Fig 4 - available from: Molecular Cytogenetics
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Fluorescence-in-situ-hybridization (FISH) on metaphase spreads of the patient and his parents' chromosomes 6. We used the locus-specific Bluegnome probes RP11-758C21 for 6q16.2 (green), targeting deletion Nr 1, and RP11-487 F5 for 6q16.3 (red), targeting deletion nr.2, and the Abbott centromere specific probe cep 6 (aqua) for control. a Patient, b Patient's father, c Patient's mother: Both loci are present in correct orientation in the parent's FISH analysis and proved a de novo origin of the deletions in the patient. Deletions in the patient are in cis position
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Background
Copy number variations play a significant role in the aetiology of developmental disabilities including non-syndromic intellectual disability and autism. Case presentationWe describe a 19-year old patient with intellectual disability and autism for whom chromosomal microarray (CMA) analysis showed the unusual finding of two de novo micro...
Context in source publication
Context 1
... and his parents. The deletions were confirmed to be in cis-position in the patient. FISH analysis of the parents showed both loci to be present in correct pos- ition and orientation which proved a de novo origin of the deletions in the patient. There was no evidence for a complex structural rearrangement in the parents. FISH results are shown in Fig. ...
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Citations
... Among the 5 significant genes after a stringent Bonferroni correction for all genes and all tissues in the analysis (Figs 3 and S20), POU3F2 (also known as BRN2) is primarily expressed in [25]. It encodes a transcription factor with important roles in neurogenesis and brain development [26,27]. ...
Recent advances in consortium-scale genome-wide association studies (GWAS) have highlighted the involvement of common genetic variants in autism spectrum disorder (ASD), but our understanding of their etiologic roles, especially the interplay with rare variants, is incomplete. In this work, we introduce an analytical framework to quantify the transmission disequilibrium of genetically regulated gene expression from parents to offspring. We applied this framework to conduct a transcriptome-wide association study (TWAS) on 7,805 ASD proband-parent trios, and replicated our findings using 35,740 independent samples. We identified 31 associations at the transcriptome-wide significance level. In particular, we identified POU3F2 (p = 2.1E-7), a transcription factor mainly expressed in developmental brain. Gene targets regulated by POU3F2 showed a 2.7-fold enrichment for known ASD genes (p = 2.0E-5) and a 2.7-fold enrichment for loss-of-function de novo mutations in ASD probands (p = 7.1E-5). These results provide a novel connection between rare and common variants, whereby ASD genes affected by very rare mutations are regulated by an unlinked transcription factor affected by common genetic variations.
... PRDM13 is required to generate the precise number of GABA (gamma-aminobutyric acid) associated neurons (i.e., GABAegic neurons) 21 . There is a report that a microdeletion of PRDM13 locus has been implicated in autism and intellectual disability in human 22 . The QTL www.nature.com/scientificreports/ ...
In livestock social interactions, social genetic effects (SGE) represent associations between phenotype of one individual and genotype of another. Such associations occur when the trait of interest is affected by transmissible phenotypes of social partners. The aim of this study was to estimate SGE and direct genetic effects (DGE, genetic effects of an individual on its own phenotype) on average daily gain (ADG) in Landrace pigs, and to conduct single-step genome-wide association study using SGE and DGE as dependent variables to identify quantitative trait loci (QTLs) and their positional candidate genes. A total of 1,041 Landrace pigs were genotyped using the Porcine SNP 60K BeadChip. Estimates of the two effects were obtained using an extended animal model. The SGE contributed 16% of the total heritable variation of ADG. The total heritability estimated by the extended animal model including both SGE and DGE was 0.52. The single-step genome-wide association study identified a total of 23 QTL windows for the SGE on ADG distributed across three chromosomes (i.e., SSC1, SSC2, and SSC6). Positional candidate genes within these QTL regions included PRDM13, MAP3K7, CNR1, HTR1E, IL4, IL5, IL13, KIF3A, EFHD2, SLC38A7, mTOR, CNOT1, PLCB2, GABRR1, and GABRR2, which have biological roles in neuropsychiatric processes. The results of biological pathway and gene network analyses also support the association of the neuropsychiatric processes with SGE on ADG in pigs. Additionally, a total of 11 QTL windows for DGE on ADG in SSC2, 3, 6, 9, 10, 12, 14, 16, and 17 were detected with positional candidate genes such as ARL15. We found a putative pleotropic QTL for both SGE and DGE on ADG on SSC6. Our results in this study provide important insights that can help facilitate a better understanding of the molecular basis of SGE for socially affected traits.
... 8,24 Recently, a chromosomal microarray (CMA) analysis describing a 19-year old patient showed two de novo microdeletions that spanned 10 genes including GRIK2. 25 Mutation screening revealed several SNPs, including one nucleotide variation changing the protein (M867I) of GRIK2, which may be functionally relevant to the development of ASD. 26 Shuang's family-based association study in Chinese Han trios demonstrated that GRIK2 rs2227281 and rs2227283 showed preferential transmission and revealed an association between the GluR6 locus and ASD. 27 However, our study suggests that the rs6922753 in GRIK2 is unlikely to confer susceptibility to ASD in the Chinese population. ...
Objective:
To evaluate the association of GRIK2 and NLGN1 with autism spectrum disorder in a Chinese population.
Methods:
We performed spatio-temporal expression analysis of GRIK2 and NLGN1 in the developing prefrontal cortex, and examined the expression of the genes in ASD cases and healthy controls using the GSE38322 data set. Following, we performed a case-control study in a Chinese population.
Results:
The analysis using the publicly available expression data showed that GRIK2 and NLGN1 may have a role in the development of human brain and contribute to the risk of ASD. Later genetic analysis in the Chinese population showed that the GRIK2 rs6922753 for the T allele, TC genotype and dominant model played a significant protective role in ASD susceptibility (respectively: OR=0.840, p=0.023; OR=0.802, p=0.038; OR=0.791, p=0.020). The NLGN1 rs9855544 for the G allele and GG genotype played a significant protective role in ASD susceptibility (respectively: OR=0.844, p=0.019; OR=0.717, p=0.022). After adjusting p values, the statistical significance was lost (p>0.05).
Conclusion:
Our results suggested that GRIK2 rs6922753 and NLGN1 rs9855544 might not confer susceptibility to ASD in the Chinese population.
... Homozygous loss-of-function GRIK2 variants have been reported in patients with moderate to severe non-syndromic autosomal recessive mental retardation [32]. In addition, two de novo, heterozygous microdeletions in cis position on chromosome 6q16.1q16.2 and 6q16.3 disrupting, among others, the PRDM13 and GRIK2 genes have been reported in a patient with intellectual disability and autism; however, the authors concluded that functional interaction between both disrupted genes most probably underlies phenotype presentation [33]. Heterozygous CNTNAP2 disruptions reported in affected individuals presenting with autism spectrum disorder [34,35] or Gilles de la Tourette syndrome and Obsessive Compulsive Disorder [36] were mostly located at the proximal part of the CNTNAP2 gene [34,36] and/or were unbalanced [36], or the rearrangements were even more complex affecting other disease-candidate genes as well [34,35]. ...
Background:
Precise characterization of apparently balanced complex chromosomal rearrangements in non-affected individuals is crucial as they may result in reproductive failure, recurrent miscarriages or affected offspring.
Case presentation:
We present a family, where the non-affected father and daughter were found, using FISH and karyotyping, to be carriers of a three-way complex chromosomal rearrangement [t(6;7;10)(q16.2;q34;q26.1), de novo in the father]. The family suffered from two stillbirths, one miscarriage, and has a son with severe intellectual disability. In the present study, the family was revisited using whole-genome mate-pair sequencing. Interestingly, whole-genome mate-pair sequencing revealed a cryptic breakpoint on derivative (der) chromosome 6 rendering the rearrangement even more complex. FISH using a chromosome (chr) 6 custom-designed probe and a chr10 control probe confirmed that the interstitial chr6 segment, created by the two chr6 breakpoints, was translocated onto der(10). Breakpoints were successfully validated with Sanger sequencing, and small imbalances as well as microhomology were identified. Finally, the complex chromosomal rearrangement breakpoints disrupted the SIM1, GRIK2, CNTNAP2, and PTPRE genes without causing any phenotype development.
Conclusions:
In contrast to the majority of maternally transmitted complex chromosomal rearrangement cases, our study investigated a rare case where a complex chromosomal rearrangement, which most probably resulted from a Type IV hexavalent during the pachytene stage of meiosis I, was stably transmitted from a fertile father to his non-affected daughter. Whole-genome mate-pair sequencing proved highly successful in identifying cryptic complexity, which consequently provided further insight into the meiotic segregation of chromosomes and the increased reproductive risk in individuals carrying the specific complex chromosomal rearrangement. We propose that such complex rearrangements should be characterized in detail using a combination of conventional cytogenetic and NGS-based approaches to aid in better prenatal preimplantation genetic diagnosis and counseling in couples with reproductive problems.
