Xq28 duplications including MECP2 in five females: Expanding the phenotype to severe mental retardation

Bijlsma, Emilia K.; Collins, Amanda; Papa, Filomena Tiziana; Tejada, María-Isabel; Wheeler, Patricia G.; Peeters, Els; Gijsbers, Antoinet C.J.; Kamp, Jiddeke M. van de; Kriek, Marjolein; Losekoot, Monique; Broekma, A.J.; Crolla, John A.; Pollazzon, Marzia; Mucciolo, Mafalda; Katzaki, Eleni; Disciglio, Vittoria; Ferreri, Maria Immacolata; Marozza, Annabella; Mencarelli, Maria Antonietta; Castagnini, Cinzia; Dosa, Laura; Ariani, Francesca; Mari, Francesca; Canitano, Roberto; Hayek, Joussef; Botella, M.P.; Gener, Blanca; Mínguez, Mónica; Renieri, Alessandra; Ruivenkamp, Claudia

doi:10.1016/j.ejmg.2012.02.009

Cited by 44 publications

(79 citation statements)

References 34 publications

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“…Similarly, a paternal origin was demonstrated in other two females with de novo Xq28 interstitial duplications [32] in agreement with the X chromosome vulnerability at male meiosis [38]. …”

Section: Discussionsupporting

confidence: 53%

MECP2 duplication phenotype in symptomatic females: report of three further cases

et al. 2014

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BackgroundXq28 duplications, including MECP2 (methyl CpG-binding protein 2; OMIM 300005), have been identified in approximately 140 male patients presenting with hypotonia, severe developmental delay/intellectual disability, limited or absent speech and ambulation, and recurrent respiratory infections. Female patients with Xq28 duplication have been rarely reported and are usually asymptomatic. Altogether, only fifteen symptomatic females with Xq28 duplications including MECP2 have been reported so far: six of them had interstitial duplications while the remaining had a duplication due to an unbalanced X;autosome translocation. Some of these females present with unspecific mild to moderate intellectual disability whereas a more complex phenotype is reported for females with unbalanced X;autosome translocations.FindingsHere we report on the clinical features of three other adolescent to adult female patients with Xq28 interstitial duplications of variable size, all including MECP2 gene.ConclusionsMild to moderate cognitive impairment together with learning difficulties and speech delay were evident in each of our patients. Moreover, early inadequate behavioral patterns followed by persistent difficulties in the social and communication domains, as well as the occurrence of mild psychiatric disturbances, are common features of these three patients.

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“…Similarly, a paternal origin was demonstrated in other two females with de novo Xq28 interstitial duplications [32] in agreement with the X chromosome vulnerability at male meiosis [38]. …”

Section: Discussionsupporting

confidence: 53%

MECP2 duplication phenotype in symptomatic females: report of three further cases

et al. 2014

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“…To date, 14 female patients with an intraC dupMECP2 of various sizes have been described in the literature . Among these, seven (50%) had inherited the duplication from their mother (Table , Figs and ).…”

Section: Discussionmentioning

confidence: 99%

Xq28 duplication including MECP2 in six unreported affected females: what can we learn for diagnosis and genetic counselling?

et al. 2017

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Duplication of the Xq28 region, involving MECP2 (dupMECP2), has been primarily described in males with severe developmental delay, spasticity, epilepsy, stereotyped movements and recurrent infections. Carrier mothers are usually asymptomatic with an extremely skewed X chromosome inactivation (XCI) pattern. We report a series of six novel symptomatic females carrying a de novo interstitial dupMECP2, and review the 14 symptomatic females reported to date, with the aim to further delineate their phenotype and give clues for genetic counselling. One patient was adopted and among the other 19 patients, seven (37%) had inherited their duplication from their mother, including three mildly (XCI: 70/30, 63/37, 100/0 in blood and random in saliva), one moderately (XCI: random) and three severely (XCI: uninformative and 88/12) affected patients. After combining our data with data from the literature, we could not show a correlation between XCI in the blood or duplication size and the severity of the phenotype, or explain the presence of a phenotype in these females. These findings confirm that an abnormal phenotype, even severe, can be a rare event in females born to asymptomatic carrier mothers, making genetic counselling difficult in couples at risk in terms of prognosis, in particular in prenatal cases.

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“…This phenotype differs from that of male patients with MECP2 duplications (Van Esch, 2012). Heterozygous females with MECP2 duplication usually show extreme to complete skewing of X‐chromosome inactivation and are asymptomatic or have mainly neuropsychiatric disorders, but severe mental retardation has been reported (Bijlsma et al, 2012). We were not able to determine the mechanism through which the pericentric inversion is affecting the methylation and the transcriptional regulation of the MECP2 gene.…”

Section: Discussionmentioning

confidence: 99%

“…Recently Bijlsma et al reviewed MECP2 duplication in eleven females; five were from their study and six had been previously reported. Intellectual disability was a prominent feature while hand stereotypies, epilepsy, dysmorphism and recurrent infections were less frequent (Bijlsma et al, 2012). Overexpression of normal MeCP2 has also been shown to cause a progressive neurological disorder in a mouse model, showing that the nervous system requires a very precise dosage of this protein for proper functioning (Collins et al, 2004).…”

Section: Introductionmentioning

confidence: 99%

Variant Rett syndrome in a girl with a pericentric X‐chromosome inversion leading to epigenetic changes and overexpression of the MECP2 gene

Vieira

Lopes

Silva‐Fernandes

et al. 2015

Intl J of Devlp Neuroscience

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a b s t r a c tRett syndrome is a neurodevelopmental disorder caused by mutations in the MECP2 gene. We investigated the genetic basis of disease in a female patient with a Rett-like clinical. Karyotype analysis revealed a pericentric inversion in the X chromosome −46,X,inv(X)(p22.1q28), with breakpoints in the cytobands where the MECP2 and CDKL5 genes are located. FISH analysis revealed that the MECP2 gene is not dislocated by the inversion. However, and in spite of a balanced pattern of X inactivation, this patient displayed hypomethylation and an overexpression of the MECP2 gene at the mRNA level in the lymphocytes (mean fold change: 2.55 ± 0.38) in comparison to a group of control individuals; the expression of the CDKL5 gene was similar to that of controls (mean fold change: 0.98 ± 0.10). No gains or losses were detected in the breakpoint regions encompassing known or suspected transcription regulatory elements. We propose that the de-regulation of MECP2 expression in this patient may be due to alterations in long-range genomic interactions caused by the inversion and hypothesize that this type of epigenetic de-regulation of the MECP2 may be present in other RTT-like patients.

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Xq28 duplications including MECP2 in five females: Expanding the phenotype to severe mental retardation

Cited by 44 publications

References 34 publications

MECP2 duplication phenotype in symptomatic females: report of three further cases

MECP2 duplication phenotype in symptomatic females: report of three further cases

Xq28 duplication including MECP2 in six unreported affected females: what can we learn for diagnosis and genetic counselling?

Variant Rett syndrome in a girl with a pericentric X‐chromosome inversion leading to epigenetic changes and overexpression of the MECP2 gene

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