Identification of novel <i>FMR1</i> variants by massively parallel sequencing in developmentally delayed males

Collins, Stephen C.; Bray, Steven M.; Suhl, Joshua A.; Cutler, David J.; Coffee, Bradford; Zwick, Michael E.; Warren, Stephen T.

doi:10.1002/ajmg.a.33626

Cited by 104 publications

(109 citation statements)

References 63 publications

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“…15,16 However, other loss-of-function mutations, including deletions, missense mutations and splice-site mutations, have been reported. [17][18][19][20] The case described here has an 86-kb microduplication that only encompasses the FMR1 and ASFMR1 genes. The ASFMR1 gene promoter is located within intron 2 of the FMR1 gene.…”

Section: Discussionmentioning

confidence: 95%

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: 95%

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

et al. 2012

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“…FMRP is an RNA binding protein that serves as a critical regulator of experience-dependent translation in neurons (8). Loss of FMRP perturbs experience-dependent plasticity and results in the autism-related disorder Fragile X syndrome (FXS) (8)(9)(10)(11)(12)(13). In addition to its role in the somatodendritic compartment, FMRP also associates with a distinct granule termed the FXG (Fragile X granule).…”

Section: Introductionmentioning

confidence: 99%

Axonal ribosomes and mRNAs associate with fragile X granules in adult rodent and human brains

et al. 2017

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Local mRNA translation in growing axons allows for rapid and precise regulation of protein expression in response to extrinsic stimuli. However, the role of local translation in mature CNS axons is unknown. Such a mechanism requires the presence of translational machinery and associated mRNAs in circuit-integrated brain axons. Here we use a combination of genetic, quantitative imaging and super-resolution microscopy approaches to show that mature axons in the mammalian brain contain ribosomes, the translational regulator FMRP and a subset of FMRP mRNA targets. This axonal translational machinery is associated with Fragile X granules (FXGs), which are restricted to axons in a stereotyped subset of brain circuits. FXGs and associated axonal translational machinery are present in hippocampus in humans as old as 57 years. This FXGassociated axonal translational machinery is present in adult rats, even when adult neurogenesis is blocked. In contrast, in mouse this machinery is only observed in juvenile hippocampal axons. This differential developmental expression was specific to the hippocampus, as both mice and rats exhibit FXGs in mature axons in the adult olfactory system. Experiments in Fmr1 null mice show that FMRP regulates axonal protein expression but is not required for axonal transport of ribosomes or its target mRNAs. Axonal translational machinery is thus a feature of adult CNS neurons. Regulation of this machinery by FMRP could support complex behaviours in humans throughout life.

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“…This gene does not appear any less mutable than other typical X-linked genes. A recent study sequencing FMR1 in 963 developmentally delayed males observed five silent (synonymous) sites and two replacement (nonsynonymous) sites, 19 which compares favorably with X-linked genome-wide averages of B3.7 silent sites and 2.5 replacement sites. 20 However, if one examines other X-linked monogenic causes of intellectual disability and/or developmental delay (ID/DD), the small number of FMR1 missense mutations is striking.…”

Section: Discussionmentioning

confidence: 85%

Fragile X syndrome due to a missense mutation

et al. 2014

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Fragile X syndrome is a common inherited form of intellectual disability and autism spectrum disorder. Most patients exhibit a massive CGG-repeat expansion mutation in the FMR1 gene that silences the locus. In over two decades since the discovery of FMR1, only a single missense mutation (p.(Ile304Asn)) has been reported as causing fragile X syndrome. Here we describe a 16-year-old male presenting with fragile X syndrome but without the repeat expansion mutation. Rather, we find a missense mutation, c.797G4A, that replaces glycine 266 with glutamic acid (p. (Gly266Glu)). The Gly266Glu FMR protein abolished many functional properties of the protein. This patient highlights the diagnostic utility of FMR1 sequencing.

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Identification of novel FMR1 variants by massively parallel sequencing in developmentally delayed males

Cited by 104 publications

References 63 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

Axonal ribosomes and mRNAs associate with fragile X granules in adult rodent and human brains

Fragile X syndrome due to a missense mutation

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