Tbx1, a gene encoded in 22q11.2 copy number variant, is a link between alterations in fimbria myelination and cognitive speed in mice

Copy number variants (CNVs) have provided a reliable entry point to identify the structural correlates of atypical cognitive development. Hemizygous deletion of human chromosome 22q11.2 is associated with impaired cognitive function; however, the mechanisms by which the CNVs contribute to cognitive deficits via diverse structural alterations in the brain remain unclear. This study aimed to determine the cellular basis of the link between alterations in brain structure and cognitive functions in mice with a heterozygous deletion of Tbx1, one of the 22q11.2-encoded genes. Ex vivo whole-brain diffusion-tensor imaging (DTI)–magnetic resonance imaging (MRI) in Tbx1 heterozygous mice indicated that the fimbria was the only region with significant myelin alteration. Electron microscopic and histological analyses showed that Tbx1 heterozygous mice exhibited an apparent absence of large myelinated axons and thicker myelin in medium axons in the fimbria, resulting in an overall decrease in myelin. The fimbria of Tbx1 heterozygous mice showed reduced mRNA levels of Ng2, a gene required to produce oligodendrocyte precursor cells. Moreover, postnatal progenitor cells derived from the subventricular zone, a source of oligodendrocytes in the fimbria, produced fewer oligodendrocytes in vitro. Behavioral analyses of these mice showed selectively slower acquisition of spatial memory and cognitive flexibility with no effects on their accuracy or sensory or motor capacities. Our findings provide a genetic and cellular basis for the compromised cognitive speed in patients with 22q11.2 hemizygous deletion.

Autism Spectrum Disorders: Analysis of Mobile Elements at 7q11.23 Williams–Beuren Region by Comparative Genomics

Autism spectrum disorders (ASD) are a group of complex neurodevelopmental disorders, characterized by a deficit in social interaction and communication. Many genetic variants are associated with ASD, including duplication of 7q11.23 encompassing 26–28 genes. Symmetrically, the hemizygous deletion of 7q11.23 causes Williams–Beuren syndrome (WBS), a multisystem disorder characterized by “hyper-sociability” and communication skills. Interestingly, deletion of four non-exonic mobile elements (MEs) in the “canine WBS locus” were associated with the behavioral divergence between the wolf and the dog and dog sociability and domestication. We hypothesized that indel of these MEs could be involved in ASD, associated with its different phenotypes and useful as biomarkers for patient stratification and therapeutic design. Since these MEs are non-exonic they have never been discovered before. We searched the corresponding MEs and loci in humans by comparative genomics. Interestingly, they mapped on different but ASD related genes. The loci in individuals with phenotypically different autism and neurotypical controls were amplified by PCR. A sub-set of each amplicon was sequenced by Sanger. No variant resulted associated with ASD and neither specific phenotypes were found but novel small-scale insertions and SNPs were discovered. Since MEs are hyper-methylated and epigenetically modulate gene expression, further investigation in ASD is necessary.

Computational identification of variables in neonatal vocalizations predictive for postpubertal social behaviors in a mouse model of 16p11.2 deletion

Autism spectrum disorder (ASD) is often signaled by atypical cries during infancy. Copy number variants (CNVs) provide genetically identifiable cases of ASD, but how early atypical cries predict a later onset of ASD among CNV carriers is not understood in humans. Genetic mouse models of CNVs have provided a reliable tool to experimentally isolate the impact of CNVs and identify early predictors for later abnormalities in behaviors relevant to ASD. However, many technical issues have confounded the phenotypic characterization of such mouse models, including systematically biased genetic backgrounds and weak or absent behavioral phenotypes. To address these issues, we developed a coisogenic mouse model of human proximal 16p11.2 hemizygous deletion and applied computational approaches to identify hidden variables within neonatal vocalizations that have predictive power for postpubertal dimensions relevant to ASD. After variables of neonatal vocalizations were selected by least absolute shrinkage and selection operator (Lasso), random forest, and Markov model, regression models were constructed to predict postpubertal dimensions relevant to ASD. While the average scores of many standard behavioral assays designed to model dimensions did not differentiate a model of 16p11.2 hemizygous deletion and wild-type littermates, specific call types and call sequences of neonatal vocalizations predicted individual variability of postpubertal reciprocal social interaction and olfactory responses to a social cue in a genotype-specific manner. Deep-phenotyping and computational analyses identified hidden variables within neonatal social communication that are predictive of postpubertal behaviors.

Tbx1, a 22q11.2-encoded gene, is a link between alterations in fimbria myelination and cognitive speed in mice

Copy number variants (CNVs) have provided a reliable entry point to identify structural correlates of atypical cognitive development. Hemizygous deletion of human chromosome 22q11.2 is associated with impaired cognitive function; however, the mechanisms by which numerous genes encoded in this CNV contribute to cognitive deficits via diverse structural alterations in the brain remain unclear. This study aimed to determine the cellular basis of the link between alterations in brain structure and cognitive functions in a mouse model. The heterozygosity of Tbx1, a 22q11.2 gene, altered the composition of myelinated axons in the fimbria, reduced oligodendrocyte production capacity, and slowed the acquisition of spatial memory and cognitive flexibility. Our findings provide a cellular basis for specific cognitive dysfunctions that occur in patients with loss-of-function TBX1 variants and 22q11.2 hemizygous deletion.

Atypical Deletion of Williams-beuren Syndrome Reveals the Mechanism of Neurodevelopmental Disorders

Background The Williams-Beuren syndrome (WBS) is a multiple phylogenetic disorder, caused by the hemizygous deletion of 1.55 to 1.84 Mb on chromosome 7q11.23, which encodes a fragment of 26 to 28 genes. Among these genes, the deletion of the elastin (ELN) gene haplotype is the main cause of cardiovascular abnormalities. Other genes, such as CLIP2, GTF2IRD1, and GTF2I, may be associated with specific cognitive and craniofacial features. However, genes associated with specific neurocognitive phenotypes are still controversially discussed. The purpose of this study is to further explore the mechanism of neurodevelopmental disorders in patients with Williams-Beuren syndrome.Patients and methods Patients who had been diagnosed with WBS were recruited. The deletion was precisely defined by chromosome microarray analysis and the clinical phenotype was evaluated. Results This study identified nine patients with atypical deletions from 111 patients with WBS. One patient had normal neurodevelopmental with deletion of Williams-Beuren syndrome chromosomal region (WBSCR) telomere side genes, including GTF2I and GTF2IRD1, while another patient retained these genes but showed neurodevelopmental abnormalities. Seven of the eight patients with the WBSCR22 gene deletion developed growth restriction.Conclusions By comparing the genotype and phenotype of patients with typical deletions and atypical deletions, the deletion of GTF2I and GTF2IRD1 genes alone insufficient to induce typical neurocognitive phenotypes in WBS patients. The BAZ1B, FZD9, and STX1A genes may play an important role in the neurodevelopment of patients with WBS. Furthermore, the deletion of the WBSCR22 gene may be the main cause of physical growth restriction in WBS patients.

Atypical Deletion of Williams-Beuren Syndrome Reveals the Mechanism of Neurodevelopmental Disorders

Background The Williams-Beuren syndrome (WBS) is a multiple phylogenetic disorder, caused by the hemizygous deletion of 1.55 to 1.84 Mb on chromosome 7q11.23, which encodes a fragment of 26 to 28 genes. Among these genes, the deletion of the elastin (ELN) gene haplotype is the main cause of cardiovascular abnormalities. Other genes, such as CLIP2, GTF2IRD1, and GTF2I, may be associated with specific cognitive and craniofacial features. However, genes associated with specific neurocognitive phenotypes are still controversially discussed. The purpose of this study is to further explore the mechanism of neurodevelopmental disorders in patients with Williams-Beuren syndrome.Patients and methods Patients who had been diagnosed with WBS were recruited. The deletion was precisely defined by chromosome microarray analysis and the clinical phenotype was evaluated. Results This study identified nine patients with atypical deletions from 111 patients with WBS. One patient had normal neurodevelopmental with deletion of Williams-Beuren syndrome chromosomal region (WBSCR) telomere side genes, including GTF2I and GTF2IRD1, while another patient retained these genes but showed neurodevelopmental abnormalities. Seven of the eight patients with the WBSCR22 gene deletion developed growth restriction.Conclusions By comparing the genotype and phenotype of patients with typical deletions and atypical deletions, the deletion of GTF2I and GTF2IRD1 genes alone insufficient to induce typical neurocognitive phenotypes in WBS patients. The BAZ1B, FZD9, and STX1A genes may play an important role in the neurodevelopment of patients with WBS. Furthermore, the deletion of the WBSCR22 gene may be the main cause of physical growth restriction in WBS patients.

Clinical impact of hemizygous deletion detection and panel-size in comprehensive genomic profiling.

e15671 Background: Comprehensive genomic profiling (CGP) identified single nucleotide variants (SNVs), copy number alteration (CNA), indels, and rearrangements in cancer-related genes. Only limited CGP detects hemizygous deletion. Also panel size differs among CGPs. Clinical impact of hemizygous deletion and panel-size are not well characterized. Methods: Formalin-fixed paraffin-embedded tissues from 10 cancer patients were analyzed by two CGPs: 1) test A (ACT Onc+) that interrogates SNVs, indels, rearrangement, and CNA including amplification, hemizygous and homozygous deletions in 440 genes, 2) test B that interrogates SNV, indels, rearrangement and CNA including amplification and homozygous deletion in 114 genes, but hemizygous deletion only in limited genes. Result was discussed in molecular tumor board and actionable genes and candidate drug were determined. Primary objective was the number of actionable genomic alterations. Secondary objectives are the number of candidate drugs, SNVs, CAN, and rearrangement. When there was difference of results in two tests, other validation test, such as PCR-based copy number evaluation, was performed. The difference of two tests was statistically evaluated using student t-test. Results: Median age of patients was 56 (range 48 – 70), and 50% were male. Tumor types were neuroendocrine tumor (60%), ovarian cancer (30%) and pancreatic cancer (10%). In 10 patients, actionable genes were found as follows: 39 in test A and 9 in test B (P = 0.0056). Total 64 genomic alterations were found in test A compared 12 in test B. SNV was not statistically different among two tests (10 in test A, 6 in test B; P = 0.269). However, the number of CNA was different: 54 in test A and 6 in test B (P = 0.007). Among CNA, hemizygous alteration explained majority of the difference (30 in test A and 1 in test B, P = 0.059), followed by amplification (24 in test A and 5 in test B, P = 0.201). The number of drug candidates was 38 in test A and 11 in test B (P = 0.014). Conclusions: Detection of hemizygous deletion and larger panel size resulted in more actionable genes and drug candidates, which might impact clinical practice. Future study of clinical utility of hemizygous deletion and panel size is warranted.