Clinical impacts of genomic copy number gains at Xq28

Yamamoto, Toshiyuki; Shimojima, Keiko; Shimada, Shino; Yokochi, Kenji; Yoshitomi, Shinsaku; Yanagihara, Keiko; Imai, Katsumi; Okamoto, Nobuhiko

doi:10.1038/hgv.2014.1

Cited by 37 publications

(45 citation statements)

References 49 publications

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“…Duplications in the Xq28 chromosomal region, known as Xq28 duplication syndromes (MIM# 300815), result in various types of X‐linked intellectual disability syndromes (XLIDS), depending on the subset of genes involved in the duplication. However, multiple organ systems are usually involved in these syndromes, due to the high gene density of the Xq28 region (Kolb‐Kokocinski et al, 2006; Unique, 2016; Yamamoto et al, 2014). XLIDS generally present with more severe manifestations in males compared with females, since affected males are hemizygous, while affected females are usually heterozygous for the underlying defect.…”

Section: Introductionmentioning

confidence: 99%

“…In addition, heterozygous females undergo skewed inactivation of the X chromosome harboring the duplication or deletion, which further attenuates their phenotypic manifestations. Nonetheless, because X inactivation patterns are unpredictable, affected females can exhibit a wide phenotypic spectrum; these can range from subtle or no abnormalities in some, to varying degrees of intellectual disability and neurodevelopmental delays in others who nearly phenocopy affected males (Van Esch et al, 2005; Yamamoto et al, 2014). Males, on the other hand, tend to be more phenotypically uniform.…”

Section: Introductionmentioning

confidence: 99%

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Int22h1/Int22h2 ‐mediated Xq28 duplication syndrome: de novo duplications, prenatal diagnoses, and additional phenotypic features

et al. 2020

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Int22h1/Int22h2‐mediated Xq28 duplication syndrome is a relatively new X‐linked intellectual disability syndrome, arising from duplications of the subregion flanked by intron 22 homologous regions 1 and 2 on the q arm of chromosome X. Its primary manifestations include variable cognitive deficits, distinct facial dysmorphia, and neurobehavioral abnormalities that mainly include hyperactivity, irritability, and autistic behavior. Affected males are hemizygous for the duplication, which explains their often more severe manifestations compared with heterozygous females. In this report, we describe the cases of nine individuals recently identified having the syndrome, highlighting unique and previously unreported findings of this syndrome. Specifically, we report for the first time in this syndrome, two cases with de novo duplications, three receiving prenatal diagnosis with the syndrome, and three others having atypical versions of the duplication. Among the latter, one proband has a shortened version spanning only the centromeric half of the typical duplication, while the other two cases have a nearly identical length duplication as the classical duplication, with the exception that their duplication's breakpoints are telomerically shifted by about 0.2 Mb. Finally, we shed light on two new manifestations in this syndrome, vertebral anomalies and multiple malignancies, which possibly expand the phenotypic spectrum of the syndrome.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Int22h1/Int22h2 ‐mediated Xq28 duplication syndrome: de novo duplications, prenatal diagnoses, and additional phenotypic features

et al. 2020

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“…Six years later micro‐duplications involving the MECP2 gene were reported to be a cause of severe intellectual disability in males . Subsequent studies have established MECP2 duplication as a specific syndrome (OMIM 300260) that might account for approximately 1% of unexplained X‐linked intellectual disability in males . Considering its phenotypic variability, we acknowledge the possible involvement of other genes located on Xq28 such as FLNA and IRAK1 in MECP2 Duplication syndrome.…”

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confidence: 99%

Expanding the clinical picture of the MECP2 Duplication syndrome

et al. 2016

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Individuals with two or more copies of the MECP2 gene, located at Xq28, share clinical features and a distinct facial phenotype known as MECP2 Duplication syndrome. We have examined perinatal characteristics, early childhood development and medical co-morbidities in this disorder. The International Rett Syndrome Phenotype Database (InterRett), which collects information from caregivers and clinicians on individuals with Rett syndrome and MECP2 associated disorders, was used as the data source. Data were available on 56 cases (49 males and 7 females) with MECP2 Duplication syndrome. Median age at ascertainment was 7.9 years (range: 1.2-37.6 years) and at diagnosis 3.0 years (range: 3 weeks-37 years). Less than a third (29%) learned to walk. Speech deterioration was reported in 34% and only 20% used word approximations or better at ascertainment. Over half (55%) had been hospitalised for respiratory infections in the first 2 years of life. Just under half (44%) had seizures, occurring daily in nearly half of this group. The majority (89%) had gastrointestinal problems and a third had a gastrostomy. Following the recent demonstration of phenotype reversal in a mouse model of MECP2 Duplication, a clear understanding of the natural history is crucial to the design and implementation of future therapeutic strategies.

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“…Xq28 duplications are the most frequently observed chromosomal duplications in patients with intellectual disability of unknown etiology. 7 These duplications occur by variable mechanisms, including interstitial duplications mediated by segmental duplications in this region as well as terminal duplications derived from translocation with other chromosomes. The most commonly observed pattern is the interstitial duplication that includes MECP2, which is due to regional genomic instability caused by segmental duplications that are densely located in this region.…”

Section: Variable Patterns Of Xq28 Duplicationsmentioning

confidence: 99%

“…A 7-year-old boy who was previously reported by us as patient 5 showed poor sucking and recurrent vomiting since his early infancy. 7 Early developmental delay and axial hypotonia were also noted. He was frequently admitted to the hospital due to recurrent pneumonia.…”

Section: Patientmentioning

confidence: 99%

Xq28 Duplications and Epilepsy: Influence of the Combinatory Duplication of MECP2 and GDI1

et al. 2015

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Xq28 duplications including the MECP2 (Methyl-CpG-binding protein 2) cause an X-linked recessive neurodegenerative disorder that presents symptoms such as early developmental delay, progressive deterioration, and intractable epilepsy. Submicroscopic interstitial duplication in the MECP2 region is one of the most frequently observed submicroscopic chromosomal aberrations in patients with intellectual disability. This high prevalence is derived from the genomic instability characteristic of this region due to segmental duplications that are densely located in this region, which are prone to cause nonallelic homologous recombination during meiosis. Patients with MECP2 duplications generally begin to show epilepsy after 6 years of age. Therefore, incidence of epilepsy is high in adolescents. Although many types of seizures have been reported in patients, the most frequently observed seizure types were absence seizure and generalized tonic?clonic seizures. Because drop attacks are frequently seen, such epileptic attacks are sometimes life-threatening. We encountered a patient who showed epileptic spasms during infancy with a relatively larger duplication that encompasses MECP2 and GDI1 (GDP dissociation inhibitor-1). This led us to speculate that the combinatory duplication that includes MECP2 and GDI1 may cause severe epileptic features; however, most of the previously reported patients with combined duplications of MECP2 and GDI1 did not showed early occurrence of epilepsy. Therefore, further information would be required to confirm if the combinatory duplication of MECP2 and GDI1 exerts any influence on the severity of epilepsy.

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Clinical impacts of genomic copy number gains at Xq28

Cited by 37 publications

References 49 publications

Int22h1/Int22h2 ‐mediated Xq28 duplication syndrome: de novo duplications, prenatal diagnoses, and additional phenotypic features

Int22h1/Int22h2 ‐mediated Xq28 duplication syndrome: de novo duplications, prenatal diagnoses, and additional phenotypic features

Expanding the clinical picture of the MECP2 Duplication syndrome

Xq28 Duplications and Epilepsy: Influence of the Combinatory Duplication of MECP2 and GDI1

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