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Diagnostic yields of genetic testing in 10,351 consecutive children with neurodevelopmental disorders by diagnostic referral codes.
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Copy number variants (CNVs) detected by chromosomal microarray analysis (CMA) significantly contribute to understanding the etiology of autism spectrum disorder (ASD) and other related conditions. In recognition of the value of CMA testing and its impact on medical management, CMA is in medical guidelines as a first-tier test in the evaluation of c...
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Constitutional interstitial deletions of the long arm of chromosome 5 (5q) are quite rare, and the corresponding phenotype is not yet clearly delineated. Severe mental retardation has been described in most patients who present 5q deletions. Specifically, the interstitial deletion of chromosome 5q33.3q35.1, an extremely rare chromosomal aberration,...
Citations
... identified syndromes (e.g., Williams, Phelan-McDermid, and Shprintzen velocardiofacial), or single gene disorders resulting in behavioral and psychiatric conditions [23]. Hence, chromosomal microarrays may be applied with high diagnostic yield [23,24]. In addition, pharmacogenetics testing may be used to guide the selection of medications in ASD, a technique which is also used in Down syndrome, Fragile X syndrome (FMR1 gene), and the PTEN gene mutation, which encodes a phosphatase associated with extreme macrocephaly [25]. ...
Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by severe deficits in social communication and interaction, repetitive movements, abnormal focusing on objects, or activity that can significantly affect the quality of life of the afflicted. Neuronal and glial cells have been implicated. It has a genetic component but can also be triggered by environmental factors or drugs. For example, prenatal exposure to valproic acid or acetaminophen, or ingestion of propionic acid, can increase the risk of ASD. Recently, epigenetic influences on ASD have come to the forefront of investigations on the etiology, prevention, and treatment of this disorder. Epigenetics refers to DNA modifications that alter gene expression without making any changes to the DNA sequence. Although an increasing number of pharmaceuticals and environmental chemicals are being implicated in the etiology of ASD, here, we specifically focus on the molecular influences of the abovementioned chemicals on epigenetic alterations in neuronal and glial cells and their potential connection to ASD. We conclude that a better understanding of these phenomena can lead to more effective interventions in ASD.
... resulting in behavioral and psychiatric conditions [21]. Hence, chromosomal microarrays may be applied with high diagnostic yield [21,22]. In addition, pharmacogenetics testing may be used to guide the selection of medications in ASD, a technique which is also used in Down syndrome, Fragile X syndrome (FMR1 gene) and the PTEN gene mutation, which encodes a phosphatase associated with extreme macrocephaly [23] . ...
Autism spectrum disorder (ASD) is a neurodevelopmental disease characterized by persistent deficits in social interaction and communication, repetitive movements, abnormal focusing on objects, or activity that can significantly affect the quality of life of the afflicted. Brain neuronal and glial cells have been implicated. It has a genetic component but can also be triggered by environmental factors or drugs. For example, prenatal exposure to valproic acid (VPA) or acetaminophen (APAP) or ingestion of propionic acid (PPA) can increase the risk of ASD. Recently, epigenetic influences on ASD have been brought to the forefront of investigations on the etiology, prevention, and treatment of this disorder. Epigenetics refers to DNA modifications that alter gene expression without making any changes to the DNA sequence. Although an increasing number of pharmaceuticals and environmental chemicals are being implicated in the etiology of ASD, here we specifically focus on the molecular influence of the above-mentioned drugs on epigenetic alterations in neuronal and glial cells and their potential connection to ASD. It is concluded that a better understanding of these phenomena can lead to more effective interventions in ASD.
... Specifically for ASD, the mean diagnostic yield is usually lower than for a typical neurodevelopmental cohort. However, among autism subtypes, higher diagnostic usually occurs when ASD is syndromic accompanied with other features and is syndromic (or complex) ASD 78,99 . ...
Chromosomal microarray (CMA) is the reference in evaluation of copy number variations (CNVs) in individuals with neurodevelopmental disorders (NDDs), such as intellectual disability (ID) and/or autism spectrum disorder (ASD), which affect around 3–4% of the world’s population. Modern platforms for CMA, also include probes for single nucleotide polymorphisms (SNPs) that detect homozygous regions in the genome, such as long contiguous stretches of homozygosity (LCSH). These regions result from complete or segmental chromosomal homozygosis and may be indicative of uniparental disomy (UPD), inbreeding, population characteristics, as well as replicative DNA repair events. In this retrospective study, we analyzed CMA reading files requested by geneticists and neurologists for diagnostic purposes along with available clinical data. Our objectives were interpreting CNVs and assess the frequencies and implications of LCSH detected by Affymetrix CytoScan HD (41%) or 750K (59%) platforms in 1012 patients from the south of Brazil. The patients were mainly children with NDDs and/or congenital anomalies (CAs). A total of 206 CNVs, comprising 132 deletions and 74 duplications, interpreted as pathogenic, were found in 17% of the patients in the cohort and across all chromosomes. Additionally, 12% presented rare variants of uncertain clinical significance, including LPCNVs, as the only clinically relevant CNV. Within the realm of NDDs, ASD carries a particular importance, owing to its escalating prevalence and its growing repercussions for individuals, families, and communities. ASD was one clinical phenotype, if not the main reason for referral to testing, for about one-third of the cohort, and these patients were further analyzed as a sub-cohort. Considering only the patients with ASD, the diagnostic rate was 10%, within the range reported in the literature (8–21%). It was higher (16%) when associated with dysmorphic features and lower (7%) for "isolated" ASD (without ID and without dysmorphic features). In 953 CMAs of the whole cohort, LCSH (≥ 3 Mbp) were analyzed not only for their potential pathogenic significance but were also explored to identify common LCSH in the South Brazilians population. CMA revealed at least one LCSH in 91% of the patients. For about 11.5% of patients, the LCSH suggested consanguinity from the first to the fifth degree, with a greater probability of clinical impact, and in 2.8%, they revealed a putative UPD. LCSH found at a frequency of 5% or more were considered common LCSH in the general population, allowing us to delineate 10 regions as potentially representing ancestral haplotypes of neglectable clinical significance. The main referrals for CMA were developmental delay (56%), ID (33%), ASD (33%) and syndromic features (56%). Some phenotypes in this population may be predictive of a higher probability of indicating a carrier of a pathogenic CNV. Here, we present the largest report of CMA data in a cohort with NDDs and/or CAs from the South of Brazil. We characterize the rare CNVs found along with the main phenotypes presented by each patient and show the importance and usefulness of LCSH interpretation in CMA results that incorporate SNPs, as well as we illustrate the value of CMA to investigate CNV in ASD.
... The 15q11.2 BP1-BP2 microdeletion is the most common pathogenic copy number variation (CNV) associated with neurodevelopmental diseases, cognition, behavior, and brain structure and morphology changes [1,2]. In 2004, Bulter et al. [3] identified 15q11.2 ...
... However, cohort studies show that the 15q11.2 BP1-BP2 microdeletion is the most common genetic cause of ASD and schizophrenia [2,10]; 15q11.2 BP1-BP2 is a susceptible region site for schizophrenia [11,12] and developmental delay [13], and is associated with epilepsy [14,15]. ...
... Most CNV are inherited from phenotypic parents, particularly from the paternal line [2,7,31]. This may be related to a female protective effect, wherein females at a genetic risk of exhibiting a neurodevelopmental disorder phenotype require a higher mutation load than males [22,32]. ...
Objectives
The 15q11.2 BP1-BP2 microdeletion is associated with neurodevelopmental diseases. However, most studies on this microdeletion have focused on adults and children. Thus, in this study, we summarized the molecular characteristics of fetuses with the 15q11.2 BP1-BP2 microdeletion and their postnatal follow-up to guide prenatal diagnosis.
Methods
Ten thousand fetuses were retrospectively subjected to karyotype analysis and chromosome microarray analysis.
Results
Chromosome microarray analysis revealed that 37 (0.4%) of the 10,000 fetuses had 15q11.2 BP1-BP2 microdeletions. The fragment size of the 15q11.2 BP1-BP2 region was approximately 312–855 kb and encompassed TUBGCP5, CYFIP1, NIPA2, and NIPA1 genes. Twenty-five of the 37 fetuses with this microdeletion showed phenotypic abnormalities. The most common ultrasonic structural abnormality was congenital heart disease, followed by renal dysplasia and Dandy–Walker malformation. The 15q11.2 BP1-BP2 microdeletion was inherited from the father and mother in 6 and 10 cases, respectively, and de novo inherited in 4 cases. In the postnatal follow-up, 16.1% of the children had postnatal abnormalities.
Conclusion
Fetuses with the 15q11.2 BP1-BP2 microdeletion showed high proportions of phenotypic abnormalities, but the specificity of penetrance was low. Thus, fetuses with this syndrome are potentially at a higher risk of postnatal growth/behavioral problems and require continuous monitoring of growth and development.
... As a result, some variants may be classified as "variants of uncertain significance" (VUS) based on the available evidence. Studies have shown that patients undergoing CMA for developmental delay, intellectual disability, autism spectrum disorder, or multiple congenital anomalies carry at least one VUS an estimated 7.9-19% of the time [29][30][31][32]. The frequency of VUS in patients undergoing ES varies greatly, with reported rates of 25.3-86% [33][34][35]. ...
Advances in disease-related gene discovery have led to tremendous innovations in the field of epilepsy genetics. Identification of genetic mutations that cause epileptic encephalopathies has opened new avenues for the development of targeted therapies. Clinical testing using extensive gene panels, exomes, and genomes is currently accessible and has resulted in higher rates of diagnosis and better comprehension of the disease mechanisms underlying the condition. Children with developmental disabilities have a higher risk of developing epilepsy. As our understanding of the mechanisms underlying encephalopathies and epilepsies improves, there may be greater potential to develop innovative therapies tailored to an individual’s genotype. This article provides an overview of the significant progress in epilepsy genomics in recent years, with a focus on developmental and epileptic encephalopathies in children. The aim of this review is to enhance comprehension of the clinical utilization of genetic testing in this particular patient population. The development of effective and precise therapeutic strategies for epileptic encephalopathies may be facilitated by a comprehensive understanding of their molecular pathogenesis.
... ASD is a heterogenous genetic disorder with a 4:1 male-to-female ratio and over 800 ASD-related genes recognized with hundreds of chromosome aberrations, dozens of identified syndromes and a complex interplay between inheritance and environmental factors influenced by epigenetics [9][10][11]. Advances in understanding the role of genetics in human disease, particularly disorders of neurodevelopment, have been achieved by revolutionary changes in genomic technology with next-generation sequencing (NGS), computer program analysis and bioinformatics. ...
... Additional cytogenetic disorders have been found with new ultra-high-resolution microarray technology, including the emerging 15q11.2 BP1-BP2 deletions and duplications [10]. GWAS findings in ASD and broad autism phenotypes in extended pedigrees were studied in large cohorts in Canada and the United States showing other chromosome regions such as 1p36.22, ...
... Microarrays are considered to be a first-tier genetic test and are best utilized to identify deletions or duplications of multiple or single genes that might be implicated at the chromosome level. For example, Ho et al. [10] in 2016 summarized the results of ultra-high-resolution microarray testing of patients presenting with neurodevelopmental disorders and/or autism for genetic services in a commercial laboratory setting. They used 2.8 million CNV and single nucleotide polymorphic (SNP) DNA probes optimized for neurodevelopmental disorders, reporting an overall CNV detection rate of 28.1% in 10,351 consecutive patients (average age 7 years, M:F ratio 2.5:1), with the overall detection rate for individuals with ASD being significant at 24.4%. ...
Autism spectrum disorder (ASD) consists of a group of heterogeneous genetic neurobehavioral disorders associated with developmental impairments in social communication skills and stereotypic, rigid or repetitive behaviors. We review common behavioral, psychiatric and genetic associations related to ASD. Autism affects about 2% of children with 4:1 male-to-female ratio and a heritability estimate between 70 and 90%. The etiology of ASD involves a complex interplay between inheritance and environmental factors influenced by epigenetics. Over 800 genes and dozens of genetic syndromes are associated with ASD. Novel gene–protein interactions with pathway and molecular function analyses have identified at least three functional pathways including chromatin modeling, Wnt, Notch and other signaling pathways and metabolic disturbances involving neuronal growth and dendritic spine profiles. An estimated 50% of individuals with ASD are diagnosed with chromosome deletions or duplications (e.g., 15q11.2, BP1-BP2, 16p11.2 and 15q13.3), identified syndromes (e.g., Williams, Phelan-McDermid and Shprintzen velocardiofacial) or single gene disorders. Behavioral and psychiatric conditions in autism impacted by genetics influence clinical evaluations, counseling, diagnoses, therapeutic interventions and treatment approaches. Pharmacogenetics testing is now possible to help guide the selection of psychotropic medications to treat challenging behaviors or co-occurring psychiatric conditions commonly seen in ASD. In this review of the autism spectrum disorder, behavioral, psychiatric and genetic observations and associations relevant to the evaluation and treatment of individuals with ASD are discussed.
... , Miller et al. (2010 demonstrated the utility of CMA as a first-tier clinical diagnostic test to enable early diagnosis of individuals with NDDs. This technology can precisely detect 10%-30% of NDD cases (Miller et al., 2010;Ho et al., 2016;Uddin et al., 2016;Chaves et al., 2019). ...
... , Miller et al. (2010 demonstrated the utility of CMA as a first-tier clinical diagnostic test to enable early diagnosis of individuals with NDDs. This technology can precisely detect 10%-30% of NDD cases (Miller et al., 2010;Ho et al., 2016;Uddin et al., 2016;Chaves et al., 2019). ...
Introduction: Copy number variations (CNVs) play a critical role in the pathogenesis of neurodevelopmental disorders (NDD) among children. In this study, we aim to identify clinically relevant CNVs, genes and their phenotypic characteristics in an ethnically underrepresented homogenous population of Bangladesh.
Methods: We have conducted chromosomal microarray analysis (CMA) for 212 NDD patients with male to female ratio of 2.2:1.0 to identify rare CNVs. To identify candidate genes within the rare CNVs, gene constraint metrics [i.e., “Critical-Exon Genes (CEGs)”] were applied to the population data. Autism Diagnostic Observation Schedule-Second Edition (ADOS-2) was followed in a subset of 95 NDD patients to assess the severity of autism and all statistical tests were performed using the R package.
Results: Of all the samples assayed, 12.26% (26/212) and 57.08% (121/212) patients carried pathogenic and variant of uncertain significance (VOUS) CNVs, respectively. While 2.83% (6/212) patients’ pathogenic CNVs were found to be located in the subtelomeric regions. Further burden test identified females are significant carriers of pathogenic CNVs compared to males (OR = 4.2; p = 0.0007). We have observed an increased number of Loss of heterozygosity (LOH) within cases with 23.85% (26/109) consanguineous parents. Our analyses on imprinting genes show, 36 LOH variants disrupting 69 unique imprinted genes and classified these variants as VOUS. ADOS-2 subset shows severe social communication deficit (p = 0.014) and overall ASD symptoms severity (p = 0.026) among the patients carrying duplication CNV compared to the CNV negative group. Candidate gene analysis identified 153 unique CEGs in pathogenic CNVs and 31 in VOUS. Of the unique genes, 18 genes were found to be in smaller (<1 MB) focal CNVs in our NDD cohort and we identified PSMC3 gene as a strong candidate gene for Autism Spectrum Disorder (ASD). Moreover, we hypothesized that KMT2B gene duplication might be associated with intellectual disability.
Conclusion: Our results show the utility of CMA for precise genetic diagnosis and its integration into the diagnosis, therapy and management of NDD patients.
... , Miller et al. (2010 demonstrated the utility of CMA as a first-tier clinical diagnostic test to enable early diagnosis of individuals with NDDs. This technology can precisely detect 10%-30% of NDD cases (Miller et al., 2010;Ho et al., 2016;Uddin et al., 2016;Chaves et al., 2019). ...
Introduction: Copy number variations (CNVs) play a critical role in the pathogenesis of neurodevelopmental disorders (NDD) among children. In this study, we aim to identify clinically relevant CNVs, genes and their phenotypic characteristics in an ethnically underrepresented homogenous population of Bangladesh.
Methods: We have conducted chromosomal microarray analysis (CMA) for 212 NDD patients with male to female ratio of 2.2:1.0 to identify rare CNVs. To identify candidate genes within the rare CNVs, gene constraint metrics [i.e., “Critical-Exon Genes (CEGs)”] were applied to the population data. Autism Diagnostic Observation Schedule-Second Edition (ADOS-2) was followed in a subset of 95 NDD patients to assess the severity of autism and all statistical tests were performed using the R package.
Results: Of all the samples assayed, 12.26% (26/212) and 57.08% (121/212) patients carried pathogenic and variant of uncertain significance (VOUS) CNVs, respectively. While 2.83% (6/212) patients’ pathogenic CNVs were found to be located in the subtelomeric regions. Further burden test identified females are significant carriers of pathogenic CNVs compared to males (OR = 4.2; p = 0.0007). We have observed an increased number of Loss of heterozygosity (LOH) within cases with 23.85% (26/109) consanguineous parents. Our analyses on imprinting genes show, 36 LOH variants disrupting 69 unique imprinted genes and classified these variants as VOUS. ADOS-2 subset shows severe social communication deficit (p = 0.014) and overall ASD symptoms severity (p = 0.026) among the patients carrying duplication CNV compared to the CNV negative group. Candidate gene analysis identified 153 unique CEGs in pathogenic CNVs and 31 in VOUS. Of the unique genes, 18 genes were found to be in smaller (<1 MB) focal CNVs in our NDD cohort and we identified PSMC3 gene as a strong candidate gene for Autism Spectrum Disorder (ASD). Moreover, we hypothesized that KMT2B gene duplication might be associated with intellectual disability.
Conclusion: Our results show the utility of CMA for precise genetic diagnosis and its integration into the diagnosis, therapy and management of NDD patients.
... BP1-BP2 region due to a deletion designated as Burnside-Butler syndrome, emerging with variable clinical findings including a neurodevelopmental-autism nondysmorphic phenotype with low penetrance. This phenotype presents with features including language and/or motor delay, cognitive impairment, aberrant behavior and autism, poor coordination with ataxia, seizures and congenital anomalies [50][51][52][53][54][55][56][57]. This small proximal 15q11.2 ...
... This small proximal 15q11.2 deletion characterized by Burnside et al. [39] in 2011 is now recognized as the most common chromosome finding in large cohorts of those presenting with neurodevelopmental problems and/or autism [50]. ...
... Ho et al. [50] in 2016 used 2.8 million DNA markers including single nucleotide polymorphic (SNP) and copy number variant (CNV) probes optimized for detection of regions of homozygosity and CNVs associated with neurodevelopmental disorders with high-resolution chromosomal microarrays. Neurodevelopmental disorders include developmental delay and intellectual disabilities with ASD, which affect up to 15% of all children. ...
Prader–Willi syndrome (PWS) is a complex genetic disorder with three PWS molecular genetic classes and presents as severe hypotonia, failure to thrive, hypogonadism/hypogenitalism and developmental delay during infancy. Hyperphagia, obesity, learning and behavioral problems, short stature with growth and other hormone deficiencies are identified during childhood. Those with the larger 15q11-q13 Type I deletion with the absence of four non-imprinted genes (NIPA1, NIPA2, CYFIP1, TUBGCP5) from the 15q11.2 BP1-BP2 region are more severely affected compared with those with PWS having a smaller Type II deletion. NIPA1 and NIPA2 genes encode magnesium and cation transporters, supporting brain and muscle development and function, glucose and insulin metabolism and neurobehavioral outcomes. Lower magnesium levels are reported in those with Type I deletions. The CYFIP1 gene encodes a protein associated with fragile X syndrome. The TUBGCP5 gene is associated with attention-deficit hyperactivity disorder (ADHD) and compulsions, more commonly seen in PWS with the Type I deletion. When the 15q11.2 BP1-BP2 region alone is deleted, neurodevelopment, motor, learning and behavioral problems including seizures, ADHD, obsessive-compulsive disorder (OCD) and autism may occur with other clinical findings recognized as Burnside–Butler syndrome. The genes in the 15q11.2 BP1-BP2 region may contribute to more clinical involvement and comorbidities in those with PWS and Type I deletions.
