Clinical and molecular consequences of disease-associated de novo mutations in SATB2.
To characterize features associated with de novo mutations affecting SATB2 function in individuals ascertained on the basis of intellectual disability.



Twenty previously unreported individuals with 19 different SATB2 mutations (11 loss-of-function and 8 missense variants) were studied. Fibroblasts were used to measure mutant protein production. Subcellular localization and mobility of wild-type and mutant SATB2 were assessed using fluorescently tagged protein.



Recurrent clinical features included neurodevelopmental impairment (19/19), absent/near absent speech (16/19), normal somatic growth (17/19), cleft palate (9/19), drooling (12/19), and dental anomalies (8/19). Six of eight missense variants clustered in the first CUT domain. Sibling recurrence due to gonadal mosaicism was seen in one family. A nonsense mutation in the last exon resulted in production of a truncated protein retaining all three DNA-binding domains. SATB2 nuclear mobility was mutation-dependent; p.Arg389Cys in CUT1 increased mobility and both p.Gly515Ser in CUT2 and p.Gln566Lys between CUT2 and HOX reduced mobility. The clinical features in individuals with missense variants were indistinguishable from those with loss of function.



SATB2 haploinsufficiency is a common cause of syndromic intellectual disability. When mutant SATB2 protein is produced, the protein appears functionally inactive with a disrupted pattern of chromatin or matrix association.Genet Med advance online publication 02 February 2017.
MRC Human Genetics Unit, IGMM, University of Edinburgh, Western General Hospital, Edinburgh, UK.
Hemant
H
Bengani
MRC Human Genetics Unit, IGMM, University of Edinburgh, Western General Hospital, Edinburgh, UK.
Mark
M
Handley
Avdeling for Medisinsk Genetikk, Oslo Universitetssykehus, Oslo, Norway.
Mohsan
0000-0003-4331-7078
M
Alvi
Department of Clinical Genetics, Oxford University Hospitals NHS Trust, Oxford, UK.
Rita
0000-0002-2887-2068
R
Ibitoye
North East Regional Genetics Service, Great Ormond Street Hospital, London, UK.
Melissa
M
Lees
National Centre for Medical Genetics, Our Lady's Children's Hospital, Dublin, Ireland.
Sally Ann
0000-0003-0287-4134
SA
Lynch
South East Scotland Genetic Service, Western General Hospital, Edinburgh, UK.
Wayne
W
Lam
Avdeling for Medisinsk Genetikk, Oslo Universitetssykehus, Oslo, Norway.
Madeleine
M
Fannemel
Clinical Genetics Unit, Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.
Ann
0000-0003-3338-8382
A
Nordgren
Clinical Genetics Unit, Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.
H
0000-0003-3285-4281
H
Malmgren
Clinical Genetics Unit, Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.
M
M
Kvarnung
Department of Clinical Genetics, Cambridge University Hospitals NHS Foundation, Cambridge, UK.
Sarju
S
Mehta
Northern Ireland Regional Genetics Centre, Belfast City Hospital, Belfast, UK.
Shane
0000-0003-0446-3435
S
McKee
West of Scotland Genetic Services, Queen Elizabeth University Hospital, Glasgow, UK.
Margo
0000-0002-1772-0106
M
Whiteford
Northern Ireland Regional Genetics Centre, Belfast City Hospital, Belfast, UK.
Fiona
F
Stewart
South East Thames Regional Genetics Service, Guy's and St Thomas' NHS Foundation Trust, London, UK.
Fiona
0000-0002-0444-8203
F
Connell
Genetic Medicine, North West Regional Genetics Service, Manchester, UK.
Jill
J
Clayton-Smith
Department of Clinical Genetics, St Georges Hospital, Tooting, UK.
Sahar
S
Mansour
South East Thames Regional Genetics Service, Guy's and St Thomas' NHS Foundation Trust, London, UK.
Shehla
0000-0001-6629-4118
S
Mohammed
Cheshire &Merseyside Regional Genetics Service, Liverpool Women's NHS foundation Trust, Liverpool, UK.
Alan
A
Fryer
West Midlands Regional Genetics Service, Birmingham Women's NHS Foundation Trust, Birmingham, UK.
Jenny
J
Morton
Cambridge Institute for Medical Research, University of Cambridge, Cambridge, UK.
Detelina
D
Grozeva
South-East Scotland Regional Genetics Laboratories, Western General Hospital, Edinburgh, UK.
Tara
T
Asam
South-East Scotland Regional Genetics Laboratories, Western General Hospital, Edinburgh, UK.
David
D
Moore
Wellcome Trust Sanger Institute, Wellcome Genome Campus, Cambridge, UK.
Alejandro
0000-0001-9308-5741
A
Sifrim
Wellcome Trust Sanger Institute, Wellcome Genome Campus, Cambridge, UK.
Jeremy
0000-0001-8247-4020
J
McRae
Wellcome Trust Sanger Institute, Wellcome Genome Campus, Cambridge, UK.
Matthew E
ME
Hurles
Department of Clinical Genetics, Cambridge University Hospitals NHS Foundation, Cambridge, UK.
Helen V
HV
Firth
Cambridge Institute for Medical Research, University of Cambridge, Cambridge, UK.
F Lucy
FL
Raymond
Department of Clinical Genetics, Oxford University Hospitals NHS Trust, Oxford, UK.|Spires Cleft Centre, John Radcliffe Hospital, Oxford, UK.
Usha
0000-0003-2652-3355
U
Kini
Nuffield Department of Obstetrics &Gynaecology, University of Oxford, Women's Centre, John Radcliffe Hospital, Oxford, UK.|Department of Engineering Science, University of Oxford, Institute of Biomedical Engineering, Oxford, UK.|Big Data Institute, University of Oxford, Oxford, UK.
Christoffer
C
Nellåker
Wellcome Trust Sanger Institute, Wellcome Genome Campus, Cambridge, UK.
Ddd Study
MRC Human Genetics Unit, IGMM, University of Edinburgh, Western General Hospital, Edinburgh, UK.
David R
0000-0001-7609-3504
DR
FitzPatrick
D002460:Cell Line; D015331:Cohort Studies; D056726:Genetic Association Studies; D057895:Haploinsufficiency / Q000235:genetics; D006367:HeLa Cells; D006801:Humans; D008607:Intellectual Disability / Q000235:genetics* / Q000503:physiopathology; D000073658:Loss of Function Mutation; D036961:Matrix Attachment Region Binding Proteins / Q000235:genetics* / Q000502:physiology; D020125:Mutation, Missense; D011485:Protein Binding / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics* / Q000502:physiology; D000073336:Whole Genome Sequencing
D036961:Matrix Attachment Region Binding Proteins; C521297:SATB2 protein, human; D014157:Transcription Factors