Familial interstitial Xq27.3q28 duplication encompassing the FMR1 gene but not the MECP2 gene causes a new syndromic mental retardation condition

Rio, Marlène; Malan, Valérie; Boissel, Sarah; Toutain, Annick; Royer, Guilhem; Gobin, Stéphanie; Morichon-Delvallez, Nicole; Turleau, C; Bonnefont, Jean‐Paul; Münnich, Arnold; Vekemans, Michel; Colleaux, Laurence

doi:10.1038/ejhg.2009.159

Cited by 31 publications

(29 citation statements)

References 42 publications

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“…8 Three adult men in this family had a syndrome consisting of short stature, microcephaly, small hands and feet, low testicular volume, as well as facial features including deep-set eyes, bulbous nasal tip and thin lips. The individuals had a history of intrauterine growth restriction, failure to thrive in infancy, undescended testes requiring orchidopexy, walking after the age of 16 months and mild learning difficulties, with preserved verbal skills.…”

Section: Discussionmentioning

confidence: 96%

“…6,7 Few cases presenting a clinical phenotype typical of fragile X have been reported to be caused by relative gross duplication in the FMR1 gene. 8 Microduplications involving the FMR1 gene alone have not been reported. A prior report in the literature described a family with a 5.1 Mb duplication including both the FMR1 locus and FMR2 and 26 other genes, leading to a heritable syndrome of intellectual disability and short stature with hypogonadism 8 .…”

Section: Introductionmentioning

confidence: 99%

“…8 Microduplications involving the FMR1 gene alone have not been reported. A prior report in the literature described a family with a 5.1 Mb duplication including both the FMR1 locus and FMR2 and 26 other genes, leading to a heritable syndrome of intellectual disability and short stature with hypogonadism 8 . Members of this family had a phenotype consisting of mild developmental delay with relative preservation of verbal skills, microcephaly and small hands, feet and testicles.…”

Section: Introductionmentioning

confidence: 99%

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De novo microduplication of the FMR1 gene in a patient with developmental delay, epilepsy and hyperactivity

et al. 2012

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Loss-of-function due to expansion of a CGG repeat located in the 5'UTR of the FMR1 gene is the most frequent cause of fragile X syndrome. Less than 1% of individuals with fragile X syndrome have been reported to have a partial or full deletion or point mutation of the FMR1 gene. However, whether a copy number gain of the FMR1 gene could result in certain clinical phenotypes has not been fully investigated. Here, we report the case of a child who presented with developmental delay starting at 9 months of age, fine motor and speech delay, progressive seizures since 18 months of age and hyperactivity. Molecular workup identified a de novo microduplication in the Xq27.3 region, including the FMR1 gene and the ASFMR1 gene. The expression level of the FMR1 gene in peripheral blood did not differ from that of the controls. In addition, an inherited 363-kb duplication on the chromosome 1q44 region and an inherited deletion of 168 kb on the chromosome 4p15.31 region were detected. It is not clear whether these inherited copy number variations (CNVs) also have a modifying role in the clinical phenotype of this patient.

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Section: Discussionmentioning

confidence: 96%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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De novo microduplication of the FMR1 gene in a patient with developmental delay, epilepsy and hyperactivity

et al. 2012

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“…Several cases of this syndrome have been reported with common features that include severe mental retardation, developmental delay, and seizures. 53–56 Transgenic mice massively over-expressing human FMRP at 10- to 15-fold above normal WT levels of the mouse gene showed increased anxiety and reduced motor activity. 48 These results differ from the current results where Fmr1 KO mice treated with the high expressing Syn-mCMV-FMRP vector showed no major changes in anxiety behavior and a robust increase in motor activity.…”

Section: Discussionmentioning

confidence: 99%

FMRP Expression Levels in Mouse Central Nervous System Neurons Determine Behavioral Phenotype

et al. 2016

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Fragile X mental retardation protein (FMRP) is absent or highly reduced in Fragile X Syndrome, a genetic disorder causing cognitive impairment and autistic behaviors. Previous proof-of-principle studies have demonstrated that restoring FMRP in the brain using viral vectors can improve pathological abnormalities in mouse models of fragile X. However, unlike small molecule drugs where the dose can readily be adjusted during treatment, viral vector–based biological therapeutic drugs present challenges in terms of achieving optimal dosing and expression levels. The objective of this study was to investigate the consequences of expressing varying levels of FMRP selectively in neurons of Fmr1 knockout and wild-type (WT) mice. A wide range of neuronal FMRP transgene levels was achieved in individual mice after intra-cerebroventricular administration of adeno-associated viral vectors coding for FMRP. In all treated knockout mice, prominent FMRP transgene expression was observed in forebrain structures, whereas lower levels were present in more caudal regions of the brain. Reduced levels of the synaptic protein PSD-95, elevated levels of the transcriptional modulator MeCP2, and abnormal motor activity, anxiety, and acoustic startle responses in Fmr1 knockout mice were fully or partially rescued after expression of FMRP at about 35–115% of WT expression, depending on the brain region examined. In the WT mouse, moderate FMRP over-expression of up to about twofold had little or no effect on PSD-95 and MeCP2 levels or on behavioral endophenotypes. In contrast, excessive over-expression in the Fmr1 knockout mouse forebrain (approximately 2.5–6-fold over WT) induced pathological motor hyperactivity and suppressed the startle response relative to WT mice. These results delineate a range of FMRP expression levels in the central nervous system that confer phenotypic improvement in fragile X mice. Collectively, these findings are pertinent to the development of long-term curative gene therapy strategies for treating Fragile X Syndrome and other neurodevelopmental disorders.

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“…FM alleles induce complete methylation of the FMR1 promoter, leading to absence of mRNA transcription and loss of the fragile X mental protein (FMRP), which is essential for normal brain development (4 ). Rare FMR1 loss-of-function mutations involving deletions (small to large), macro duplication, and point mutation can also cause FXS without promoter hypermethylation (5)(6)(7).…”

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confidence: 99%

Identification of Males with Cryptic Fragile X Alleles by Methylation-Specific Quantitative Melt Analysis

et al. 2016

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Familial interstitial Xq27.3q28 duplication encompassing the FMR1 gene but not the MECP2 gene causes a new syndromic mental retardation condition

Cited by 31 publications

References 42 publications

De novo microduplication of the FMR1 gene in a patient with developmental delay, epilepsy and hyperactivity

De novo microduplication of the FMR1 gene in a patient with developmental delay, epilepsy and hyperactivity

FMRP Expression Levels in Mouse Central Nervous System Neurons Determine Behavioral Phenotype

Identification of Males with Cryptic Fragile X Alleles by Methylation-Specific Quantitative Melt Analysis

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