
C.R. Boustred
  • Function : Author
M.J. Caulfield
  • Function : Author
G.C. Chan
  • Function : Author
C.E.H. Craig
  • Function : Author
L.C. Daugherty
  • Function : Author
A. de Burca
  • Function : Author
A. Devereau
  • Function : Author
G. Elgar
  • Function : Author
R.E. Foulger
  • Function : Author
T. Fowler
  • Function : Author
P. Furió-Tarí
  • Function : Author
J.M. Hackett
  • Function : Author
D. Halai
  • Function : Author
J.E. Holman
  • Function : Author
T.J.P. Hubbard
  • Function : Author
D. Kasperaviciute
  • Function : Author
M. Kayikci
  • Function : Author
L. Lahnstein
  • Function : Author
K. Lawson
  • Function : Author
S.E.A. Leigh
  • Function : Author
I.U.S. Leong
  • Function : Author
F.J. Lopez
  • Function : Author
F. Maleady-Crowe
  • Function : Author
J. Mason
  • Function : Author
E.M. Mcdonagh
  • Function : Author
L. Moutsianas
  • Function : Author
M. Mueller
  • Function : Author
A.C. Need
  • Function : Author
C.A. Odhams
  • Function : Author
C. Patch
  • Function : Author
D. Perez-Gil
  • Function : Author
D. Polychronopoulos
  • Function : Author
J. Pullinger
  • Function : Author
T. Rahim
  • Function : Author
A. Rendon
  • Function : Author
T. Rogers
  • Function : Author
M. Ryten
  • Function : Author
K. Savage
  • Function : Author
R.H. Scott
  • Function : Author
A. Siddiq
  • Function : Author
A. Sieghart
  • Function : Author
D. Smedley
  • Function : Author
K.R. Smith
  • Function : Author
A. Sosinsky
  • Function : Author
W. Spooner
  • Function : Author
H.E. Stevens
  • Function : Author
A. Stuckey
  • Function : Author
E.R.A. Thomas
  • Function : Author
S.R. Thompson
  • Function : Author
C. Tregidgo
  • Function : Author
A. Tucci
  • Function : Author
E. Walsh
  • Function : Author
S.A. Watters
  • Function : Author
M.J. Welland
  • Function : Author
E. Williams
  • Function : Author
K. Witkowska
  • Function : Author
S.M. Wood
  • Function : Author
M. Zarowiecki
  • Function : Author

Abstract

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.

Dates and versions

hal-04576904 , version 1 (15-05-2024)

Identifiers

Cite

Dara Tolchin, Jessica Yeager, Priya Prasad, Naghmeh Dorrani, Alvaro Serrano Russi, et al.. De Novo SOX6 Variants Cause a Neurodevelopmental Syndrome Associated with ADHD, Craniosynostosis, and Osteochondromas. American Journal of Human Genetics, 2020, 106 (6), pp.830-845. ⟨10.1016/j.ajhg.2020.04.015⟩. ⟨hal-04576904⟩
0 View
0 Download

Altmetric

Share

Gmail Facebook X LinkedIn More