Clinical and molecular characterization of a patient with interstitial 6q21q22.1 deletion

Tassano, Elisa; Mirabelli-Badenier, Marisol; Veneselli, Edvige; Puliti, Aldamaria; Lerone, Margherita; Vaccari, Carlotta Maria; Morana, Giovanni; Porta, Simona; Gimelli, Giorgio; Cuoco, Cristina

doi:10.1186/s13039-015-0134-7

Cited by 16 publications

(18 citation statements)

References 23 publications

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“…2). Moreover, Tassano et al have described a patient with a 4,7 Mb deletion on 6q without CHD (Tassano et al 2015). Therefore, we can further narrow the CHD-ACFS critical region to include only 108 075 953 to 111 091 086 (Rosenfeld et al 2012) (Fig.…”

Section: Discussionmentioning

confidence: 99%

Insights into 6q21‐q22: Refinement of the critical region for acro‐cardio‐facial syndrome

Milani

Cagnoli

Baccarin

et al. 2016

Congenital Anomalies

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Section: Discussionmentioning

confidence: 99%

Insights into 6q21‐q22: Refinement of the critical region for acro‐cardio‐facial syndrome

Milani

Cagnoli

Baccarin

et al. 2016

Congenital Anomalies

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“…Clinical data from 120 sporadic PS patients, 115 new and 5 already reported [1, 8, 9] were collected and their clinical features summarised in Table 1. Rarely, PS patients can show associated anomalies involving other structures/organs [20].…”

Section: Resultsmentioning

confidence: 99%

“…Two recently reported cases of de novo deletions contribute to support the genetic origin of PS and suggests the involvement of the deleted regions in PS pathogenesis. A deletion of chromosome 11q12.3 in monozygotic twins both affected by PS [8] and a large deletion of chromosome 6q21-q22.1 in a patient with a complex phenotype mainly characterized by mental disability and PS [9]. Genomic imbalances and copy number variants (CNV) represent a main source of genetic variation in humans and contribute to different congenital and neurodevelopmental defects [10–14].…”

Section: Introductionmentioning

confidence: 99%

Assessment of copy number variations in 120 patients with Poland syndrome

et al. 2016

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BackgroundPoland Syndrome (PS) is a rare congenital disorder presenting with agenesis/hypoplasia of the pectoralis major muscle variably associated with thoracic and/or upper limb anomalies. Most cases are sporadic, but familial recurrence, with different inheritance patterns, has been observed. The genetic etiology of PS remains unknown. Karyotyping and array-comparative genomic hybridization (CGH) analyses can identify genomic imbalances that can clarify the genetic etiology of congenital and neurodevelopmental disorders. We previously reported a chromosome 11 deletion in twin girls with pectoralis muscle hypoplasia and skeletal anomalies, and a chromosome six deletion in a patient presenting a complex phenotype that included pectoralis muscle hypoplasia. However, the contribution of genomic imbalances to PS remains largely unknown.MethodsTo investigate the prevalence of chromosomal imbalances in PS, standard cytogenetic and array-CGH analyses were performed in 120 PS patients.ResultsFollowing the application of stringent filter criteria, 14 rare copy number variations (CNVs) were identified in 14 PS patients in different regions outside known common copy number variations: seven genomic duplications and seven genomic deletions, enclosing the two previously reported PS associated chromosomal deletions. These CNVs ranged from 0.04 to 4.71 Mb in size. Bioinformatic analysis of array-CGH data indicated gene enrichment in pathways involved in cell-cell adhesion, DNA binding and apoptosis processes. The analysis also provided a number of candidate genes possibly causing the developmental defects observed in PS patients, among others REV3L, a gene coding for an error-prone DNA polymerase previously associated with Möbius Syndrome with variable phenotypes including pectoralis muscle agenesis.ConclusionsA number of rare CNVs were identified in PS patients, and these involve genes that represent candidates for further evaluation. Rare inherited CNVs may contribute to, or represent risk factors of PS in a multifactorial mode of inheritance.Electronic supplementary materialThe online version of this article (doi:10.1186/s12881-016-0351-x) contains supplementary material, which is available to authorized users.

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“…Confirming the data previously shown and described above, GO-term analysis (PANTHER Over-representation Test, Figure 8A) shows that Tcf4 is involved in the regulation of (neuronal) differentiation, cell signaling, synaptic plasticity, and development of the telencephalon and hippocampus. Further analysis of the genes regulated by Tcf4 shows that 26 of the 137 genes regulated by Tcf4 (19%) have previously been shown to be mutated in cases of ID (Figure 8B) (Alders et al, 2014;Backx et al, 2010;Brockschmidt et al, 2007;Cocchella et al, 2010;Ehmke et al, 2017;Gerber et al, 2016;Gillentine et al, 2017;Guo et al, 2016;Labonne et al, 2016;Magoulas and El-Hattab, 2012;Merla et al, 2002;Metsu et al, 2014;Mikhail et al, 2011;Montesinos, 2014;Moore et al, 2016;Mulatinho et al, 2012;Myers et al, 2012;Nesbitt et al, 2015;Poot et al, 2010;Schoonjans et al, 2016;Schuurs-Hoeijmakers et al, 2013;Srivatsa et al, 2014;Tassano et al, 2015;Thevenon et al, 2014;Ţuţulan-Cunită et al, 2012). Characteristics of these cases range from moderate to severe ID, autistic phenotypes, brain malformations, speech impairments, and epilepsy.…”

Section: Tcf4 Acts As a Transcriptional Activator During Cortical Devmentioning

confidence: 97%

Tcf4 encodescortical differentiation during development

Mesman

Bakker

Smidt

2018

Preprint

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Tcf4 has been linked to autism, schizophrenia, and Pitt-Hopkins Syndrome (PTHS) in humans, however, the mechanisms behind its role in disease development is still elusive. In the present study, we provide evidence that Tcf4 has a critical function in the differentiation of cortical regions during development.We show that Tcf4 is present throughout the developing brain at the peak of neurogenesis. Deletion of Tcf4 results in mis-specification of the cortical layers, malformation of the corpus callosum and hypoplasia of the hippocampus. RNA-sequencing on E14.5 cortex material shows that Tcf4 functions as a transcriptional activator and loss of Tcf4 results in downregulation of genes linked to the emergence of other neurodevelopmental disorders. Taken together, we show that neurogenesis and differentiation are severely affected in Tcf4 mutants, phenocopying morphological brain defects detected in PTHS patients. The presented data identifies new leads to understand the mechanism of human brain defects and will assist in genetic counseling programs.show aberrant co-localization with SATB2. Besides these differentiation defects, the corpus callosum and both hippocampi are severely underdeveloped in these mutants. Transcriptome analyzes through RNA-sequencing on E14.5 cortical material indicate that Tcf4 is an activator of gene expression in the developing cortex and is activates genes that are linked to neurogenesis and neuronal maturation. Importantly, Tcf4 regulates genes that are known for their involvement in clinical syndromes related to PTHS and ID. Finally, the observed brain malformations phenocopy clinical features observed in PTHS patients, further establishing this mouse mutant as an excellent model for this human developmental disorder, providing mechanistic insight to the syndrome and assist in the identification of novel factors for genetic screening and genetic counseling for human patients with neurodevelopmental disorders.

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Clinical and molecular characterization of a patient with interstitial 6q21q22.1 deletion

Cited by 16 publications

References 23 publications

Insights into 6q21‐q22: Refinement of the critical region for acro‐cardio‐facial syndrome

Insights into 6q21‐q22: Refinement of the critical region for acro‐cardio‐facial syndrome

Assessment of copy number variations in 120 patients with Poland syndrome

Tcf4 encodescortical differentiation during development

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