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De novo microdeletions and point mutations affecting SOX2 in three individuals with intellectual disability but without major eye malformations.
Am. J. Med. Genet. A 173, 435-443 (2017)
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.
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Publication type Article: Journal article
Document type Scientific Article
Keywords Genotype First ; Intellectual Disability ; Microdeletion ; Sox2 ; Whole Exome Sequencing; Phenotypically Normal Mother; Anophthalmia Syndrome; Hypogonadotropic Hypogonadism; Familial Recurrence; Aeg Syndrome; Deletion; Gene; Anophthalmia/microphthalmia; Microphthalmia; Mosaicism
Institute(s) Institute of Human Genetics (IHG)