17p13.1 microdeletion: Genetic and clinical findings in a new patient with epilepsy and comparison with literature

Giordano, Lucio; Palestra, Filippo; Maria, Grazia Giuffrida; Molinaro, Anna; Iodice, Alessandro; Bernardini, Laura; Boria, P La; Accorsi, Patrizia; Novelli, Antonio

doi:10.1002/ajmg.a.36225

Cited by 7 publications

(13 citation statements)

References 16 publications

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“…The FXR2 gene is located on chromosome 17. Microdeletions in the 17p13.1 comprise a syndrome that is often associated with dysmorphic features and developmental delay [16,17]. Given that this microdeletion syndrome is accompanied by the loss of multiple genes, it is hard to identify the specific role of FXR2 .…”

Section: Introductionmentioning

confidence: 99%

Comparative Behavioral Phenotypes of Fmr1 KO, Fxr2 Het, and Fmr1 KO/Fxr2 Het Mice

et al. 2019

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Fragile X syndrome (FXS) is caused by silencing of the FMR1 gene leading to loss of the protein product fragile X mental retardation protein (FMRP). FXS is the most common monogenic cause of intellectual disability. There are two known mammalian paralogs of FMRP, FXR1P, and FXR2P. The functions of FXR1P and FXR2P and their possible roles in producing or modulating the phenotype observed in FXS are yet to be identified. Previous studies have revealed that mice lacking Fxr2 display similar behavioral abnormalities as Fmr1 knockout (KO) mice. In this study, we expand upon the behavioral phenotypes of Fmr1 KO and Fxr2+/− (Het) mice and compare them with Fmr1 KO/Fxr2 Het mice. We find that Fmr1 KO and Fmr1 KO/Fxr2 Het mice are similarly hyperactive compared to WT and Fxr2 Het mice. Fmr1 KO/Fxr2 Het mice have more severe learning and memory impairments than Fmr1 KO mice. Fmr1 KO mice display significantly impaired social behaviors compared to WT mice, which are paradoxically reversed in Fmr1 KO/Fxr2 Het mice. These results highlight the important functional consequences of loss or reduction of FMRP and FXR2P.

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Section: Introductionmentioning

confidence: 99%

Comparative Behavioral Phenotypes of Fmr1 KO, Fxr2 Het, and Fmr1 KO/Fxr2 Het Mice

et al. 2019

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“…Our patients and the previously reported patients with microduplications of 17p13.1 have overlapping clinical features including neurodevelopmental delays and absolute/relative macrocephaly (Table ). Neurodevelopmental delays and microcephaly have previously been associated with microdeletions of 17p13.1 [Adam et al, ; Krepischi‐Santos et al, ; Schwarzbraun et al, ; Komoike et al, ; Schluth‐Bolard et al, ; Shlien et al, ; Zeesman et al, ; Giordano et al, ]. Microcephaly and macrocephaly have been reported in individuals with reciprocal microdeletions and microduplications, respectively.…”

Section: Discussionmentioning

confidence: 99%

“…Microduplications of chromosome 17p13.1 have recently been reported to be associated with neurodevelopmental delays [Belligni et al, ; Coutton et al, ]. Microdeletions associated with neurodevelopmental delays and microcephaly which overlap the same region of 17p13.1 have previously been reported in 16 patients [Adam et al, ; Krepischi‐Santos et al, ; Schwarzbraun et al, ; Komoike et al, ; Schluth‐Bolard et al, ; Shlien et al, ; Zeesman et al, ; Giordano et al, ]. It has been proposed that alteration of a dose‐dependent gene may be responsible for the neurodevelopmental delays in individuals with overlapping microdeletions and microduplications of 17p13.1 [Belligni et al, ; Coutton et al, ].…”

Section: Introductionmentioning

confidence: 98%

Neurodevelopmental delays and macrocephaly in 17p13.1 microduplication syndrome

Mooneyham

Holden

Cathey

et al. 2014

American J of Med Genetics Pt A

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Microduplication of chromosome 17p13.1 is a rarely reported chromosome abnormality associated with neurodevelopmental delays. We describe two unrelated patients with overlapping microduplications of chromosome 17p13.1. The first patient is a 2-year-old male who presented with neurodevelopmental delays and macrocephaly. He was found to have a de novo 788 kb copy gain of 17p13.2p13.1 and a de novo 134 kb copy gain of 17p13.1. These duplications include multiple candidate genes, including EFNB3, NLGN2, DLG4, GABARAP, and DULLARD, which may be responsible for neurodevelopmental delays in affected individuals. The second patient is a 29-year-old female with mild intellectual disability and relative macrocephaly. She was found to have a 62.5 kb copy gain of chromosome 17p13.1 that includes the DLG4, GABARAP, and DULLARD genes. The DLG4, GABARAP, and DULLARD genes included in the microduplications of both our patients appear to be candidate genes for neurodevelopmental delays and macrocephaly in individuals with 17p13.1 microduplication syndrome.

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“…Beyond repeat expansions in the FMR1 gene, a number of rare pathogenic point mutations have been reported that cause developmental delay and ID reminiscent of FXS [153][154][155][156][157]. Further evidence suggests that mutations in the autosomal homolog FXR2 gene might also contribute to ID [158][159][160]. Whilst variants affecting the related FXR1 gene confer risk to schizophrenia, bipolar disorder, and autism [161][162][163][164][165], the genetic link between FMR1 and psychiatric disorders derives from enrichment of association within the gene targets of FMRP (among which the fragile-X family genes themselves are included).…”

Section: Fmrp and Fmrp Targets In Psychiatric Genomic Studiesmentioning

confidence: 99%

FMRP and CYFIP1 at the Synapse and Their Role in Psychiatric Vulnerability

et al. 2020

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There is increasing awareness of the role genetic risk variants have in mediating vulnerability to psychiatric disorders such as schizophrenia and autism. Many of these risk variants encode synaptic proteins, influencing biological pathways of the postsynaptic density and, ultimately, synaptic plasticity. Fragile-X mental retardation 1 (FMR1) and cytoplasmic fragile-X mental retardation protein (FMRP)-interacting protein 1 (CYFIP1) contain 2 such examples of highly penetrant risk variants and encode synaptic proteins with shared functional significance. In this review, we discuss the biological actions of FMRP and CYFIP1, including their regulation of (i) protein synthesis and specifically FMRP targets, (ii) dendritic and spine morphology, and (iii) forms of synaptic plasticity such as long-term depression. We draw upon a range of preclinical studies that have used genetic dosage models of FMR1 and CYFIP1 to determine their biological function. In parallel, we discuss how clinical studies of fragile X syndrome or 15q11.2 deletion patients have informed our understanding of FMRP and CYFIP1, and highlight the latest psychiatric genomic findings that continue to implicate FMRP and CYFIP1. Lastly, we assess the current limitations in our understanding of FMRP and CYFIP1 biology and how they must be addressed before mechanism-led therapeutic strategies can be developed for psychiatric disorders.

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17p13.1 microdeletion: Genetic and clinical findings in a new patient with epilepsy and comparison with literature

Cited by 7 publications

References 16 publications

Comparative Behavioral Phenotypes of Fmr1 KO, Fxr2 Het, and Fmr1 KO/Fxr2 Het Mice

Comparative Behavioral Phenotypes of Fmr1 KO, Fxr2 Het, and Fmr1 KO/Fxr2 Het Mice

Neurodevelopmental delays and macrocephaly in 17p13.1 microduplication syndrome

FMRP and CYFIP1 at the Synapse and Their Role in Psychiatric Vulnerability

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