Sex chromosome variations (SCV) are characterised by an atypical variation in the number or function of sex chromosomes. They are some of the most common genetic differences in human beings, and include 47 XXY; one in six hundred live births, 45X ; one in two thousand and 47 XYY; one in one thousand. However, by comparison with other chromosomal variations, such as Trisomy 21 (one in six hundred), clinicians have relatively little awareness about diagnosis or management of associated cognitive, psychiatric, and neurological symptoms.
These circumstances create a potential gap in clinical practice, with risk of missed diagnoses and high disease burden for patients who might otherwise receive treatments that would improve outcomes. As an example, about 50–85% of individuals who are XXY or XYY are not identified. Taken together with evidence that earlier detection could positively affect psychosocial, cognitive, physiological, and reproductive outcomes, it is imperative for health professionals to increase their familiarity with this group of SCV’s.
In addition to improvements in clinical practice, increased understanding of SCV’S provide an important opportunity to advance knowledge of sex-related differences in clinical disease in general. Advances in genomics and neuro-imaging research have made it increasingly possible that genotype–phenotype links will be established in the foreseeable future. Sex chromosome variations are ideal models for investigation of genotype–phenotype correlations because of their well defined genetic basis and relatively well described phenotypic characteristics.
Targeted research can elucidate how disrupted expression of sex chromosome genes and aberrant sex hormone production specifically affects cognitive and neurological function, and how this disruption can affect sex differences in clinical patho-physiology in general. Many immunological, cognitive, and motor features associated with sex chromosome differences are also commonly associated with disease states that have highly skewed sex differences in prevalence and symptom-atology. As such, improved knowledge of the inter-relation between genetics and nervous system function in sex chromosome differences can provide clinicians with an expanded understanding of mechanisms underlying sex differences in the nervous system.
In this Review, we summarise the major clinical features of sex chromosome variations, focusing mainly on XO (Turner’s), XXY (Klinefelter’s), and XYY (Jacobs), although we also briefly review other supernumerary sex chromosome variations. We present cognitive, motor, and other neurological outcomes associated with these variations, and mechanistic models and treatment frameworks that are used. Additionally, we delineate clinical features for each of these variations and discuss how continuing research in this area has broad implications for future understanding of sex differences in cognitive and neurological functioning in human beings.