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Am J Med Genet A. 2017 Feb;173(2):435-443. doi: 10.1002/ajmg.a.38034. Epub 2016 Nov 14.

De novo microdeletions and point mutations affecting SOX2 in three individuals with intellectual disability but without major eye malformations.

Author information

Institute of Human Genetics, University of Bonn, Bonn, Germany.
Institut für Humangenetik, Universitätsklinikum Essen, Universität Duisburg-Essen, Essen, Germany.
Institute of Human Genetics, Medical Faculty, Heinrich-Heine-University, Düsseldorf, Germany.
Nottingham Clinical Genetics Service, Nottingham University Hospitals NHS Trust, City Hospital Campus, Nottingham, United Kingdom.
Medical Genetics Unit, University of Siena, Siena, Italy.
Department of Radiology, University of Bonn, Bonn, Germany.
Institute of Human Genetics, Helmholtz Zentrum München, Neuherberg, Germany.
Laboratory of Medical Genetics, Hôpital Jeanne de Flandre University Hospital, Lille, France.
Clinical Genetics, Hôpital Jeanne de France University Hospital, Lille, France.


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.


SOX2; genotype first; intellectual disability; microdeletion; whole exome sequencing

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