The 15q11.2 BP1-BP2 Microdeletion (Burnside–Butler) Syndrome: In Silico Analyses of the Four Coding Genes Reveal Functional Associations with Neurodevelopmental Disorders

Rafi, Syed K.; Butler, Merlin G.

doi:10.3390/ijms21093296

Cited by 48 publications

(44 citation statements)

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“…Genetic analysis showed that these deletions were inherited from one of the normal parents. However, there are some reports of 15q11.2 deletions causing neurodevelopmental alterations 25,26 . Thus, we also defined the 15q11.2 deletions as VUS.…”

Section: Discussionmentioning

confidence: 99%

Copy number variations in ultrasonically abnormal late pregnancy fetuses with normal karyotypes

Cai

Lin

et al. 2020

Sci Rep

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Many fetuses are found to have ultrasonic abnormalities in the late pregnancy. The association of fetal ultrasound abnormalities in late pregnancy with copy number variations (CNVs) is unclear. We attempted to explore the relationship between types of ultrasonically abnormal late pregnancy fetuses and CNVs. Fetuses (n = 713) with ultrasound-detected abnormalities in late pregnancy and normal karyotypes were analyzed. Of these, 237 showed fetal sonographic structural malformations and 476 showed fetal non-structural abnormalities. Single nucleotide polymorphism (SNP)-based chromosomal microarray (CMA) was performed on the Affymetrix CytoScan HD platform. Using the SNP array, abnormal CNVs were detected in 8.0% (57/713) of the cases, with pathogenic CNVs in 32 cases and variants of uncertain clinical significance (VUS) in 25 cases. The detection rate of abnormal CNVs in fetuses with sonographic structural malformations (12.7%, 30/237) was significantly higher (P = 0.001) than that in the fetuses with non-structural abnormalities (5.7%, 27/476). Overall, we observed that when fetal sonographic structural malformations or non-structural abnormalities occurred in the third trimester of pregnancy, the use of SNP analysis could improve the accuracy of prenatal diagnosis and reduce the rate of pregnancy termination.

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Section: Discussionmentioning

confidence: 99%

Copy number variations in ultrasonically abnormal late pregnancy fetuses with normal karyotypes

Cai

Lin

et al. 2020

Sci Rep

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“…Further, mutations in this cluster have been marked as recurrent pathogenic CNV regions for neurodevelopmental disorders such as autism. Either side of its flanking regions contains autism genes such as UBE3A and ATP10A [41].…”

Section: Discussionmentioning

confidence: 99%

Identification of primary copy number variations reveal enrichment of Calcium, and MAPK pathways sensitizing secondary sites for autism

Agarwala

Veerappa

Ramachandra

2020

Egypt J Med Hum Genet

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Background Autism is a neurodevelopmental condition with genetic heterogeneity. It is characterized by difficulties in reciprocal social interactions with strong repetitive behaviors and stereotyped interests. Copy number variations (CNVs) are genomic structural variations altering the genomic structure either by duplication or deletion. De novo or inherited CNVs are found in 5–10% of autistic subjects with a size range of few kilobases to several megabases. CNVs predispose humans to various diseases by altering gene regulation, generation of chimeric genes, and disruption of the coding region or through position effect. Although, CNVs are not the initiating event in pathogenesis; additional preceding mutations might be essential for disease manifestation. The present study is aimed to identify the primary CNVs responsible for autism susceptibility in healthy cohorts to sensitize secondary-hits. In the current investigation, primary-hit autism gene CNVs are characterized in 1715 healthy cohorts of varying ethnicities across 12 populations using Affymetrix high-resolution array study. Thirty-eight individuals from twelve families residing in Karnataka, India, with the age group of 13–73 years are included for the comparative CNV analysis. The findings are validated against global 179 autism whole-exome sequence datasets derived from Simons Simplex Collection. These datasets are deposited at the Simons Foundation Autism Research Initiative (SFARI) database. Results The study revealed that 34.8% of the subjects carried 2% primary-hit CNV burden with 73 singleton-autism genes in different clusters. Of these, three conserved CNV breakpoints were identified with ARHGAP11B, DUSP22, and CHRNA7 as the target genes across 12 populations. Enrichment analysis of the population-specific autism genes revealed two signaling pathways—calcium and mitogen-activated protein kinases (MAPK) in the CNV identified regions. These impaired pathways affected the downstream cascades of neuronal function and physiology, leading to autism behavior. The pathway analysis of enriched genes unravelled complex protein interaction networks, which sensitized secondary sites for autism. Further, the identification of miRNA targets associated with autism gene CNVs added severity to the condition. Conclusion These findings contribute to an atlas of primary-hit genes to detect autism susceptibility in healthy cohorts, indicating their impact on secondary sites for manifestation.

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“…Mosaicism/tissue-specific gene expression should be considered and further studied in view of more males than females affected with ASD, particularly X-linked genes. Additionally, hormonal-mediated gender influences or differential expression in the brain should be examined for dysregulation in ASD including methylation status of brain-expressed genes on the X chromosome and interaction with autosomal genes (e.g., X-linked FMR1 gene causing fragile X syndrome [116] and CYFIP1 gene at 15q11.2 involved with coding transporter for FMR1 protein [117]). These investigations will require more specialized methods with increased sensitivity such as droplet digital PCR [118].…”

Section: Future Directionsmentioning

confidence: 99%

Clinical Assessment, Genetics, and Treatment Approaches in Autism Spectrum Disorder (ASD)

Genovese

Butler

2020

IJMS

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157

107

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Autism spectrum disorder (ASD) consists of a genetically heterogenous group of neurobehavioral disorders characterized by impairment in three behavioral domains including communication, social interaction, and stereotypic repetitive behaviors. ASD affects more than 1% of children in Western societies, with diagnoses on the rise due to improved recognition, screening, clinical assessment, and diagnostic testing. We reviewed the role of genetic and metabolic factors which contribute to the causation of ASD with the use of new genetic technology. Up to 40 percent of individuals with ASD are now diagnosed with genetic syndromes or have chromosomal abnormalities including small DNA deletions or duplications, single gene conditions, or gene variants and metabolic disturbances with mitochondrial dysfunction. Although the heritability estimate for ASD is between 70 and 90%, there is a lower molecular diagnostic yield than anticipated. A likely explanation may relate to multifactorial causation with etiological heterogeneity and hundreds of genes involved with a complex interplay between inheritance and environmental factors influenced by epigenetics and capabilities to identify causative genes and their variants for ASD. Behavioral and psychiatric correlates, diagnosis and genetic evaluation with testing are discussed along with psychiatric treatment approaches and pharmacogenetics for selection of medication to treat challenging behaviors or comorbidities commonly seen in ASD. We emphasize prioritizing treatment based on targeted symptoms for individuals with ASD, as treatment will vary from patient to patient based on diagnosis, comorbidities, causation, and symptom severity.

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The 15q11.2 BP1-BP2 Microdeletion (Burnside–Butler) Syndrome: In Silico Analyses of the Four Coding Genes Reveal Functional Associations with Neurodevelopmental Disorders

Cited by 48 publications

References 47 publications

Copy number variations in ultrasonically abnormal late pregnancy fetuses with normal karyotypes

Copy number variations in ultrasonically abnormal late pregnancy fetuses with normal karyotypes

Identification of primary copy number variations reveal enrichment of Calcium, and MAPK pathways sensitizing secondary sites for autism

Clinical Assessment, Genetics, and Treatment Approaches in Autism Spectrum Disorder (ASD)

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