ABSTRACT & COMMENTARY

Synopsis: Significantly poorer social cognitive skills were found in the patients with Turner syndrome whose monosomic X chromosome was maternal in origin.

Source: Skuse DH, et al. Evidence from Turner syndrome of an imprinted X-linked local effecting cognitive function. Nature 1997;387:705-708.
Males have a significantly higher frequency of developmental disorders that affect language and social functioning than females. Since normal females have two X chromosomes and normal males have only one X and a Y chromosome, males must always receive their X chromosome from their mother (XM). One possible explanation for this gender difference in social dysfunctional behavior may result from the same genes on the X chromosome imprinted differently. Imprinting refers to the finding that the same genes can result in different expressed characteristics depending on whether they are inherited from the mother or father. Skuse and colleagues analyzed 80 patients with 45 XO Turner syndrome for their cognitive skills as well as verbal and non-verbal IQ. In addition, the parental origin of the X chromosome was determined by comparing DNA polymorphism in parents' and daughters' X chromosomes. Forty-five females were found to have their fathers' 45 XP, and 25 patients had monosome X that were maternal in origin. All patients had similar decreased verbal and non-verbal IQs. However, a scale measuring social cognition was significantly different in Turner patients with XM or XP. Patients with the maternally derived X chromosome had poorer social cognitive skills than those who were monosomic for an X chromosome of paternal origin. Skuse et al postulate a yet-to-be-defined gene locus, which is silent in normal 46XY males and 45XM females with Turner syndrome. This locus could interact with other genes to increase the male to female prevalence-ratio of mild disorders of speech and language, and severe conditions such as autism.

COMMENT BY LOUIS J. ELSAS, II, MD

Why do males have a higher frequency of developmental disorders, such as autism, than females? Although these differences in social cognition might be acquired and reflect differing environmental effects on the upbringing of males and females in society, an alternative possibility is that these frequency differences could be caused by genetic differences between males and females. Imprinting is a poorly understood molecular mechanism by which specific functional genes are turned off by processes that include methylatin of DNA. In normal individuals, for example, if the two alleles are deleted or remain unmethylated, the patient will express a clinically distinct disorder called Angelman syndrome. Thus, the imprinting on the 15 q autosome is important in maintaining normal behavior, and different syndromes occur when imprinting is altered. Skuse et al address for the first time the possibility of imprinting on the human X chromosome that might affect behavior. In this study, patients with Turner syndrome who have a paternally derived X chromosome (XP) have better social skills than those with the maternally derived X chromosome (XM). Skuse et al suggest that, in normal XPXM females, the adverse social behavior gene on XM is "off" but that this adverse gene on the XM is "on" in 46 XMYH males and in 45 XM females with Turner syndrome. Among the girls of school age with Turner syndrome who were studied, many needed special education, and these patients had one X chromosome derived from their mothers (XM). Although the precise gene(s) involved in this imprinting phenomenon may be defined in the future, these studies must be repeated by others for validity to assure that trivial issues such as basic Y chromosome mosaicism in specific tissues is not the cause of the poor male social skills. Several important points from this study have been made. The most important and controversial concerns differences in behavior between genders. In our current social context, which emphasizes sexual equality, there is a tendency to overlook biological and genetic differences between men and women. Observations presented in this paper challenge this prevailing belief and offer evidence for a gene that determines behavior located on the X chromosome.

Important clinical problems for the physician will arise as parents become aware of this word. For example, will patients undergoing prenatal diagnosis and found to have a 45XO fetus ask whether the X chromosome was maternally or paternally derived to make decisions regarding continuation of the pregnancy? In pediatric patients found to have Turner syndrome, will the parental origins of the X chromosome be requested to predict future social cognition of the patient? Confirmation of this observation must occur as soon as possible to enable appropriate information transfer to our patients.