A de novo duplication of Xp11.22–p11.4 in a girl with intellectual disability, structural brain anomalies, and preferential inactivation of the normal X chromosome

In females carrying structural rearrangements of an X-chromosome, cells with the best dosage balance are preferentially selected, frequently resulting in a skewed inactivation pattern and amelioration of the phenotype. The Xp11.23-p11.22 region is involved in a recently described microduplication syndrome associated with severe clinical consequences in males and females, causing intellectual disability, behavior problems, epilepsy with electroencephalogram anomalies, minor facial anomalies, and early onset of puberty. Female carriers usually present an unusual X-chromosome inactivation pattern in favor of the aberrant chromosome, resulting in functional disomy of the duplicated segment. Here, we describe a girl carrying a de novo ∼9.7 Mb Xp11.3-p11.22 duplication of paternal origin and skewed X-chromosome inactivation pattern of the normal X-chromosome. We reviewed other cases previously reported and determined the minimal critical region possibly responsible for this unusual inactivation pattern. The critical region encompasses 36 RefSeq genes, including at least 10 oncogenes and/or genes related to the cell cycle control. We discuss the molecular mechanisms that underlie the positive selection of the cells with the active duplicated chromosome. © 2016 Wiley Periodicals, Inc.

Section: Discussionsupporting

confidence: 91%

Section: Discussionmentioning

confidence: 99%

Unusual X‐chromosome inactivation pattern in patients with Xp11.23‐p11.22 duplication: Report and review

Di-Battista

Meloni

Silva

et al. 2016

“…In recent years, small duplications of the proximal short arm of the X chromosome, in particular duplications encompassing Xp11.23, have been reported to be associated with neurodevelopmental disorders both in males and females [Bonnet et al, ; Froyen et al, ; Marshall et al, ; Monnot et al, ; Giorda et al, ; Holden et al, ; Chung et al, ; Edens et al, ; El‐Hattab et al, ]. Surprisingly, and in contrast to previously described larger duplications in Xp with selective inactivation of the aberrant X‐chromosome and a commonly normal phenotype in most carrier women [Matsuo et al, ], females with microduplications including Xp11.23 repeatedly showed preferential inactivation of the normal X‐chromosome.…”

Section: Introductionmentioning

confidence: 98%

Duplication Xp11.22‐p14 in females: Does X‐inactivation help in assessing their significance?

Evers

Mitter

Strobl‐Wildemann

et al. 2015

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.

“…This individual was described as having ID (IQ of 68), mild receptive and expressive language delay, moderate speech delay, autism, dysmorphic features, and severe hypotonia. Holden et al, [] reported a girl with de novo duplication at (40.4–52.7 Mb), described as having EEG abnormalities, brain MRI abnormalities, global developmental delay, expressive language delay, hypotonia, and indistinct speech.…”

Section: Discussionmentioning

confidence: 99%

“…Duplications involving HUWE1 (HECT, UBA, and WWE Domains‐Containing Protein 1) have been associated with non‐syndromic ID [Madrigal et al, ; Froyen et al, ] (MIM 300705). However, not all duplications of Xp11.22‐p11.23 in patients with ID include the HUWE1 gene, suggesting the involvement of other important ID genes in the Xp11.22‐p11.23 region [Giorda, ; Yan et al, ; Holden et al, ]. We report a cohort of 13 patients with overlapping Xp11.22‐p11.23 duplications to further study potential critical dosage‐sensitive genes in the region (Table ).…”

Section: Introductionmentioning

confidence: 94%

Genotype–phenotype characterization in 13 individuals with chromosome Xp11.22 duplications

Grams

Argiropoulos

Lines

et al. 2015

We report 13 new individuals with duplications in Xp11.22-p11.23. The index family has one male and two female members in three generations with mild-severe intellectual disability (ID), speech delay, dysmorphic features, early puberty, constipation, and/or hand and foot abnormalities. Affected individuals were found to have two small duplications in Xp11.22 at nucleotide position (hg19) 50,112,063-50,456,458 bp (distal) and 53,160,114-53,713,154 bp (proximal). Collectively, these two regions include 14 RefSeq genes, prompting collection of a larger cohort of patients, in an attempt to delineate critical genes associated with the observed phenotype. In total, we have collected data on nine individuals with duplications overlapping the distal duplication region containing SHROOM4 and DGKK and eight individuals overlapping the proximal region including HUWE1. Duplications of HUWE1 have been previously associated with non-syndromic ID. Our data, with previously published reports, suggest that duplications involving SHROOM4 and DGKK may represent a new syndromic X-linked ID critical region associated with mild to severe ID, speech delay +/- dysarthria, attention deficit disorder, precocious puberty, constipation, and motor delay. We frequently observed foot abnormalities, 5th finger clinodactyly, tapering fingers, constipation, and exercise intolerance in patients with duplications of these two genes. Regarding duplications including the proximal region, our observations agree with previous studies, which have found associations with intellectual disability. In addition, expressive language delay, failure to thrive, motor delay, and 5th finger clinodactyly were also frequently observed in patients with the proximal duplication.