Antisense may make sense of 1q44 deletions, seizures, and <i>HNRNPU</i>

Poot, Martin; Kas, Martien

doi:10.1002/ajmg.a.35770

Cited by 12 publications

(9 citation statements)

References 21 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The CNV at 1q44 containing HNRNPU has been reported in cases with seizures, brain malformation, and developmental delay [38,39]. However, an association of this CNV with IS has not been reported previously.…”

Section: Discussionmentioning

confidence: 99%

A genomic copy number variant analysis implicates the MBD5 and HNRNPUgenes in Chinese children with infantile spasms and expands the clinical spectrum of 2q23.1 deletion

et al. 2014

BMC Med Genet

View full text Add to dashboard Cite

BackgroundInfantile spasms (IS) is a specific type of epileptic encephalopathy associated with severe developmental disabilities. Genetic factors are strongly implicated in IS, however, the exact genetic defects remain unknown in the majority of cases. Rare mutations in a single gene or in copy number variants (CNVs) have been implicated in IS of children in Western countries. The objective of this study was to dissect the role of copy number variations in Chinese children with infantile spasms.MethodsWe used the Agilent Human Genome CGH microarray 180 K for genome-wide detection of CNVs. Real-time qPCR was used to validate the CNVs. We performed genomic and medical annotations for individual CNVs to determine the pathogenicity of CNVs related to IS.ResultsWe report herein the first genome-wide CNV analysis in children with IS, detecting a total of 14 CNVs in a cohort of 47 Chinese children with IS. Four CNVs (4/47 = 8.5%) (1q21.1 gain; 1q44, 2q31.1, and 17p13 loss) are considered to be pathogenic. The CNV loss at 17p13.3 contains PAFAH1B1 (LIS1), a causative gene for lissencephaly. Although the CNVs at 1q21.1, 1q44, and 2q23.1 have been previously implicated in a wide spectrum of clinical features including autism spectrum disorders (ASD) and generalized seizure, our study is the first report identifying them in individuals with a primary diagnosis of IS. The CNV loss in the 1q44 region contains HNRNPU, a strong candidate gene recently suggested in IS by the whole exome sequencing of children with IS. The CNV loss at 2q23.1 includes MBD5, a methyl-DNA binding protein that is a causative gene of ASD and a candidate gene for epileptic encephalopathy. We also report a distinct clinical presentation of IS, microcephaly, intellectual disability, and absent hallux in a case with the 2q23.1 deletion.ConclusionOur findings strongly support the role of CNVs in infantile spasms and expand the clinical spectrum associate with 2q23.1 deletion. In particular, our study implicates the HNRNPU and MBD5 genes in Chinese children with IS. Our study also supports that the molecular mechanisms of infantile spasms appear conserved among different ethnic backgrounds.

show abstract

Section: Discussionmentioning

confidence: 99%

A genomic copy number variant analysis implicates the MBD5 and HNRNPUgenes in Chinese children with infantile spasms and expands the clinical spectrum of 2q23.1 deletion

et al. 2014

BMC Med Genet

View full text Add to dashboard Cite

show abstract

“…This genomic mechanism is not necessarily limited to these disorders. Recently, losses of cis -regulatory elements, imbalance in coding and noncoding elements, illegitimate adoption of enhancer sequences and the like, resulting from CNVs have been proposed as a general mechanism of 'genomic' disease [Klopocki and Mundlos, 2011;Lettice et al, 2011;Poot and Kas, 2013;Spielmann and Klopocki, 2013;Gordon et al, 2014;Ibn-Salem et al, 2014;Lupiáñez et al, 2015]. CNVs may also cause 'side effects', i.e.…”

Section: Mechanisms Based On Disruption Of the Genomic Architecturementioning

confidence: 99%

Mechanisms of Origin, Phenotypic Effects and Diagnostic Implications of Complex Chromosome Rearrangements

Poot

Haaf

2015

Mol Syndromol

Self Cite

View full text Add to dashboard Cite

Complex chromosome rearrangements (CCRs) are currently defined as structural genome variations that involve more than 2 chromosome breaks and result in exchanges of chromosomal segments. They are thought to be extremely rare, but their detection rate is rising because of improvements in molecular cytogenetic technology. Their population frequency is also underestimated, since many CCRs may not elicit a phenotypic effect. CCRs may be the result of fork stalling and template switching, microhomology-mediated break-induced repair, breakage-fusion-bridge cycles, or chromothripsis. Patients with chromosomal instability syndromes show elevated rates of CCRs due to impaired DNA double-strand break responses during meiosis. Therefore, the putative functions of the proteins encoded by ATM, BLM, WRN, ATR, MRE11, NBS1, and RAD51 in preventing CCRs are discussed. CCRs may exert a pathogenic effect by either (1) gene dosage-dependent mechanisms, e.g. haploinsufficiency, (2) mechanisms based on disruption of the genomic architecture, such that genes, parts of genes or regulatory elements are truncated, fused or relocated and thus their interactions disturbed - these mechanisms will predominantly affect gene expression - or (3) mixed mutation mechanisms in which a CCR on one chromosome is combined with a different type of mutation on the other chromosome. Such inferred mechanisms of pathogenicity need corroboration by mRNA sequencing. Also, future studies with in vitro models, such as inducible pluripotent stem cells from patients with CCRs, and transgenic model organisms should substantiate current inferences regarding putative pathogenic effects of CCRs. The ramifications of the growing body of information on CCRs for clinical and experimental genetics and future treatment modalities are briefly illustrated with 2 cases, one of which suggests KDM4C(JMJD2C) as a novel candidate gene for mental retardation.

show abstract

“…in patients with losses in region 1q44 [Boland et al, 2007;van Bon et al, 2008;Caliebe et al, 2010]. By taking a converse approach, an individual gene or part of a gene can be linked to specific phenotypes in a series of patients with different, but overlapping losses and diverging combinations of phenotypes [Poot and Kas, 2013]. This approach has allowed to successively pinpoint HNRNPU and HNRPU-AS1 , also known as C1orf199 or NCRN00201, as a candidate gene for seizures within region 1q44 [Ballif et al, 2012;Thierry et al, 2012].…”

Section: Molecular Effects Of Cntnap2 Disruptionsmentioning

confidence: 99%

Connecting the CNTNAP2 Networks with Neurodevelopmental Disorders

Poot¹

2015

Mol Syndromol

Self Cite

View full text Add to dashboard Cite

Based on genomic rearrangements and copy number variations, the contactin-associated protein-like 2 gene (CNTNAP2) has been implicated in neurodevelopmental disorders such as Gilles de la Tourette syndrome, intellectual disability, obsessive compulsive disorder, cortical dysplasia-focal epilepsy syndrome, autism, schizophrenia, Pitt-Hopkins syndrome, and attention deficit hyperactivity disorder. To explain the phenotypic pleiotropy of CNTNAP2 alterations, several hypotheses have been put forward. Those include gene disruption, loss of a gene copy by a heterozygous deletion, altered regulation of gene expression due to loss of transcription factor binding and DNA methylation sites, and mutations in the amino acid sequence of the encoded protein which may provoke altered interactions of the CNTNAP2-encoded protein, Caspr2, with other proteins. Also exome sequencing, which covers <0.2% of the CNTNAP2 genomic DNA, has revealed numerous single nucleotide variants in healthy individuals and in patients with neurodevelopmental disorders. In some of these disorders, disruption of CNTNAP2 may be interpreted as a susceptibility factor rather than a directly causative mutation. In addition to being associated with impaired development of language, CNTNAP2 may turn out to be a central node in the molecular networks controlling neurodevelopment. This review discusses the impact of CNTNAP2 mutations on its functioning at multiple levels of the combinatorial genetic networks that govern brain development. In addition, recommendations for genomic testing in the context of clinical genetic management of patients with neurodevelopmental disorders and their families are put forward.

show abstract

Antisense may make sense of 1q44 deletions, seizures, and HNRNPU

Cited by 12 publications

References 21 publications

A genomic copy number variant analysis implicates the MBD5 and HNRNPUgenes in Chinese children with infantile spasms and expands the clinical spectrum of 2q23.1 deletion

A genomic copy number variant analysis implicates the MBD5 and HNRNPUgenes in Chinese children with infantile spasms and expands the clinical spectrum of 2q23.1 deletion

Mechanisms of Origin, Phenotypic Effects and Diagnostic Implications of Complex Chromosome Rearrangements

Connecting the CNTNAP2 Networks with Neurodevelopmental Disorders

Contact Info

Product

Resources

About