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

Dara Tolchin; Jessica Yeager; Priya Prasad; Naghmeh Dorrani; Alvaro Serrano Russi; Julian 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 Krantz; Bryan Krock; Kieran Pechter; Alexandre Arkader; 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; Cédric Le Caignec; 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

doi:10.1016/j.ajhg.2020.04.015

Journal Articles American Journal of Human Genetics Year : 2020

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

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Dara Tolchin

Function : Author

Children’s Hospital of Philadelphia

Jessica Yeager

Function : Author

Children’s Hospital of Philadelphia

Priya Prasad

Function : Author

Wayne State University School of Medicine

Naghmeh Dorrani

Function : Author

University of California [Los Angeles]

Alvaro Serrano Russi

Function : Author

Children’s Hospital Los Angeles [Los Angeles]

Julian Martinez-Agosto

Function : Author

University of California [Los Angeles]

Abdul Haseeb

Function : Author

Children’s Hospital of Philadelphia

Marco Angelozzi

Function : Author

Children’s Hospital of Philadelphia

G.W.E. Santen

Function : Author

Leiden University Medical Center

Claudia Ruivenkamp

Function : Author

Leiden University Medical Center

Saadet Mercimek-Andrews

Function : Author

University of Toronto

Christel Depienne

Function : Author

Institut du Cerveau = Paris Brain Institute

University Hospital Essen

Alma Kuechler

Function : Author

University Hospital Essen

Barbara Mikat

Function : Author

University Hospital Essen

Hermann-Josef Ludecke

Function : Author

Heinrich Heine Universität Düsseldorf = Heinrich Heine University [Düsseldorf]

Frederic Bilan

Function : Author

Université de Poitiers = University of Poitiers

Gwenael Le Guyader

Function : Author

Université de Poitiers = University of Poitiers

Brigitte Gilbert-Dussardier

Function : Author
PersonId : 1236595
ORCID : 0000-0001-7182-9914
IdRef : 081235380

Université de Poitiers = University of Poitiers

Boris Keren

Function : Author

CHU Pitié-Salpêtrière [AP-HP]

Solveig Heide

Function : Author

CHU Pitié-Salpêtrière [AP-HP]

Damien Haye

Function : Author

Hôpital Archet 2 [Nice]

Hilde van Esch

Function : Author

University Hospitals Leuven [Leuven]

Liesbeth Keldermans

Function : Author

University Hospitals Leuven [Leuven]

Damara Ortiz

Function : Author

University of Pittsburgh School of Medicine

Emily Lancaster

Function : Author

University of Pittsburgh School of Medicine

Ian Krantz

Function : Author

Children’s Hospital of Philadelphia

Bryan Krock

Function : Author

Children’s Hospital of Philadelphia

Kieran Pechter

Function : Author

Children’s Hospital of Philadelphia

Alexandre Arkader

Function : Author

Children’s Hospital of Philadelphia

Livija Medne

Function : Author

Children’s Hospital of Philadelphia

Elizabeth Dechene

Function : Author

Children’s Hospital of Philadelphia

Eduardo Calpena

Function : Author

John Radcliffe Hospital [Oxford University Hospital]

Giada Melistaccio

Function : Author

John Radcliffe Hospital [Oxford University Hospital]

Andrew O.M. Wilkie

Function : Author

John Radcliffe Hospital [Oxford University Hospital]

Mohnish Suri

Function : Author

Nottingham University Hospitals NHS Trust

Nicola Foulds

Function : Author

University Hospital Southampton NHS Foundation Trust

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

Véronique Lefebvre

Function : Author

Children’s Hospital of Philadelphia

Cédric Le Caignec

Function : Author

Centre Hospitalier Universitaire de Nantes = Nantes University Hospital

Centre Hospitalier Universitaire de Toulouse

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.

Keywords

ADHD SOX6 SOXopathy craniosynostosis developmental delay dysmorphism genetic variant human disease intellectual disability osteochondroma

Domains

Human health and pathology

Gestionnaire HAL 2 Sorbonne Université : Connect in order to contact the contributor

https://hal.sorbonne-universite.fr/hal-04576904

Submitted on : Wednesday, May 15, 2024-5:51:04 PM

Last modification on : Tuesday, November 19, 2024-2:04:08 PM

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

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HAL Id : hal-04576904 , version 1
DOI : 10.1016/j.ajhg.2020.04.015
PUBMED : 32442410
PUBMEDCENTRAL : PMC7273536

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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⟩

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

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