A number sign (#) is used with this entry because it represents a contiguous gene syndrome involving duplication of chromosome Xp11.23-p11.22.

Giorda et al. (2009) described a syndrome characterized by borderline to severe mental retardation, speech delay, and EEG abnormalities associated with a microduplication at chromosome Xp11.23-p11.22. A total of 12 affected males and females were reported. One carrier female (a patient's mother) with a small duplication was not affected. The duplication segregated with the disorder in 2 families. Early puberty was described in 7 of 9 individuals examined, and 6 of 12 were significantly overweight. Eight individuals had lower-extremity anomalies, including pes planus or pes cavus, fifth-toe hypoplasia, and syndactyly. The 1 child with the smallest duplication showed mild mental retardation and language delay, but no early puberty, excessive weight gain, or foot anomalies. In all other affected individuals, clinical features were apparently independent of sex and duplication size. Five had rare or isolated absence seizures, and 6 had abnormal EEG recordings with significant diffuse paroxysmal discharges. The EEG pattern showed secondary bisynchronism associated with atypical absences during wakefulness, and continuous spike-wave pattern during sleep that persisted during adolescence even in the absence of clear epileptic seizures. Behavioral signs included shyness, stubbornness, and autistic-like features.

Using array-based genomic hybridization to screen 2,400 individuals with isolated or syndromic mental retardation for copy number variation, Giorda et al. (2009) identified 8 (0.33%) unrelated individuals, 2 males and 6 females, with a microduplication at chromosome Xp11.23-p11.22. The rearrangement was familial in 3 patients. A female patient shared a 4.5-Mb duplication with her affected mother and sister, and an unrelated male patient shared a 4.5-Mb duplication with his affected mother and sister. A third unrelated male inherited a smaller 0.8-Mb duplication from his unaffected mother. Three additional individuals had de novo 4.5-Mb duplications, and 2 more had partially overlapping de novo 6.0- and 9.2-Mb duplications. Paternal origin of the duplication was demonstrated in all de novo female cases. Six affected females had selective inactivation of the normal X chromosome, whereas 3 had random X inactivation. Breakpoints could be identified in 8 individuals. The recurrent duplication was flanked distally by a segmental duplication (D-REP at 47.8-48.2 Mb) containing a cluster of genes and pseudogenes of the synovial sarcoma X breakpoint (SSX; 312820) and proximally by a complex repeat (P-REP at 52.1-53.1 Mb) rich in SSX, melanoma antigen (see, e.g., MAGED1; 300224), and X antigen (e.g., XAGE1B, 300289) genes. Sequence analysis of the junctions demonstrated that the recurrent 4.5-Mb duplications were mediated by nonallelic homologous or Alu-mediated recombination. The SYP gene (313475), in which mutation causes a form of X-linked mental retardation (300802), is located within the 4.5-Mb duplication region.