Identifying candidate genes for 2p15p16.1 microdeletion syndrome using clinical, genomic, and functional analysis

Bagheri, Hani; Badduke, Chansonette; Qiao, Ying; Colnaghi, Rita; I, Abramowicz; Alcantara, Diana; Dunham, Christopher; Wen, Jiadi; Wildin, Robert S.; Nowaczyk, Małgorzata J.M.; Eichmeyer, Jennifer N.; Lehman, Anna; Maranda, Bruno; Martell, Sally; Shan, Xianghong; Lewis, Suzanne M.; O’Driscoll, Mark; Gregory‐Evans, Cheryl Y.; Rajcan‐Separovic, Evica

doi:10.1172/jci.insight.85461

Cited by 25 publications

(34 citation statements)

References 65 publications

(89 reference statements)

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“…Repeated brain MRI at 1.5 and 3 Tesla failed to demonstrate any CNS structural anomaly, similar to patients with missense and LoF mutations of BCL11A (Dias et al, 2016), but dissimilar to patients with the 2p15‐p16.1 microdeletion syndrome, for which at least three genes have been shown to participate to the brain malformation phenotype in zebrafish models (Bagheri et al, 2016). Our patient did not meet the diagnostic criteria of ASD, concordant with the low frequency of ASD in the 11 reported patients (Dias et al, 2016).…”

Section: Discussionmentioning

confidence: 87%

BCL11A frameshift mutation associated with dyspraxia and hypotonia affecting the fine, gross, oral, and speech motor systems

Soblet

Dimov

Kalckreuth

et al. 2017

American J of Med Genetics Pt A

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We report the case of a 7‐year‐old male of Western European origin presenting with moderate intellectual disability, severe childhood apraxia of speech in the presence of oral and manual dyspraxia, and hypotonia across motor systems including the oral and speech motor systems. Exome sequencing revealed a de novo frameshift protein truncating mutation in the fourth exon of BCL11A, a gene recently demonstrated as being involved in cognition and language development. Making parallels with a previously described patient with a 200 kb 2p15p16.1 deletion encompassing the entire BCL11A gene and displaying a similar phenotype, we characterize in depth how BCL11A is involved in clinical aspects of language development and oral praxis.

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Section: Discussionmentioning

confidence: 87%

BCL11A frameshift mutation associated with dyspraxia and hypotonia affecting the fine, gross, oral, and speech motor systems

Soblet

Dimov

Kalckreuth

et al. 2017

American J of Med Genetics Pt A

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“…; Bagheri et al. ). In this study, our two patients (Patients 1 and 2) exhibiting deletion at the 2p15p16.1 region and Patient 4 exhibiting deletion at the 2p16.1 region, involving BCL11A , PAPOLG , and REL had similar MRI findings, which showed proportional hypoplasia/atrophy of the cerebellar hemispheres along with vermis and hypoplastic pons in all three cases as well as intact corpus callosum in two cases (Fig.…”

Section: Discussionmentioning

confidence: 98%

“…; Bagheri et al. ). REL is also candidate gene related to not only structural brain abnormalities but also abnormal growth and dysmorphism (Bagheri et al.…”

Section: Discussionmentioning

confidence: 98%

“…REL is also candidate gene related to not only structural brain abnormalities but also abnormal growth and dysmorphism (Bagheri et al. ). However, patients with microdeletion including only REL or intragenic mutation in REL have not been reported in the literature.…”

Section: Discussionmentioning

confidence: 99%

“…A recent functional study by Bagheri et al. () suggested that BCL11A (MIM 606557), REL (MIM 164910), and XPO1 (MIM 602559) represented candidate genes for structural brain abnormalities in 2p15p16.1 microdeletion syndrome. One of these genes, Kruppel‐like transcription factor BCL11A (B cell CLL/lymphoma 11A, also known as CTIP1 ) associated with the BRG1/BRM‐associated factor (BAF) chromatin remodeling complex has been identified to be critical for neural development (Lessard et al.…”

Section: Introductionmentioning

confidence: 99%

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Haploinsufficiency of BCL11A associated with cerebellar abnormalities in 2p15p16.1 deletion syndrome

Shimbo

Yokoi

Aida

et al. 2017

Molec Gen & Gen Med

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BackgroundChromosome 2p15p16.1 deletion syndrome is a rare genetic disorder characterized by intellectual disability (ID), neurodevelopmental delay, language delay, growth retardation, microcephaly, structural brain abnormalities, and dysmorphic features. More than 30 patients with 2p15p16.1 microdeletion syndrome have been reported in the literature.MethodsMolecular analysis was performed using microarray‐based comparative genomic hybridization (array CGH). Clinical characteristics and brain magnetic resonance imaging features of these patients were also reviewed.ResultsWe identified four patients with ID, neurodevelopmental delay, brain malformations, and dysmorphic features; two patients with 2p15p16.1 deletions (3.24 Mb, 5.04 Mb), one patient with 2p16.1 deletion (1.12 Mb), and one patient with 2p14p16.1 deletion (5.12 Mb). Three patients with 2p15p16.1 deletions or 2p16.1 deletions encompassing BCL11A,PAPOLG, and REL showed hypoplasia of the pons and cerebellum. The patient with 2p14p16.1 deletion, which did not include three genes showed normal size and shape of the cerebellar hemispheres and pons.ConclusionThe zinc finger transcription factor BCL11A associated with the BAF chromatin remodeling complex has been identified to be critical for neural development and BCL11A haploinsufficiency is closely related to cerebellar abnormalities.

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Molecular and clinical delineation of 2p15p16.1 microdeletion syndrome

Lévy

Coussement

Dupont

et al. 2017

American J of Med Genetics Pt A

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Interstitial 2p15p16.1 microdeletion is a rare chromosomal syndrome previously reported in 33 patients. It is characterized by intellectual disability, developmental delay, autism spectrum disorders, microcephaly, short stature, dysmorphic features, and multiple congenital organ defects. It is defined as a contiguous gene syndrome and two critical regions have been proposed at 2p15 and 2p16.1 loci. Nevertheless, patients with deletion of both critical regions shared similar features of the phenotype and the correlation genotype-phenotype is still unclear. We review all published cases and describe three additional patients, to define the phenotype-genotype correlation more precisely. We reported on two patients including the first prenatal case described so far, carrying a 2p15 deletion affecting two genes: XPO1 and part of USP34. Both patients shared similar features including facial dysmorphism and cerebral abnormalities. We considered the genes involved in the deleted segment to further understand the abnormal phenotype. The third case we described here was a 4-year-old boy with a heterozygous de novo 427 kb deletion encompassing BCL11A and PAPOLG at 2p16.1. He displayed speech delay, autistic traits, and motor stereotypies associated with brain structure abnormalities. We discuss the contribution of the genes included in the deletion to the abnormal phenotype. Our three new patients compared to previous cases, highlighted that despite two critical regions, both distal deletion at 2p16.1 and proximal deletion at 2p15 are associated with phenotypes that are very close to each other. Finally, we also discuss the genetic counseling of this microdeletion syndrome particularly in the course of prenatal diagnosis.

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Identifying candidate genes for 2p15p16.1 microdeletion syndrome using clinical, genomic, and functional analysis

Cited by 25 publications

References 65 publications

BCL11A frameshift mutation associated with dyspraxia and hypotonia affecting the fine, gross, oral, and speech motor systems

BCL11A frameshift mutation associated with dyspraxia and hypotonia affecting the fine, gross, oral, and speech motor systems

Haploinsufficiency of BCL11A associated with cerebellar abnormalities in 2p15p16.1 deletion syndrome

Molecular and clinical delineation of 2p15p16.1 microdeletion syndrome

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