Xp11.2 duplication is a genomic variation marked by the duplication of an X chromosome region on the short arm p at position 11.2, defined by standard karyotyping (G-banding). This gene-rich, rearrangement prone region can be further divided into three loci - Xp11.21, Xp11.22 and Xp11.23. The duplication could involve any combination of these three loci. While the length of the duplication can vary from 0.5Mb to 55 Mb, most duplications measure about 4.5Mb and typically occur in the region of 11.22-11.23. Most affected females show preferential activation of the duplicated X chromosome. Features of affected individuals vary significantly, even among members of the same family. The Xp11.2 duplication can be 'silent' - presenting no obvious symptoms in carriers - which is known from the asymptomatic parents of affected children carrying the duplication. The common symptoms include intellectual disabilities, speech delay and learning difficulties, while in rare cases, children have seizures and a recognizable brain wave pattern when assessed by EEG (electroencephalography).
Symptoms and signs Information on the clinical symptoms and features is taken from the Human Phenotype Ontology database and the Unique database. All affected individuals needn't show all the symptoms. Some of the most noted features are:
Intellectual and Learning Disabilities Speech delay Early puberty Significant weight and height problems Lower-extremity anomalies (anomalies of the legs and/ or feet) Epileptic Seizures Unusual pattern of EEG with centro-temporal focal spike waves in children Minor facial features
Intellectual and Learning Disabilities Among people who need support with their learning, at least 3% are believed to carry the duplication. It is noted that affected members of the same family with the same Xp11.2 microduplication generally have similar learning profiles. Children with small duplications of 0.5-1.3 Mb seem to have a mild learning difficulty, while others with the typical duplication of around 4.5 Mb generally have a borderline, mild or moderate learning disability. An extreme case with a very large duplication of 55 Mb has shown to have a severe intellectual disability.
Speech Delay Speech is very commonly affected and usually the first sign. Both speech and comprehension seem to be affected, to various degrees of extent. Low facial muscle tone underlies difficulty in making certain sounds of speech. Nasal or hoarse voice are also observed. Babies are known to be unable to suck from breast in their infancy due to weak facial muscles.
Early Puberty Early puberty occurs in 80% of the affected children or adults, with girls starting their menstrual cycles as early as age 9 and boys showing signs of puberty at age 8.5. One boy from Unique had completed puberty by age 13.
Weight problems Affected children show tendency to be overweight. This might indicate metabolism issues.
Lower-extremity Anomalies Anomalies of lower limbs or feet are common in people with an Xp11.2 duplication, affecting about 71% cases. Features include flat feet, arched feet (pes cavus), clubfoot (talipes), narrow feet, webbed or joined toes/fingers (syndactyly), 5th finger clinodactyly, 5th toe hypoplasia, and tapering fingers.
Unusual EEG Pattern A typical pattern of electrical activity in the brain of affected children, described as 'subclinical seizures' has been noted. A peculiar electroencephalographic pattern characterized by rolandic-like spikes and/or continuous spike wave during slow sleep (CSWS), also called centro-temporal focal spike, exists in childhood.
Minor Facial Features The common unusual features include a short or flat groove between the nose and upper lip (philtrum), a large, high or deep nasal bridge, bushy eyebrows and/or uni-brow (synophrys), and thin lips.
Cause Using array-based Comparative Genomic Hybridization (aCGH) to screen 2,400 individuals with isolated or syndromic intellectual disability 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) and proximally by a complex repeat (P-REP at 52.1-53.1 Mb) rich in SSX, melanoma antigen and X antigen (XAGE) genes. Sequence analysis of the junctions demonstrated that the recurrent 4.5-Mb duplications were mediated by non-allelic homologous recombination (NAHR) or Alu-mediated recombination. The majority of these recombinations occurred between flanking complex segmental duplications. Region of duplication and copy number variation can be further confirmed by Fluorescence In-Situ Hybridization (FISH) and PCR.
Genetics The duplication at Xp11.2, especially the Xp11.22-11.23 region is syndromic and is implicated in X-linked mental retardation. The chromosomal duplication can be de novo or familial. Familial carriers of small duplication (<1 Mb) show X-linked recessive inheritance. All other affected individuals with larger duplication present dominant expression and comparable clinical phenotypes irrespective of sex, duplication size, and X-inactivation pattern. Xp11.22 comprises approximately 5 Mb of DNA (chrX:49,800,001–54,800,000, hg19). A number of pathogenic deletions and duplications involving Xp11.22 have been described in individuals with developmental delay, intellectual disability and/or autism. These phenotypes have been attributed to changes in the copy number of several genes including HUWE1, KDM5C, IQSEC2, TSPYL2, SHROOM4, PHF8 and FAM120C.
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