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We describe two unrelated patients with developmental delay due to similar interstitial duplications at Xp21\u2010p22. The first patient is a 6\u2010month\u2010old male with multiple affected family members including many females. The second patient is a 5\u2010year\u2010old adopted female. In both patients, chromosome analysis and array comparative genomic hybridization (aCGH) showed duplications of overlapping regions at Xp21\u2010p22. The duplicated segments contain numerous genes associated with MR, including <jats:italic>AP1S2<\/jats:italic>, <jats:italic>NHS, CDKL5<\/jats:italic>, <jats:italic>RPS6KA3<\/jats:italic>, <jats:italic>SMS<\/jats:italic>, and <jats:italic>ARX<\/jats:italic>. Except for developmental delay, there is little phenotypic overlap between the male and the female patient. Additionally, the female patient and affected female relatives of the male patient have variable severities of cognitive impairment, likely due to different X\u2010inactivation patterns and effects of other, nonduplicated genes important for normal development. These cases illustrate that increased gene dosage of X\u2010linked MR genes lead to cognitive impairment. Precise delineation of chromosome rearrangements by aCGH and identification of genes within duplicated segments helped in establishing genotype\u2013phenotype correlations for each of our patients, in comparing them to each other, as well as with previously reported cases of Xp21\u2010p22 duplications. However, we show that even with detailed molecular characterization, phenotype prediction remains challenging in patients with structural abnormalities of the X chromosome. \u00a9 2010 Wiley\u2010Liss, Inc.<\/jats:p>","DOI":"10.1002\/ajmg.a.33340","type":"journal-article","created":{"date-parts":[[2010,3,26]],"date-time":"2010-03-26T18:24:00Z","timestamp":1269627840000},"page":"904-915","source":"Crossref","is-referenced-by-count":15,"title":["Clinical and molecular characterization of overlapping interstitial Xp21\u2010p22 duplications in two unrelated 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