Overlapping 16p13.11 deletion and gain of copies variations associated with childhood onset psychosis include genes with mechanistic implications for autism associated pathways: Two case reports

Brownstein, Catherine A.; Kleiman, Robin J.; Engle, Elizabeth C.; Towne, Meghan C.; D’Angelo, Eugene J.; Yu, Timothy W.; Beggs, Alan H.; Picker, Jonathan; Fogler, Jason; Carroll, Devon; Schmitt, Rachel C. O.; Wolff, Robert R.; Shen, Yiping; Lip, Va; Bilgüvar, Kaya; Kim, April; Tembulkar, Sahil; O’Donnell, Kyle L.; Gonzalez–Heydrich, Joseph

doi:10.1002/ajmg.a.37595

Cited by 20 publications

(15 citation statements)

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“…In this regard it is noteworthy that case 3 carries both the 16p13.11 microduplication and also a de novo loss-of-function mutation in TSC2 , yet demonstrates a similar cellular phenotype to cases 1 and 2. Several published clinical case reports describe patients with a combination of two rare genetic variants, one of which includes 16p13.11 duplications49, 50 which has led to the proposal of a ‘two-hit model’ in which the 16p13.11 duplication may contribute to the phenotype, not only as a single event but also in association with another mutation49.…”

Section: Discussionmentioning

confidence: 99%

Reversal of proliferation deficits caused by chromosome 16p13.11 microduplication through targeting NFκB signaling: an integrated study of patient-derived neuronal precursor cells, cerebral organoids and in vivo brain imaging

et al. 2018

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The molecular basis of how chromosome 16p13.11 microduplication leads to major psychiatric disorders is unknown. Here we have undertaken brain imaging of patients carrying microduplications in chromosome 16p13.11 and unaffected family controls, in parallel with iPS cell-derived cerebral organoid studies of the same patients. Patient MRI revealed reduced cortical volume, and corresponding iPSC studies showed neural precursor cell (NPC) proliferation abnormalities and reduced organoid size, with the NPCs therein displaying altered planes of cell division. Transcriptomic analyses of NPCs uncovered a deficit in the NFκB p65 pathway, confirmed by proteomics. Moreover, both pharmacological and genetic correction of this deficit rescued the proliferation abnormality. Thus, chromosome 16p13.11 microduplication disturbs the normal program of NPC proliferation to reduce cortical thickness due to a correctable deficit in the NFκB signalling pathway. This is the first study demonstrating a biologically relevant, potentially ameliorable, signalling pathway underlying chromosome 16p13.11 microduplication syndrome in patient-derived neuronal precursor cells.

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Section: Discussionmentioning

confidence: 99%

Reversal of proliferation deficits caused by chromosome 16p13.11 microduplication through targeting NFκB signaling: an integrated study of patient-derived neuronal precursor cells, cerebral organoids and in vivo brain imaging

et al. 2018

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“…Among pathogenic CNVs, the16p13.11 microduplication was initially considered as a rare benign CNV 38 , however, we interpreted this duplication as pathogenic because several previous studies have supported the positive association between this duplication and a variety of neuropsychiatric disorders including ASD, unexplained ID, schizophrenia, epilepsy, and attention-deficit hyperactivity disorder (ADHD). This duplication region contains two strong candidate genes, NTAN1 and NDE1 , which are both expressed in the brain and have been proposed as candidate genes for ASD and other neuropsychiatric disorders 39 – 42 . Most of the pathogenic, likely pathogenic CNVs and VOUS identified in this study were transmitted from a healthy parent (18 cases from 23 families, from which parental DNA samples were available).…”

Section: Discussionmentioning

confidence: 99%

Chromosomal microarray analysis in a cohort of underrepresented population identifies SERINC2 as a novel candidate gene for autism spectrum disorder

Hnoonual

Thammachote

Tim‐Aroon

et al. 2017

Sci Rep

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Chromosomal microarray (CMA) is now recognized as the first-tier genetic test for detection of copy number variations (CNVs) in patients with autism spectrum disorder (ASD). The aims of this study were to identify known and novel ASD associated-CNVs and to evaluate the diagnostic yield of CMA in Thai patients with ASD. The Infinium CytoSNP-850K BeadChip was used to detect CNVs in 114 Thai patients comprised of 68 retrospective ASD patients (group 1) with the use of CMA as a second line test and 46 prospective ASD and developmental delay patients (group 2) with the use of CMA as the first-tier test. We identified 7 (6.1%) pathogenic CNVs and 22 (19.3%) variants of uncertain clinical significance (VOUS). A total of 29 patients with pathogenic CNVs and VOUS were found in 22% (15/68) and 30.4% (14/46) of the patients in groups 1 and 2, respectively. The difference in detected CNV frequencies between the 2 groups was not statistically significant (Chi square = 1.02, df = 1, P = 0.31). In addition, we propose one novel ASD candidate gene, SERINC2, which warrants further investigation. Our findings provide supportive evidence that CMA studies using population-specific reference databases in underrepresented populations are useful for identification of novel candidate genes.

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“…In addition, variable expressivity of the dup16p13.11 phenotypes may occur as a result of the size of the duplication, reportedly ranging from several kilobases to a few megabases. A majority of the known 16p13.11 microduplications include duplication of the gene NDE1 , which has long been suggested as the primary candidate gene for the neurological and behavioral phenotypes in affected patients [ 1 , 4 , 6 - 8 ].…”

Section: Introductionmentioning

confidence: 99%

Underrepresentation of Phenotypic Variability of 16p13.11 Microduplication Syndrome Assessed With an Online Self-Phenotyping Tool (Phenotypr): Cohort Study

Li¹,

Hojlo²,

Chennuri³

et al. 2021

J Med Internet Res

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Background 16p13.11 microduplication syndrome has a variable presentation and is characterized primarily by neurodevelopmental and physical phenotypes resulting from copy number variation at chromosome 16p13.11. Given its variability, there may be features that have not yet been reported. The goal of this study was to use a patient “self-phenotyping” survey to collect data directly from patients to further characterize the phenotypes of 16p13.11 microduplication syndrome. Objective This study aimed to (1) discover self-identified phenotypes in 16p13.11 microduplication syndrome that have been underrepresented in the scientific literature and (2) demonstrate that self-phenotyping tools are valuable sources of data for the medical and scientific communities. Methods As part of a large study to compare and evaluate patient self-phenotyping surveys, an online survey tool, Phenotypr, was developed for patients with rare disorders to self-report phenotypes. Participants with 16p13.11 microduplication syndrome were recruited through the Boston Children's Hospital 16p13.11 Registry. Either the caregiver, parent, or legal guardian of an affected child or the affected person (if aged 18 years or above) completed the survey. Results were securely transferred to a Research Electronic Data Capture database and aggregated for analysis. Results A total of 19 participants enrolled in the study. Notably, among the 19 participants, aggression and anxiety were mentioned by 3 (16%) and 4 (21%) participants, respectively, which is an increase over the numbers in previously published literature. Additionally, among the 19 participants, 3 (16%) had asthma and 2 (11%) had other immunological disorders, both of which have not been previously described in the syndrome. Conclusions Several phenotypes might be underrepresented in the previous 16p13.11 microduplication literature, and new possible phenotypes have been identified. Whenever possible, patients should continue to be referenced as a source of complete phenotyping data on their condition. Self-phenotyping may lead to a better understanding of the prevalence of phenotypes in genetic disorders and may identify previously unreported phenotypes.

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Overlapping 16p13.11 deletion and gain of copies variations associated with childhood onset psychosis include genes with mechanistic implications for autism associated pathways: Two case reports

Cited by 20 publications

References 50 publications

Reversal of proliferation deficits caused by chromosome 16p13.11 microduplication through targeting NFκB signaling: an integrated study of patient-derived neuronal precursor cells, cerebral organoids and in vivo brain imaging

Reversal of proliferation deficits caused by chromosome 16p13.11 microduplication through targeting NFκB signaling: an integrated study of patient-derived neuronal precursor cells, cerebral organoids and in vivo brain imaging

Chromosomal microarray analysis in a cohort of underrepresented population identifies SERINC2 as a novel candidate gene for autism spectrum disorder

Underrepresentation of Phenotypic Variability of 16p13.11 Microduplication Syndrome Assessed With an Online Self-Phenotyping Tool (Phenotypr): Cohort Study

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