Abstract
Deletions spanning the STS (steroid sulfatase) gene at Xp22.31 are associated with X-linked ichthyosis, corneal opacities, testicular maldescent, cardiac arrhythmia, and higher rates of developmental and mood disorders/traits, possibly related to the smaller volume of some basal ganglia structures. The consequences of duplication of the same genomic region have not been systematically assessed in large or adult samples, although evidence from case reports/series has indicated high rates of developmental phenotypes. We compared multiple measures of physical and mental health, cognition and neuroanatomy in male (n = 414) and female (n = 938) carriers of 0.8–2.5 Mb duplications spanning STS, and non-carrier male (n = 192, 826) and female (n = 227, 235) controls from the UK Biobank (recruited aged 40–69 from the UK general population). Clinical and self-reported diagnoses indicated a higher prevalence of inguinal hernia and mania/bipolar disorder respectively in male duplication carriers, and a higher prevalence of gastro-oesophageal reflux disease and blistering/desquamating skin disorder respectively in female duplication carriers; duplication carriers also exhibited reductions in several depression-related measures, and greater happiness. Cognitive function and academic achievement did not differ between comparison groups. Neuroanatomical analysis suggested greater lateral ventricle and putamen volume in duplication carriers. In conclusion, Xp22.31 duplications appear largely benign, but could slightly increase the likelihood of specific phenotypes (although results were only nominally-significant). In contrast to deletions, duplications might protect against depressive symptoms, possibly via higher STS expression/activity (resulting in elevated endogenous free steroid levels), and through contributing towards an enlarged putamen volume. These results should enable better genetic counselling of individuals with Xp22.31 microduplications.
Highlights
The X-linked STS gene encodes the enzyme steroid sulfatase which catalyses the desulfation of sulfated steroids to their free steroid counterparts; these may subsequently act as precursors for a variety of androgens and oestrogens (1)
We identified ICD-10 unique descriptive codes that were the most common in duplication carriers (present in at least 1 in 40 (>2.5%) carriers), and that were recorded in a significant proportion (>1.5%) of individuals in the overall male and female samples; these selection criteria, analogous to those used in our previous Xp22.31 deletion study (3), were designed to detect robust between-group effects
Just one ‘Unilateral or unspecified inguinal hernia, without obstruction or gangrene’ was nominally-significantly more commonly observed in male duplication carriers than in male non-carrier controls (9.4% vs. 6.8%, OR: 1.42, χ 2[1] = 3.95, P = 0.047); this result did not remain significant after correction for multiple testing
Summary
The X-linked STS gene encodes the enzyme steroid sulfatase which catalyses the desulfation of sulfated steroids (e.g. dehydroepiandrosterone sulfate, DHEAS) to their free steroid counterparts; these may subsequently act as precursors for a variety of androgens and oestrogens (1). Genetic deletions at Xp22.31 encompassing STS are associated with the rare skin condition X-linked ichthyosis (XLI, OMIM: 308100) (2). XLI predominantly affects males, and is associated with a number of conditions including cryptorchidism and benign corneal opacities; some female deletion carriers have corneal opacities and can exhibit prolonged/delayed labour during childbirth as a consequence of STS deficiency in the fetal portion of the placenta (2). We exploited the power of the genotyped and extensively-characterised large UK Biobank sample comprising adults recruited from the general population of the UK (24) to compare a wide range of physical and psychiatric illnesses (and treatments), cognitive function, and subcortical brain structure, in male and female Xp22.31 duplication carriers to that of sexmatched control subjects not carrying the variant of interest. A priori, we considered the possibilities that duplication carriers within our sample may exhibit similar, contrasting, and/or distinct phenotypes to deletion carriers, or that duplications carriers may exhibit few, if any, phenotypic differences from non-carrier controls
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