A de novo non-sense mutation in ZBTB18 in a patient with features of the 1q43q44 microdeletion syndrome

Munnik, Sonja A de; García‐Miñaúr, Sixto; Hoischen, Alexander; Bon, Bregje W.M. van; Boycott, Kym M.; Schoots, Jeroen; Hoefsloot, Lies H.; Knoers, Nine V A M; Bongers, Ernie M.H.F.; Brunner, Han G.

doi:10.1038/ejhg.2013.249

Cited by 47 publications

(39 citation statements)

References 21 publications

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“…In support for the neuronal functions for AKT3 and ZNF238, studies in mice have demonstrated their critical roles in neurogenesis, neuronal migration, and the formation of the brain [Okado et al, 2009;Poduri et al, 2012;Ohtaka-Maruyama et al, 2013;Heng et al, 2015]. Also, whole exome sequencing studies have revealed that abnormalities in brain growth are associated with point mutations to AKT3 [Lee et al, 2012;Riviere et al, 2012] and ZNF238 [Rauch et al, 2012;de Munnik et al, 2014]. In the case of SDCCAG8, recent functional studies with mice demonstrated that SDCCAG8 regulates neuronal migration during fetal brain development [Insolera et al, 2014] while CEP170 is a component of the microtubule cytoskeleton which influences protein complex formation at the mitotic spindle of dividing cells [Welburn and Cheeseman, 2012], and these functions may be relevant to the production of new neurons from local neuroprogenitors within the fetal cerebral cortex.…”

Section: Reinforcing the Association Between 1q43-q44mentioning

confidence: 97%

Reinforcing the association between distal 1q CNVs and structural brain disorder: A case of a complex 1q43‐q44 CNV and a review of the literature

Hemming

Forrest

Shipman

et al. 2016

American J of Med Genetics Pt B

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Copy Number Variations (CNVs) comprising the distal 1q region 1q43-q44 are associated with neurological impairments, structural brain disorder, and intellectual disability. Here, we report an extremely rare, de novo case of a 1q43-q44 deletion with an adjacent duplication, associated with severe seizures, microcephaly, agenesis of the corpus callosum, and pachygyria, a consequence of defective neuronal migration disorder. We conducted a literature survey to find that our patient is only the second case of such a 1q43-q44 CNV ever to be described. Our data support an association between 1q43-q44 deletions and microcephaly, as well as an association between 1q43-q44 duplications and macrocephaly. We compare and contrast our findings with previous studies reporting on critical 1q43-q44 regions and their constituent genes associated with seizures, microcephaly, and corpus callosum abnormalities [Ballif et al., 2012; Hum Genet 131:145-156; Nagamani et al., 2012; Eur J Hum Genet 20:176-179]. Taken together, our study reinforces the association between 1q43-q44 CNVs and brain disorder.

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Section: Reinforcing the Association Between 1q43-q44mentioning

confidence: 97%

Reinforcing the association between distal 1q CNVs and structural brain disorder: A case of a complex 1q43‐q44 CNV and a review of the literature

Hemming

Forrest

Shipman

et al. 2016

American J of Med Genetics Pt B

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“…Molecular analysis of the region involved in the present paracentric inversion (http://www.ncbi.nlm.nih.gov) showed that 11 of the 316 genes known in the inverted region as well as 4 genes of the 210 located in proximal regions (1q42.11-1q42.12 and 1q44) are associated with intellectual disability or with the central nervous system ( table 1 ). To data, at least 30 patients with chromosome deletions of 1q42q44 with mental retardation of variable severity, autism, neuropsychiatric disorders, microcephaly, and corpus callosum anomalies have been reported [Hill et al, 2007;Williams et al, 2009;Filges et al, 2010;Ballif et al, 2011;Dutta et al, 2011;Perrone et al, 2012;Nagamani et al, 2012;Petersen et al, 2013;Au et al, 2014;Poretti et al, 2014;Delabio et al, 2014;de Munnik et al, 2014;Gai et al, 2015]. These authors proposed some genes as excellent candidates because of their role in the developing central nervous system (DISC2, MTR, FMN2, and CHRM3) or their expression in brain tissue (FBXO28,LEFTY1,LEFTY2,PSEN2,DISC1,TSNAX,B3GALNT2,AKT3,RPS7P5,SDCCAG8,and ZBTB18) .…”

Section: Discussionmentioning

confidence: 99%

A 11.7-Mb Paracentric Inversion in Chromosome 1q Detected in Prenatal Diagnosis Associated with Familial Intellectual Disability

Rigola

Baena

Català

et al. 2015

Cytogenet Genome Res

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Most apparent balanced chromosomal inversions are usually clinically asymptomatic; however, infertility, miscarriages, and mental retardation have been reported in inversion carriers. We present a small family with a paracentric inversion 1q42.13q43 detected in routine prenatal diagnosis. Molecular cytogenetic methods defined the size of the inversion as 11.7 Mb and excluded other unbalanced chromosomal alterations in the patients. Our findings suggest that intellectual disability is caused by dysfunction, disruption, or position effects of genes located at or near the breakpoints involved in this inversion.

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“…In humans, genetic mutations in ZBTB18 are associated with structural brain abnormalities, neuronal migration disorder and intellectual disability (Cohen et al, ; de Munnik et al, ; Deciphering Developmental Disorders, ; Depienne et al, ; Hemming et al, ; van der Schoot et al, ). More than half of all pathogenic variants identified in ZBTB18 are predicted to be truncating, suggesting that haploinsufficiency/loss‐of‐function represents a general pathological mechanism for disease (Depienne et al, ).…”

Section: Introductionmentioning

confidence: 99%

Disease‐associated missense variants in ZBTB18 disrupt DNA binding and impair the development of neurons within the embryonic cerebral cortex

et al. 2019

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The activities of DNA‐binding transcription factors, such as the multi‐zinc‐finger protein ZBTB18 (also known as RP58, or ZNF238), are essential to coordinate mammalian neurodevelopment, including the birth and radial migration of newborn neurons within the fetal brain. In humans, the majority of disease‐associated missense mutations in ZBTB18 lie within the DNA‐binding zinc‐finger domain and are associated with brain developmental disorder, yet the molecular mechanisms explaining their role in disease remain unclear. To address this, we developed in silico models of ZBTB18, bound to DNA, and discovered that half of the missense variants map to residues (Asn461, Arg464, Glu486) predicted to be essential to sequence‐specific DNA contact, whereas others map to residues (Leu434, Tyr447, Arg495) with limited contributions to DNA binding. We studied pathogenic variants to residues with close (N461S) and limited (R495G) DNA contact and found that each bound DNA promiscuously, displayed altered transcriptional regulatory activity in vitro, and influenced the radial migration of newborn neurons in vivo in different ways. Taken together, our results suggest that altered transcriptional regulation could represent an important pathological mechanism for ZBTB18 missense variants in brain developmental disease.

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A de novo non-sense mutation in ZBTB18 in a patient with features of the 1q43q44 microdeletion syndrome

Cited by 47 publications

References 21 publications

Reinforcing the association between distal 1q CNVs and structural brain disorder: A case of a complex 1q43‐q44 CNV and a review of the literature

Reinforcing the association between distal 1q CNVs and structural brain disorder: A case of a complex 1q43‐q44 CNV and a review of the literature

A 11.7-Mb Paracentric Inversion in Chromosome 1q Detected in Prenatal Diagnosis Associated with Familial Intellectual Disability

Disease‐associated missense variants in ZBTB18 disrupt DNA binding and impair the development of neurons within the embryonic cerebral cortex

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