title: Duplication Xp11.22-p14 in females: does X-inactivation help in assessing their significance?
abstract: In females, large duplications in Xp often lead to preferential inactivation of the aberrant X chromosome and a normal phenotype. Recently, a recurrent ∼4.5 Mb microduplication of Xp11.22-p11.23 was found in females with developmental delay/intellectual disability and other neurodevelopmental disorders (speech development disorder, epilepsy or EEG anomalies, autism spectrum disorder, or behavioral disorder). Unexpectedly, most of them showed preferential inactivation of the normal X chromosome. We describe five female patients carrying de novo Xp duplications encompassing p11.23. Patient 1 carried the recurrent microduplication Xp11.22-p11.23, her phenotype and X-chromosome inactivation (XI) pattern was consistent with previous reports. The other four patients had novel Xp duplications. Two were monozygotic twins with a similar phenotype to Patient 1 and unfavorable XI skewing carrying an overlapping ∼5 Mb duplication of Xp11.23-p11.3. Patient 4 showed a duplication of ∼5.5 Mb comparable to the twins but had a more severe phenotype and unskewed XI. Patient 5 had a ∼8.5 Mb duplication Xp11.23-p11.4 and presented with mild ID, epilepsy, behavioral problems, and inconsistent results of XI analysis. A comparison of phenotype, size and location of the duplications and XI patterns in Patients 1-5 and previously reported females with overlapping duplications provides further evidence that microduplications encompassing Xp11.23 are associated with ID and other neurodevelopmental disorders in females. To further assess the implication of XI for female carriers, we recommend systematic analysis of XI pattern in any female with X imbalances that are known or suspected to be pathogenic.
authors.affiliation: Institute of Human Genetics, Heidelberg University, Heidelberg, Germany.
authors.forename: Christina
authors.initials: C
authors.lastname: Evers
authors.forename: Diana
authors.initials: D
authors.lastname: Mitter
authors.forename: Gertrud
authors.initials: G
authors.lastname: Strobl-Wildemann
authors.forename: Ulrich
authors.initials: U
authors.lastname: Haug
authors.forename: Karl
authors.initials: K
authors.lastname: Hackmann
authors.forename: Bianca
authors.initials: B
authors.lastname: Maas
authors.forename: Johannes W G
authors.initials: JW
authors.lastname: Janssen
authors.forename: Anna
authors.initials: A
authors.lastname: Jauch
authors.forename: Katrin
authors.initials: K
authors.lastname: Hinderhofer
authors.forename: Ute
authors.initials: U
authors.lastname: Moog
mesh_terms: D000293:Adolescent; D000328:Adult; D002648:Child; D002675:Child, Preschool; D058674:Chromosome Duplication; D041321:Chromosomes, Human, X; D055028:Comparative Genomic Hybridization; D019066:Facies; D005260:Female; D056726:Genetic Association Studies; D006801:Humans; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D025064:Sex Chromosome Disorders / Q000175:diagnosis / Q000235:genetics*; D049951:X Chromosome Inactivation; D055815:Young Adult
keywords: X-inactivation; Xp duplication; Xp11.22-p11.4; Xp11.23; intellectual disability