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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

1
Institute of Human Genetics, University of Bonn, Bonn, Germany.
2
Institut für Humangenetik, Universitätsklinikum Essen, Universität Duisburg-Essen, Essen, Germany.
3
Institute of Human Genetics, Medical Faculty, Heinrich-Heine-University, Düsseldorf, Germany.
4
Nottingham Clinical Genetics Service, Nottingham University Hospitals NHS Trust, City Hospital Campus, Nottingham, United Kingdom.
5
Medical Genetics Unit, University of Siena, Siena, Italy.
6
Department of Radiology, University of Bonn, Bonn, Germany.
7
Institute of Human Genetics, Helmholtz Zentrum München, Neuherberg, Germany.
8
Laboratory of Medical Genetics, Hôpital Jeanne de Flandre University Hospital, Lille, France.
9
Clinical Genetics, Hôpital Jeanne de France University Hospital, Lille, France.

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.

KEYWORDS:

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

PMID:
27862890
DOI:
10.1002/ajmg.a.38034
[Indexed for MEDLINE]

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