Genetics of septo-optic dysplasia

Daniel Kelberman, Mehul Tulsidas Dattani

Septo-optic dysplasia (SOD) is a highly heterogeneous condition comprising a variable phenotype of optic nerve hypoplasia, midline forebrain abnormalities and pituitary hypoplasia with consequent endocrine deficits. The majority of cases are sporadic and several aetiologies including drug and alcohol abuse have been suggested to account for the pathogenesis of the condition. However, a number of familial cases have been described and the identification of mutations in the key developmental gene HESX1 in patients with SOD and associated phenotypes suggests that a genetic causation is likely in the more common sporadic cases of the condition. More recently, we have implicated duplications of SOX3 and mutations of both SOX2 and SOX3 in the aetiology of variants of SOD. As with other developmental disorders such as holoprosencephaly, the precise aetiology is most likely multifactorial involving contributions from environmental factors in addition to an important role for crucial developmental genes. This potentially complex interaction between genetics and the environment is borne out by the variability of the penetrance and phenotypes in patients with genetic SOD, but at present, the understanding of these interactions is rudimentary. Further study of these critical factors may shed light on the aetiology of this complex disorder.