Cognitive Function 1, Social

Turner syndrome is a sporadic disorder of females in which all or part of one X chromosome is deleted. Characteristic features include short stature with somatic features such as broad, 'shield-like' chest, webbed neck, low-set ears, and gonadal dysgenesis. The cytogenetically full-blown form is characterized by 45 chromosomes with only one X chromosome. Intelligence is usually normal, but social adjustment problems are common. Skuse et al. (1997) considered that it should be possible to identify the effects of an X-linked imprinted locus by comparing classes of females with Turner syndrome. In 70% of monosomic (45,X) Turner syndrome females, the single X chromosome is maternal in origin; in the remainder it is paternal. Normal 46,XX females possess both a maternally derived X chromosome, X(m), and a paternally derived chromosome, X(p), 1 of which is randomly inactivated in any given somatic cell. In monosomic X (Turner syndrome), the single chromosome is never inactivated. Skuse et al. (1997) suggested that differences in physical or behavioral phenotypes between the 2 classes of Turner syndrome subjects might indicate the existence of an imprinted genetic locus. In a study of 80 females with Turner syndrome and a 45,X karyotype, they found that 55 had their X chromosome from the mother and 25 from the father. Members of the 45,X(p) group were significantly better adjusted, with superior verbal and higher-order executive function skills, which mediate social interactions. The observations suggested the existence of a genetic locus for social cognition that is imprinted and is not expressed from the maternally-derived X chromosome. Neurophysiologic and molecular investigations of 8 females with partial deletions of the short arm of the X chromosome indicated that the putative imprinted locus escapes X inactivation and probably lies on Xq or close to the centromere on Xp. Skuse et al. (1997) speculated that, if expressed only from the paternal X chromosome, such a locus could explain why 46,XY males, whose single X chromosome is maternal, are more vulnerable to developmental disorders of language and social cognition, such as autism, than are 46,XX females. They stated that an alternative explanation might be the presence of a greater degree of cryptic mosaicism (with a normal 46,XX cell line) than among those who were 45,X(m). Some degree of mosaicism in apparently monosomic females may be essential for the fetus to avoid spontaneous abortion. However, in studies of both blood and skin fibroblast cells (tissues of mesodermal and ectodermal origin, respectively), Skuse et al. (1997) found 2 cryptic mosaics, but both were from the 45,X(m) group. In general, males are substantially more vulnerable to a variety of developmental disorders of speech, language impairment, and reading disability, as well as more severe conditions such as autism. The findings of Skuse et al. (1997) are consistent with the hypothesis that the locus they described, which they proposed is silent both in normal males and 45,X(m) females, acts synergistically with susceptibility loci elsewhere in the genome to increase the male-to-female prevalence ratio of such disorders. Their data on normally developing children suggested that the locus may also exert an effect on social and cognitive abilities in the normal range. The findings provided evidence for the evolution of an imprinted X-linked locus that contributes to the development of sexual dimorphism in social behavior.

Naumova et al. (1998) proposed that the association of transmission-ratio distortion with only 1 sex of offspring may be a hallmark of defective imprinting (or defective imprint 'erasure'). In 47 normal, genetic disease-free families, they analyzed the transmission of maternal alleles at loci spanning the length of the X chromosome and found significant deviation from the expected 1:1 ratio of grandparental:grandmaternal alleles at loci in Xp21.1-p11.4. The distortion in inheritance ratio was found only among male offspring and was manifested as a strong bias in favor of the inheritance of the alleles of the maternal grandfather. An analysis of recombinant chromosomes inherited by male offspring indicated that an 11.6-cM on the short arm of the X chromosome, bounded by DXS538 and DXS7, contains an imprinted gene that affects the survival of male embryos. Naumova et al. (1998) called the region of maximum distortion DMS1, for 'distorter male-specific-1.' They commented that the DMS1 region is in an area that contains a number of genes that escape X inactivation (Disteche, 1995; Miller et al., 1995; Jones et al., 1996).

The study of Turner syndrome subjects by Skuse et al. (1997) suggested the existence of a gene on the X chromosome for aptitude for spatial visualization (313000).

Donnelly et al. (2000) described a single case of autistic disorder (209850) in association with monosomy X (Turner syndrome). They found that the patient's X chromosome was of maternal origin, providing further support for the hypothesis that parent-of-origin of the X chromosome influences social cognition. Theirs was the fourth documented case of maternal inheritance of the syndrome and autistic disorder.

Individuals with Turner syndrome have a spectrum of anatomic, physiologic, and behavioral phenotypes with expressivity dependent on the extent of monosomy and the parental origin of the single X chromosome (Ranke and Saenger, 2001). As noted, parent-of-origin influences on social cognition in Turner syndrome may be due to the presence of imprinted genes on the X chromosome (Skuse et al., 1997). Imprinting of X-linked genes has also been implicated in the male prevalence of autistic spectrum disorders, in male sexual orientation, and in the developmental delay of XO mouse embryos (Thornhill and Burgoyne, 1993 and Jamieson et al., 1998). Using a mouse model for Turner syndrome, Raefski and O'Neill (2005) searched for locus-specific imprinting of X-linked genes in developing brain. They identified a cluster of X-linked genes containing at least 3 genes that show transcriptional repression of paternal alleles. Imprinting of these 3 genes, Xlr3b, Xlr4b, and Xlr4c, was independent of X-chromosome inactivation and had a dynamic and complex pattern of tissue and stage specificity.

Davies et al. (2005) used a 39,XO mouse model to examine the influence of the parental origin of the X chromosome on cognitive behaviors and expression of X-linked genes in brain. Their findings confirmed the existence of X-linked imprinted effects on cognitive processes and identified a new maternally expressed imprinted gene candidate on the X chromosome, Xlr3b, which may be of importance in mediating the behavioral effects.

By bioinformatic analysis of the homologous region of the human X chromosome (Xq28), Davies et al. (2005) identified an apparent pseudogene with homology to the Xlr3 gene family of the mouse. The pseudogene was most closely related to FAM9B (300478), a gene located at Xp22.3.