title: De novo microdeletions and point mutations affecting SOX2 in three individuals with intellectual disability but without major eye malformations.
abstract: Loss-of-function mutations and deletions of the SOX2 gene are known to cause uni- and bilateral anophthalmia and microphthalmia as well as related disorders such as anophthalmia-esophageal-genital syndrome. Thus, anophthalmia/microphthalmia is the primary indication for targeted, "phenotype first" analyses of SOX2. However, SOX2 mutations are also associated with a wide range of non-ocular abnormalities, such as postnatal growth retardation, structural brain anomalies, hypogenitalism, and developmental delay. The present report describes three patients without anophthalmia/microphthalmia and loss-of-function mutations or microdeletions of SOX2 who had been investigated in a "genotype first" manner due to intellectual disability/developmental delay using whole exome sequencing or chromosomal microarray analyses. This result prompted us to perform SOX2 Sanger sequencing in 192 developmental delay/intellectual disability patients without anophthalmia or microphthalmia. No additional SOX2 loss-of-function mutations were detected in this cohort, showing that SOX2 is clearly not a major cause of intellectual disability without anophthalmia/microphthalmia. In our three patients and four further, reported "genotype first" SOX2 microdeletion patients, anophthalmia/microphthalmia was present in less than half of the patients. Thus, SOX2 is another example of a gene whose clinical spectrum is broadened by the generation of "genotype first" findings using hypothesis-free, genome-wide methods. © 2016 Wiley Periodicals, Inc.
authors.affiliation: Institute of Human Genetics, University of Bonn, Bonn, Germany.
authors.forename: Nicola
authors.initials: N
authors.lastname: Dennert
authors.affiliation: Institute of Human Genetics, University of Bonn, Bonn, Germany.
authors.forename: Hartmut
authors.initials: H
authors.lastname: Engels
authors.affiliation: Institute of Human Genetics, University of Bonn, Bonn, Germany.
authors.forename: Kirsten
authors.initials: K
authors.lastname: Cremer
authors.affiliation: Institute of Human Genetics, University of Bonn, Bonn, Germany.
authors.forename: Jessica
authors.initials: J
authors.lastname: Becker
authors.affiliation: Institute of Human Genetics, University of Bonn, Bonn, Germany.
authors.forename: Eva
authors.initials: E
authors.lastname: Wohlleber
authors.affiliation: Institut für Humangenetik, Universitätsklinikum Essen, Universität Duisburg-Essen, Essen, Germany.
authors.forename: Beate
authors.initials: B
authors.lastname: Albrecht
authors.affiliation: Institute of Human Genetics, University of Bonn, Bonn, Germany.
authors.forename: Julia K
authors.initials: JK
authors.lastname: Ehret
authors.affiliation: Institut für Humangenetik, Universitätsklinikum Essen, Universität Duisburg-Essen, Essen, Germany.|Institute of Human Genetics, Medical Faculty, Heinrich-Heine-University, Düsseldorf, Germany.
authors.forename: Hermann-Josef
authors.initials: HJ
authors.lastname: Lüdecke
authors.affiliation: Nottingham Clinical Genetics Service, Nottingham University Hospitals NHS Trust, City Hospital Campus, Nottingham, United Kingdom.
authors.forename: Mohnish
authors.initials: M
authors.lastname: Suri
authors.affiliation: Medical Genetics Unit, University of Siena, Siena, Italy.
authors.forename: Giulia
authors.initials: G
authors.lastname: Carignani
authors.affiliation: Medical Genetics Unit, University of Siena, Siena, Italy.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Renieri
authors.affiliation: Department of Radiology, University of Bonn, Bonn, Germany.
authors.forename: Guido M
authors.initials: GM
authors.lastname: Kukuk
authors.affiliation: Institute of Human Genetics, Helmholtz Zentrum München, Neuherberg, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Wieland
authors.affiliation: Laboratory of Medical Genetics, Hôpital Jeanne de Flandre University Hospital, Lille, France.
authors.forename: Joris
authors.initials: J
authors.lastname: Andrieux
authors.affiliation: Institute of Human Genetics, Helmholtz Zentrum München, Neuherberg, Germany.
authors.forename: Tim M
authors.initials: TM
authors.lastname: Strom
authors.affiliation: Institut für Humangenetik, Universitätsklinikum Essen, Universität Duisburg-Essen, Essen, Germany.|Institute of Human Genetics, Medical Faculty, Heinrich-Heine-University, Düsseldorf, Germany.
authors.forename: Dagmar
authors.initials: D
authors.lastname: Wieczorek
authors.affiliation: Clinical Genetics, Hôpital Jeanne de France University Hospital, Lille, France.
authors.forename: Anne
authors.initials: A
authors.lastname: Dieux-Coëslier
authors.affiliation: Institute of Human Genetics, University of Bonn, Bonn, Germany.
authors.forename: Alexander M
authors.initials: AM
authors.lastname: Zink
mesh_terms: D001921:Brain / Q000002:abnormalities; D002675:Child, Preschool; D055028:Comparative Genomic Hybridization; D059472:Exome; D005124:Eye Abnormalities / Q000175:diagnosis / Q000235:genetics; D019066:Facies; D005260:Female; D056726:Genetic Association Studies; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D007231:Infant, Newborn; D008607:Intellectual Disability / Q000175:diagnosis* / Q000235:genetics*; D008279:Magnetic Resonance Imaging / Q000379:methods; D008297:Male; D010641:Phenotype; D017354:Point Mutation; D020641:Polymorphism, Single Nucleotide; D012042:Registries; D055748:SOXB1 Transcription Factors / Q000235:genetics*; D017384:Sequence Deletion
chemical_list: D055748:SOXB1 Transcription Factors
keywords: SOX2; genotype first; intellectual disability; microdeletion; whole exome sequencing