scholarly journals Genomic, Clinical, and Behavioral Characterization of 15q11.2 BP1-BP2 Deletion (Burnside-Butler) Syndrome in Five Families

2021 ◽  
Vol 22 (4) ◽  
pp. 1660
Author(s):  
Isaac Baldwin ◽  
Robin L. Shafer ◽  
Waheeda A. Hossain ◽  
Sumedha Gunewardena ◽  
Olivia J. Veatch ◽  
...  
Keyword(s):  
Behavioral Problems ◽  
De Novo ◽  
Clinical Laboratory ◽  
Autism Spectrum ◽  
Clinical Findings ◽  
Genomic Variation ◽  
Future Research ◽  
Symptom Presentation ◽  
Clinical Genetic ◽  
Genetic Evaluations

The 15q11.2 BP1-BP2 deletion (Burnside-Butler) syndrome is emerging as the most common cytogenetic finding in patients with neurodevelopmental or autism spectrum disorders (ASD) presenting for microarray genetic testing. Clinical findings in Burnside-Butler syndrome include developmental and motor delays, congenital abnormalities, learning and behavioral problems, and abnormal brain findings. To better define symptom presentation, we performed comprehensive cognitive and behavioral testing, collected medical and family histories, and conducted clinical genetic evaluations. The 15q11.2 BP1-BP2 region includes the TUBGCP5, CYFIP1, NIPA1, and NIPA2 genes. To determine if additional genomic variation outside of the 15q11.2 region influences expression of symptoms in Burnside-Butler syndrome, whole-exome sequencing was performed on the parents and affected children for the first time in five families with at least one parent and child with the 15q1l.2 BP1-BP2 deletion. In total, there were 453 genes with possibly damaging variants identified across all of the affected children. Of these, 99 genes had exclusively de novo variants and 107 had variants inherited exclusively from the parent without the deletion. There were three genes (APBB1, GOLGA2, and MEOX1) with de novo variants that encode proteins evidenced to interact with CYFIP1. In addition, one other gene of interest (FAT3) had variants inherited from the parent without the deletion and encoded a protein interacting with CYFIP1. The affected individuals commonly displayed a neurodevelopmental phenotype including ASD, speech delay, abnormal reflexes, and coordination issues along with craniofacial findings and orthopedic-related connective tissue problems. Of the 453 genes with variants, 35 were associated with ASD. On average, each affected child had variants in 6 distinct ASD-associated genes (x¯ = 6.33, sd = 3.01). In addition, 32 genes with variants were included on clinical testing panels from Clinical Laboratory Improvement Amendments (CLIA) approved and accredited commercial laboratories reflecting other observed phenotypes. Notably, the dataset analyzed in this study was small and reported results will require validation in larger samples as well as functional follow-up. Regardless, we anticipate that results from our study will inform future research into the genetic factors influencing diverse symptoms in patients with Burnside-Butler syndrome, an emerging disorder with a neurodevelopmental behavioral phenotype.

IL1RAPL1 Gene Deletion in a Female Patient with Developmental Delay and Continuous Spike-Wave during Sleep

2021 ◽  
Author(s):  
Evan Jiang ◽  
Mark P. Fitzgerald ◽  
Katherine L. Helbig ◽  
Ethan M. Goldberg
Keyword(s):  
Intellectual Disability ◽  
Developmental Delay ◽  
Synapse Formation ◽  
De Novo ◽  
Interleukin 1 ◽  
Autism Spectrum ◽  
Neurological Dysfunction ◽  
Behavioral Disorder ◽  
Clinical Genetic ◽  
Severe Intellectual Disability

AbstractInterleukin-1 receptor accessory protein-like 1 (IL1RAPL1) encodes a protein that is highly expressed in neurons and has been shown to regulate neurite outgrowth as well as synapse formation and synaptic transmission. Clinically, mutations in or deletions of IL1RAPL1 have been associated with a spectrum of neurological dysfunction including autism spectrum disorder and nonsyndromic X-linked developmental delay/intellectual disability of varying severity. Nearly all reported cases are in males; in the few reported cases involving females, the clinical presentation was mild or the deletion was identified in phenotypically normal carriers in accordance with X-linked inheritance. Using genome-wide microarray analysis, we identified a novel de novo 373 kb interstitial deletion of the X chromosome (Xp21.1-p21.2) that includes exons 4 to 6 of the IL1RAPL1 gene in an 8-year-old girl with severe intellectual disability and behavioral disorder with a history of developmental regression. Overnight continuous video electroencephalography revealed electrical status epilepticus in sleep (ESES). This case expands the clinical genetic spectrum of IL1RAPL1-related neurodevelopmental disorders and highlights a new genetic association of ESES.

Abstract 16066: Genomic Autopsy of 103 Sudden Deaths in the Young Reveals the Importance of Cardiomyopathy Genes and Non-Mendelian Risk

Circulation ◽  
2020 ◽  
Vol 142 (Suppl_3) ◽  
Author(s):  
Gregory Webster ◽  
Megan Puckelwartz ◽  
Lorenzo Pesce ◽  
Dellefave-Castillo Lisa ◽  
Carlos Vanoye ◽  
...  
Keyword(s):  
Sudden Death ◽  
Whole Genome Sequencing ◽  
Genome Sequencing ◽  
De Novo ◽  
Multivariable Analysis ◽  
Clinical Analysis ◽  
Clinical Findings ◽  
Whole Genome ◽  
Age At Death ◽  
Clinical Genetic

Introduction: Genetic testing after sudden death in the young can identify pathogenic cardiac gene variants. Hypothesis: Genomic methods, coupled with phenotype evaluation, reveal non-Mendalian risks. Methods: We conducted clinical analysis and whole genome sequencing on 103 decedents aged 1-40 (mean age at death 23.7 years) accrued prospectively from 2015 to 2019 across 22 states. Postmortem pathological findings were classified as: known cardiac disorders, findings of uncertain significance (FUS), or sudden unexplained death (SUD, indicating no postmortem pathological diagnosis). Parental DNA and clinical data were obtained where possible. Variants were classified by an independent clinical genetic laboratory. Results: Among the 103 decedents, 34 had a postmortem clinical diagnosis, 23 had FUS, and 46 were classified as SUD. Pathogenic/likely pathogenic (P/LP) variants in arrhythmia or cardiomyopathy genes were identified in 17 (16.5%) decedents. The distribution of P/LP variants was not associated with age at death (OR 1.01 [0.97, 1.05], p=0.54); however, a multivariable analysis including decedent phenotype, ancestry and sex demonstrated that younger decedents had a higher burden of curated P/LP/VUS variants (effect size -1.5, p=0.0019). DNA from 31 parent-decedent trios and 14 parent-decedent dyads revealed 9 transmitted P/LP variants and 1 de novo P/LP variant. More than half of parents transmitting a P/LP variant (5/9) did not have clinical findings associated with the genotype. Conclusions: Whole genome sequencing effectively revealed P/LP variants in cases of sudden death in the young, implicating both arrhythmia and cardiomyopathy genes. In addition, both genotype and phenotype analyses suggest additional non-Mendelian risk mechanisms.

scholarly journals Self-injurious behaviors in children with autism spectrum disorder enrolled in the Study to Explore Early Development

Autism ◽  
2017 ◽  
Vol 22 (5) ◽  
pp. 625-635 ◽  
Author(s):  
Gnakub Norbert Soke ◽  
Steven A Rosenberg ◽  
Cordelia Robinson Rosenberg ◽  
Roma A Vasa ◽  
Li-Ching Lee ◽  
...  
Keyword(s):  
Autism Spectrum Disorder ◽  
Early Development ◽  
Behavioral Problems ◽  
Maternal Age ◽  
Children With Autism ◽  
Autism Spectrum ◽  
Diagnostic Interview ◽  
Spectrum Disorder ◽  
Birth Certificates ◽  
Future Research

We assessed potential factors associated with “current” or “ever” self-injurious behaviors, reported in the Autism Diagnostic Interview–Revised, among children with autism spectrum disorder (n = 692) from the Study to Explore Early Development. Data on factors examined were obtained from questionnaires, standardized clinical instruments, and birth certificates. We employed a log-binomial regression to assess these associations. Although most associations were quite similar for currently and ever exhibiting self-injurious behaviors, a few differences were noted. We documented previously unreported associations of current self-injurious behaviors with maternal age and cesarean delivery, and ever self-injurious behaviors with maternal age, child sex, gestational age, and maternal race. We also confirmed previously reported associations with adaptive skills, somatic conditions (sleep, gastrointestinal, and sensory abnormalities), and other behavioral problems. These findings are informative for clinical practice and future research.

scholarly journals Prevalence of Returnable Genetic Results Based on Recognizable Phenotypes among Children with Autism Spectrum Disorder

2021 ◽  
Author(s):  
Somer Bishop ◽  
Audrey Thurm ◽  
Elise Robinson ◽  
Stephan Sanders
Keyword(s):  
Autism Spectrum Disorder ◽  
Genetic Testing ◽  
Autism Spectrum ◽  
Return Rate ◽  
Spectrum Disorder ◽  
Clinical Settings ◽  
Clinical Genetic ◽  
Genetic Evaluations ◽  
Large Research ◽  
Genetic Result

The importance of extensive genetic testing of autism spectrum disorder (ASD) cases has been demonstrated repeatedly in research settings but such testing in clinical settings remains sporadic. Determining which individuals should be prioritized for expensive tests remains a challenge. Several guidelines have been released relating to clinical genetic evaluations and testing in the context of ASD and these guidelines may be informed by the results of genetic testing in large research cohorts. The current study summarizes findings from over 2,000 individuals with ASD who received genetic testing, including microarray and exome testing, through the Simons Simplex Consortium. A returnable genetic result is identified in 10% of cases, however, this yield increases based on four readily accessible phenotypes: female sex and the presence of intellectual disability, seizures or delayed walking. Combinations of these factors increase return rate further, with some combinations yielding a return rate over 50%. In conclusion, these four phenotypes provide a simple approach to prioritize genetic testing in a clinical setting and inform future clinical guidelines. Providing a systematic approach to decisions about who to test removes barriers for, and therefore decrease disparities in, reimbursable genetic testing for individuals diagnosed with ASD.

scholarly journals Defining the genotypic and phenotypic spectrum of X-linked MSL3-related disorder

2020 ◽  
Author(s):  
Theresa Brunet ◽  
Kirsty McWalter ◽  
Katharina Mayerhanser ◽  
Grace M. Anbouba ◽  
Amy Armstrong-Javors ◽  
...  
Keyword(s):  
De Novo ◽  
Splice Variants ◽  
Muscle Tone ◽  
Three Dimensional ◽  
Autism Spectrum ◽  
Clinical Findings ◽  
Related Disorder ◽  
Aggregated Data ◽  
Phenotypic Spectrum ◽  
Gastrointestinal Problems

Abstract Purpose We sought to delineate the genotypic and phenotypic spectrum of female and male individuals with X-linked, MSL3-related disorder (Basilicata–Akhtar syndrome). Methods Twenty-five individuals (15 males, 10 females) with causative variants in MSL3 were ascertained through exome or genome sequencing at ten different sequencing centers. Results We identified multiple variant types in MSL3 (ten nonsense, six frameshift, four splice site, three missense, one in-frame-deletion, one multi-exon deletion), most proven to be de novo, and clustering in the terminal eight exons suggesting that truncating variants in the first five exons might be compensated by an alternative MSL3 transcript. Three-dimensional modeling of missense and splice variants indicated that these have a deleterious effect. The main clinical findings comprised developmental delay and intellectual disability ranging from mild to severe. Autism spectrum disorder, muscle tone abnormalities, and macrocephaly were common as well as hearing impairment and gastrointestinal problems. Hypoplasia of the cerebellar vermis emerged as a consistent magnetic resonance image (MRI) finding. Females and males were equally affected. Using facial analysis technology, a recognizable facial gestalt was determined. Conclusion Our aggregated data illustrate the genotypic and phenotypic spectrum of X-linked, MSL3-related disorder (Basilicata–Akhtar syndrome). Our cohort improves the understanding of disease related morbidity and allows us to propose detailed surveillance guidelines for affected individuals.

scholarly journals Genetic contributions to autism spectrum disorder

2021 ◽  
pp. 1-14
Author(s):  
A. Havdahl ◽  
M. Niarchou ◽  
A. Starnawska ◽  
M. Uddin ◽  
C. van der Merwe ◽  
...  
Keyword(s):  
Autism Spectrum Disorder ◽  
Rare Variants ◽  
De Novo ◽  
Point Mutations ◽  
Autism Spectrum ◽  
Repetitive Behaviors ◽  
Spectrum Disorder ◽  
Individual Risk ◽  
Future Research ◽  
Risk Genes

Abstract Autism spectrum disorder (autism) is a heterogeneous group of neurodevelopmental conditions characterized by early childhood-onset impairments in communication and social interaction alongside restricted and repetitive behaviors and interests. This review summarizes recent developments in human genetics research in autism, complemented by epigenetic and transcriptomic findings. The clinical heterogeneity of autism is mirrored by a complex genetic architecture involving several types of common and rare variants, ranging from point mutations to large copy number variants, and either inherited or spontaneous (de novo). More than 100 risk genes have been implicated by rare, often de novo, potentially damaging mutations in highly constrained genes. These account for substantial individual risk but a small proportion of the population risk. In contrast, most of the genetic risk is attributable to common inherited variants acting en masse, each individually with small effects. Studies have identified a handful of robustly associated common variants. Different risk genes converge on the same mechanisms, such as gene regulation and synaptic connectivity. These mechanisms are also implicated by genes that are epigenetically and transcriptionally dysregulated in autism. Major challenges to understanding the biological mechanisms include substantial phenotypic heterogeneity, large locus heterogeneity, variable penetrance, and widespread pleiotropy. Considerable increases in sample sizes are needed to better understand the hundreds or thousands of common and rare genetic variants involved. Future research should integrate common and rare variant research, multi-omics data including genomics, epigenomics, and transcriptomics, and refined phenotype assessment with multidimensional and longitudinal measures.

scholarly journals Exposure to sevoflurane results in changes of transcription factor occupancy in sperm and inheritance of autism

2021 ◽  
Author(s):  
Hsiao-Lin V. Wang ◽  
Samantha Forestier ◽  
Victor G. Corces
Keyword(s):  
Transcription Factor ◽  
Germ Cells ◽  
Behavioral Problems ◽  
De Novo ◽  
Germ Line ◽  
Pregnant Mouse ◽  
Autism Spectrum ◽  
General Anesthetics ◽  
General Anesthetic ◽  
Transcription Factor Occupancy

ABSTRACTOne in 54 children in the U.S. is diagnosed with Autism Spectrum Disorder (ASD). De novo germline and somatic mutations cannot account for all cases of ASD, suggesting that epigenetic alterations triggered by environmental exposures may be responsible for a subset of ASD cases. Human and animal studies have shown that exposure of the developing brain to general anesthetic (GA) agents can trigger neurodegeneration and neurobehavioral abnormalities but the effects of general anesthetics on the germ line have not been explored in detail. We exposed pregnant mice to sevoflurane during the time of embryonic development when the germ cells undergo epigenetic reprogramming and found that more than 38% of the directly exposed F1 animals exhibit impairments in anxiety and social interactions. Strikingly, 44-47% of the F2 and F3 animals, which were not directly exposed to sevoflurane, show the same behavioral problems. We performed ATAC-seq and identified more than 1,200 differentially accessible sites in the sperm of F1 animals, 69 of which are also present in the sperm of F2 animals. These sites are located in regulatory regions of genes strongly associated with ASD, including Arid1b, Ntrk2, and Stmn2. These findings suggest that epimutations caused by exposing germ cells to sevoflurane can lead to ASD in the offspring, and this effect can be transmitted through the male germline inter and trans-generationally.Summary sentencePregnant mouse F0 females exposed to sevoflurane give rise to F1 males with sociability and anxiety defects. These behaviors are transmitted to F2 and F3 males. Their sperm show changes in transcription factor occupancy in genes implicated in autism.

scholarly journals How Family Histories Can Inform Research About Germ Cell Exposures: The Example of Autism

2021 ◽  
Author(s):  
Jill Escher
Keyword(s):  
Germ Cell ◽  
De Novo ◽  
Autism Spectrum ◽  
Future Research ◽  
Epigenetic Alterations ◽  
Common Variants ◽  
De Novo Mutations ◽  
Genetic Toxicology ◽  
Genetic Heritability ◽  
Spectrum Disorders

Abstract Throughout the scientific literature, heritable traits are routinely presumed to be genetic in origin. However, as emerging evidence from the realms of genetic toxicology and epigenomics demonstrate, heritability may be better understood as encompassing not only DNA sequence passed down through generations, but also disruptions to the parental germ cells causing de novo mutations or epigenetic alterations, with subsequent shifts in gene expression and functions in offspring. The Beyond Genes conference highlighted advances in understanding these aspects at molecular, experimental and epidemiological levels. In this commentary I suggest that future research on this topic could be inspired by collecting parents’ germ cell exposure histories, with particular attention to cases of families with multiple children suffering idiopathic disorders. In so doing I focus on the endpoint of autism spectrum disorders (ASD). Rates of this serious neurodevelopment disability have climbed around the world, a growing crisis that cannot be explained by diagnostic shifts. ASD’s strong heritability has prompted a research program largely focused on DNA sequencing to locate rare and common variants, but decades of this gene-focused research have revealed surprisingly little about the molecular origins of the disorder. Based on my experience as the mother of two children with idiopathic autism, and as a research philanthropist and autism advocate, I suggest ways researchers might probe parental germ cell exposure histories to develop new hypotheses that may ultimately reveal sources of non-genetic heritability in a subset of idiopathic heritable pathologies.

scholarly journals Exposure to sevoflurane results in changes of transcription factor occupancy in sperm and inheritance of autism

2021 ◽  
Author(s):  
Hsiao-Lin V Wang ◽  
Samantha Forestier ◽  
Victor G Corces
Keyword(s):  
Germ Cells ◽  
Behavioral Problems ◽  
Animal Studies ◽  
De Novo ◽  
Germ Line ◽  
Autism Spectrum ◽  
General Anesthetics ◽  
General Anesthetic ◽  
Male Germline ◽  
Pregnant Mice

Abstract One in 54 children in the U.S. is diagnosed with Autism Spectrum Disorder (ASD). De novo germline and somatic mutations cannot account for all cases of ASD, suggesting that epigenetic alterations triggered by environmental exposures may be responsible for a subset of ASD cases. Human and animal studies have shown that exposure of the developing brain to general anesthetic (GA) agents can trigger neurodegeneration and neurobehavioral abnormalities but the effects of general anesthetics on the germ line have not been explored in detail. We exposed pregnant mice to sevoflurane during the time of embryonic development when the germ cells undergo epigenetic reprogramming and found that more than 38% of the directly exposed F1 animals exhibit impairments in anxiety and social interactions. Strikingly, 44–47% of the F2 and F3 animals, which were not directly exposed to sevoflurane, show the same behavioral problems. We performed ATAC-seq and identified more than 1200 differentially accessible sites in the sperm of F1 animals, 69 of which are also present in the sperm of F2 animals. These sites are located in regulatory regions of genes strongly associated with ASD, including Arid1b, Ntrk2, and Stmn2. These findings suggest that epimutations caused by exposing germ cells to sevoflurane can lead to ASD in the offspring, and this effect can be transmitted through the male germline inter and trans-generationally.

The Influence of Background Auditory Noise on P50 and N100 Suppression Elicited by the Paired-Click Paradigm

2020 ◽  
Vol 34 (3) ◽  
pp. 171-178
Author(s):  
Samantha Major ◽  
Kimberly Carpenter ◽  
Logan Beyer ◽  
Hannah Kwak ◽  
Geraldine Dawson ◽  
...  
Keyword(s):  
Sensory Gating ◽  
Autism Spectrum ◽  
Inhibitory Response ◽  
Future Research ◽  
Typically Developing ◽  
Optimal Outcomes ◽  
Hyperactivity Disorder ◽  
Auditory Sensory Gating ◽  
Auditory Noise ◽  
P50 Suppression

Abstract. Auditory sensory gating is commonly assessed using the Paired-Click Paradigm (PCP), an electroencephalography (EEG) task in which two identical sounds are presented sequentially and the brain’s inhibitory response to the second sound is measured. Many clinical populations demonstrate reduced P50 and/or N100 suppression. Testing sensory gating in children may help to identify individuals at risk for neurodevelopmental disorders earlier, including autism spectrum disorder (ASD) and attention-deficit/hyperactivity disorder (ADHD), which could lead to more optimal outcomes. Minimal research has been done with children because of the difficulty of performing lengthy EEG experiments with young children, requiring them to sit still for long periods of time. We designed a modified, potentially child-friendly version of the PCP and evaluated it in typically developing adults. The PCP was administered twice, once in a traditional silent room (silent movie condition) and once with an audible movie playing (audible movie condition) to minimize boredom and enhance behavioral compliance. We tested whether P50 and N100 suppression were influenced by the presence of the auditory background noise from the movie. N100 suppression was observed in both hemispheres in the silent movie condition and in the left hemisphere only during the audible movie condition, though suppression was attenuated in the audible movie condition. P50 suppression was not observed in either condition. N100 sensory gating was successfully elicited with an audible movie playing during the PCP, supporting the use of the modified task for future research in both children and adults.

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