Microdeletion of 12q24.31: Report of a girl with intellectual disability, stereotypies, seizures and facial dysmorphisms

Palumbo, Orazio; Palumbo, Pietro; Delvecchio, Maurizio; Palladino, Teresa; Stallone, Raffaella; Crisetti, Matteo; Zelante, Leopoldo; Carella, Massimo

doi:10.1002/ajmg.a.36872

Cited by 34 publications

(20 citation statements)

References 27 publications

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“…In humans, microdeletions and microduplications of CNTN6 have been reported in patients with DD, ID, speech and language delays, atypical autism suggesting that under- and overexpression of this gene is responsible for the observed phenotypes [ 16 ]. In agreement with Shoukier et al [ 6 ], we cannot exclude the existence of a position effect on the CNTN6 gene, as already reported for others copy number variations [ 17 , 18 ]. Obviously, this observation need to be elucidated by further gene expression studies either on experimental in vivo animal models or on diagnostic material.…”

Section: Discussionsupporting

confidence: 91%

De novo microduplication of CHL1 in a patient with non-syndromic developmental phenotypes

et al. 2015

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BackgroundThe CHL1 gene codes for a member of the L1 family of neural cell adhesion molecules. It is highly expressed in the central and peripheral nervous system playing an important role in the building and functioning on the brain. CHL1 proteins are also involved in axonal migration, synaptic formation and plasticity. In mice, functional studies showed that the haploinsufficiency of Chl1 gene in the developing brain results in cognitive deficits suggesting that the CHL1 gene at 3p26.3 is a candidate for an autosomal form of intellectual disability. Furthermore, in humans deletions of CHL1 have been described in patients with neurodevelopmental delay characterized by learning and language difficulties, seizures. Less is known about the potential effect of CHL1 overexpression, and microduplications of CHL1 have been rarely identified.Case presentationIn this report, we describe a male patient with a phenotype characterized by developmental delay, symptoms of hyperactivity, short attention span and speech delay. In addition, minor facial dysmorphic features have been observed. Chromosomal microarray analysis revealed a rare de novo 0.85 Mb microduplication on the short arm (p26.3) of chromosome 3, encompassing a single gene, CHL1. To the best of our knowledge, duplication of chromosome 3p26.3, including only the CHL1 gene, has been described in only one intellectually disabled girl with epilepsy. The duplication described here is the smallest reported so far. In addition, this is the first report describing a patient in which the CHL1 duplication is a de novo event.ConclusionsThe clinical and molecular findings reported here are useful to provide further evidence that CHL1 is a dosage sensitive gene suggesting that not only the deletion but also its duplication can cause non-syndromic neurodevelopmental phenotypes.

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Section: Discussionsupporting

confidence: 91%

De novo microduplication of CHL1 in a patient with non-syndromic developmental phenotypes

et al. 2015

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“…Interesting to note, in one patient (DECIPHER 333097) the deletion did not encompass any of the two mentioned genes ( CELSR1 and ATXN10 ) although he showed NDDs and seizure. Given that deletion is very close to CELSR1 , we cannot exclude the existence of a position effect on the genes located in the neighboring regions, as already reported for others copy number variations (Ibn‐Salem et al, ; Kleinjan & van Heyningen, ; Palumbo et al, ), or the influence of polymorphisms external to the deleted region that contribute to penetrance. Obviously, this observation need to be elucidated by further studies either on experimental in vivo animal models or on diagnostic material.…”

Section: Discussionmentioning

confidence: 89%

Clinical and molecular characterization of an emerging chromosome 22q13.31 microdeletion syndrome

Palumbo

Accadia

Leone

et al. 2017

American J of Med Genetics Pt A

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Microdeletion of chromosome 22q13.31 is a very rare condition. Fourteen patients have been annotated in public databases but, to date, a clinical comparison has not been done and, consequently, a specific phenotype has not been delineated yet. We describe a patient showing neurodevelopmental disorders, dysmorphic features, and multiple congenital anomalies in which SNP array analysis revealed an interstitial 3.15 Mb de novo microdeletion in the 22q13.31 region encompassing 21 RefSeq genes and seven non-coding microRNAs. To perform an accurate phenotype characterization, clinical features observed in previously reported cases of 22q13.31 microdeletions were reviewed and compared to those observed in our patient. To the best of our knowledge, this is the first time that a comparison between patients carrying overlapping 22q13.31 deletions has been done. This comparison allowed us to identify a distinct spectrum of clinical manifestations suggesting that patients with a de novo interstitial microdeletion involving 22q13.31 have an emerging syndrome characterized by developmental delay/intellectual disability, speech delay/language disorders, behavioral problems, hypotonia, urogenital, and hands/feet anomalies. The microdeletion identified in our patient is the smallest reported so far and, for this reason, useful to perform a detailed genotype-phenotype correlation. In particular, we propose the CELSR1, ATXN10, FBLN1, and UPK3A as candidate genes in the onset of the main clinical features of this contiguous gene syndrome. Thus, the patient reported here broadens our knowledge of the phenotypic consequences of 22q13.31 microdeletions facilitating genotype-phenotype correlations. Additional cases are needed to corroborate our hypothesis and confirm genotype-phenotype correlations of this emerging syndrome.

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“…There is a very similar regulatory cascade in leukemia cells, where transcription factor NFkB recruits the MLL1 histone methyltransferase complex to activate NFkB target genes after TNF treatment 41 . It was previously reported that SETD1B is a possible causative gene for the pathogenesis of the 12q24.3 deletion syndrome 42,43 . In this regard patients with de novo SETD1B mutations showed signs of epilepsy, developmental delay, intellectual disability, and autism 44 .…”

Section: Discussionmentioning

confidence: 99%

EMT transcription factor ZEB1 alters the epigenetic landscape of colorectal cancer cells

et al. 2020

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Epigenetic deregulation remarkably triggers mechanisms associated with tumor aggressiveness like epithelial-mesenchymal transition (EMT). Since EMT is a highly complex, but also reversible event, epigenetic processes such as DNA methylation or chromatin alterations must be involved in its regulation. It was recently described that loss of the cell cycle regulator p21 was associated with a gain in EMT characteristics and an upregulation of the master EMT transcription factor ZEB1. In this study, in silico analysis was performed in combination with different in vitro and in vivo techniques to identify and verify novel epigenetic targets of ZEB1, and to proof the direct transcriptional regulation of SETD1B by ZEB1. The chorioallantoic-membrane assay served as an in vivo model to analyze the ZEB1/SETD1B interaction. Bioinformatical analysis of CRC patient data was used to examine the ZEB1/ SETD1B network under clinical conditions and the ZEB1/SETD1B network was modeled under physiological and pathological conditions. Thus, we identified a self-reinforcing loop for ZEB1 expression and found that the SETD1B associated active chromatin mark H3K4me3 was enriched at the ZEB1 promoter in EMT cells. Moreover, clinical evaluation of CRC patient data showed that the simultaneous high expression of ZEB1 and SETD1B was correlated with the worst prognosis. Here we report that the expression of chromatin modifiers is remarkably dysregulated in EMT cells. SETD1B was identified as a new ZEB1 target in vitro and in vivo. Our study demonstrates a novel example of an activator role of ZEB1 for the epigenetic landscape in colorectal tumor cells.

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Microdeletion of 12q24.31: Report of a girl with intellectual disability, stereotypies, seizures and facial dysmorphisms

Cited by 34 publications

References 27 publications

De novo microduplication of CHL1 in a patient with non-syndromic developmental phenotypes

De novo microduplication of CHL1 in a patient with non-syndromic developmental phenotypes

Clinical and molecular characterization of an emerging chromosome 22q13.31 microdeletion syndrome

EMT transcription factor ZEB1 alters the epigenetic landscape of colorectal cancer cells

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