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
(12)
,
Hilde van Esch
(13)
,
Liesbeth Keldermans
(13)
,
Damara Ortiz
(14)
,
Emily Lancaster
(14)
,
Ian Krantz
(1)
,
Bryan Krock
(1)
,
Kieran Pechter
(1)
,
Alexandre Arkader
(1)
,
Livija Medne
(1)
,
Elizabeth Dechene
(1)
,
Eduardo Calpena
(15)
,
Giada Melistaccio
(15)
,
Andrew O.M. Wilkie
(15)
,
Mohnish Suri
(16)
,
Nicola Foulds
(17)
,
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
(18, 19)
,
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
1
CHOP -
Children’s Hospital of Philadelphia
2 Wayne State University School of Medicine
3 UCLA - University of California [Los Angeles]
4 Children’s Hospital Los Angeles [Los Angeles]
5 LUMC - Leiden University Medical Center
6 University of Toronto
7 ICM - Institut du Cerveau = Paris Brain Institute
8 AöR - University Hospital Essen
9 Heinrich Heine Universität Düsseldorf = Heinrich Heine University [Düsseldorf]
10 UP - Université de Poitiers = University of Poitiers
11 CHU Pitié-Salpêtrière [AP-HP]
12 CHU - Hôpital Archet 2 [Nice]
13 University Hospitals Leuven [Leuven]
14 University of Pittsburgh School of Medicine
15 John Radcliffe Hospital [Oxford University Hospital]
16 NUH - Nottingham University Hospitals NHS Trust
17 University Hospital Southampton NHS Foundation Trust
18 CHU Nantes - Centre Hospitalier Universitaire de Nantes = Nantes University Hospital
19 CHU Toulouse - Centre Hospitalier Universitaire de Toulouse
2 Wayne State University School of Medicine
3 UCLA - University of California [Los Angeles]
4 Children’s Hospital Los Angeles [Los Angeles]
5 LUMC - Leiden University Medical Center
6 University of Toronto
7 ICM - Institut du Cerveau = Paris Brain Institute
8 AöR - University Hospital Essen
9 Heinrich Heine Universität Düsseldorf = Heinrich Heine University [Düsseldorf]
10 UP - Université de Poitiers = University of Poitiers
11 CHU Pitié-Salpêtrière [AP-HP]
12 CHU - Hôpital Archet 2 [Nice]
13 University Hospitals Leuven [Leuven]
14 University of Pittsburgh School of Medicine
15 John Radcliffe Hospital [Oxford University Hospital]
16 NUH - Nottingham University Hospitals NHS Trust
17 University Hospital Southampton NHS Foundation Trust
18 CHU Nantes - Centre Hospitalier Universitaire de Nantes = Nantes University Hospital
19 CHU Toulouse - Centre Hospitalier Universitaire de Toulouse
Brigitte Gilbert-Dussardier
- Function : Author
- PersonId : 1236595
- ORCID : 0000-0001-7182-9914
- IdRef : 081235380
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.