Pathogenic copy number variants and SCN1A mutations in patients with intellectual disability and childhood-onset epilepsy.
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ABSTRACT:
SUBMITTER: Fry AE
PROVIDER: S-EPMC4845474 | biostudies-literature | 2016 Apr
REPOSITORIES: biostudies-literature
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Pathogenic copy number variants and SCN1A mutations in patients with intellectual disability and childhood-onset epilepsy.
Fry Andrew E AE Rees Elliott E Thompson Rose R Mantripragada Kiran K Blake Penny P Jones Glyn G Morgan Sian S Jose Sian S Mugalaasi Hood H Archer Hayley H McCann Emma E Clarke Angus A Taylor Clare C Davies Sally S Gibbon Frances F Te Water Naude Johann J Hartley Louise L Thomas Gareth G White Catharine C Natarajan Jaya J Thomas Rhys H RH Drew Cheney C Chung Seo-Kyung SK Rees Mark I MI Holmans Peter P Owen Michael J MJ Kirov George G Pilz Daniela T DT Kerr Michael P MP
BMC medical genetics 20160426 1
<h4>Background</h4>Copy number variants (CNVs) have been linked to neurodevelopmental disorders such as intellectual disability (ID), autism, epilepsy and psychiatric disease. There are few studies of CNVs in patients with both ID and epilepsy.<h4>Methods</h4>We evaluated the range of rare CNVs found in 80 Welsh patients with ID or developmental delay (DD), and childhood-onset epilepsy. We performed molecular cytogenetic testing by single nucleotide polymorphism array or microarray-based compara ...[more]
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Project description:Importance:Copy number variation (CNV) is an important cause of neuropsychiatric disorders. Little is known about the role of CNV in adults with epilepsy and intellectual disability. Objectives:To evaluate the prevalence of pathogenic CNVs and identify possible candidate CNVs and genes in patients with epilepsy and intellectual disability. Design, Setting, and Participants:In this cross-sectional study, genome-wide microarray was used to evaluate a cohort of 143 adults with unexplained childhood-onset epilepsy and intellectual disability who were recruited from the Toronto Western Hospital epilepsy outpatient clinic from January 1, 2012, through December 31, 2014. The inclusion criteria were (1) pediatric seizure onset with ongoing seizure activity in adulthood, (2) intellectual disability of any degree, and (3) no structural brain abnormalities or metabolic conditions that could explain the seizures. Main Outcomes and Measures:DNA screening was performed using genome-wide microarray platforms. Pathogenicity of CNVs was assessed based on the American College of Medical Genetics guidelines. The Residual Variation Intolerance Score was used to evaluate genes within the identified CNVs that could play a role in each patient's phenotype. Results:Of the 2335 patients, 143 probands were investigated (mean [SD] age, 24.6 [10.8] years; 69 male and 74 female). Twenty-three probands (16.1%) and 4 affected relatives (2.8%) (mean [SD] age, 24.1 [6.1] years; 11 male and 16 female) presented with pathogenic or likely pathogenic CNVs (0.08-18.9 Mb). Five of the 23 probands with positive results (21.7%) had more than 1 CNV reported. Parental testing revealed de novo CNVs in 11 (47.8%), with CNVs inherited from a parent in 4 probands (17.4%). Sixteen of 23 probands (69.6%) presented with previously cataloged human genetic disorders and/or defined CNV hot spots in epilepsy. Eight nonrecurrent rare CNVs that overlapped 1 or more genes associated with intellectual disability, autism, and/or epilepsy were identified: 2p16.1-p15 duplication, 6p25.3-p25.1 duplication, 8p23.3p23.1 deletion, 9p24.3-p23 deletion, 10q11.22-q11.23 duplication, 12p13.33-13.2 duplication, 13q34 deletion, and 16p13.2 duplication. Five genes are of particular interest given their potential pathogenicity in the corresponding phenotypes and least tolerability to variation: ABAT, KIAA2022, COL4A1, CACNA1C, and SMARCA2. ABAT duplication was associated with Lennox-Gastaut syndrome and KIAA2022 deletion with Jeavons syndrome. Conclusions and Relevance:The high prevalence of pathogenic CNVs in this study highlights the importance of microarray analysis in adults with unexplained childhood-onset epilepsy and intellectual disability. Additional studies and comparison with similar cases are required to evaluate the effects of deletions and duplications that overlap specific genes.
| S-EPMC5710585 | biostudies-literature
Project description:BackgroundEpilepsy is genetically complex but common brain disorder of the world affecting millions of people with almost of all age groups. Novel Copy number variations (CNVs) are considered as important reason for the numerous neurodevelopmental disorders along with intellectual disability and epilepsy. DNA array based studies contribute to explain a more severe clinical presentation of the disease but interoperation of many detected CNVs are still challenging.ResultsIn order to study novel CNVs with epilepsy related genes in Saudi family with six affected and two normal individuals with several forms of epileptic seizures, intellectual disability (ID), and minor dysmorphism, we performed the high density whole genome Agilent sure print G3 Hmn CGH 2x 400 K array-CGH chips analysis. Our results showed de novo deletions, duplications and deletion plus duplication on differential chromosomal regions in the affected individuals that were not shown in the normal fathe and normal kids by using Agilent CytoGenomics 3.0.6.6 softwear. Copy number gain were observed in the chromosome 1, 16 and 22 with LCE3C, HPR, GSTT2, GSTTP2, DDT and DDTL genes respectively whereas the deletions observed in the chromosomal regions 8p23-p21 (4303127-4337759) and the potential gene in this region is CSMD1 (OMIM: 612279). Moreover, the array CGH results deletions and duplication were also validated by using primer design of deleted regions utilizing the flanked SNPs using simple PCR and also by using quantitative real time PCR.ConclusionsWe found some of the de novo deletions and duplication in our study in Saudi family with intellectual disability and epilepsy. Our results suggest that array-CGH should be used as a first line of genetic test for epilepsy except there is a strong indication for a monogenic syndrome. The advanced high through put array-CGH technique used in this study aim to collect the data base and to identify new mechanisms describing epileptic disorder, may help to improve the clinical management of individual cases in decreasing the burden of epilepsy in Saudi Arabia.
| S-EPMC5073808 | biostudies-literature
Project description:Introduction: The concurrence of intellectual disability/global developmental delay and epilepsy (ID/GDD-EP) is very common in the pediatric population. The etiologies for both conditions are complex and largely unknown. The predictors of significant copy number variations (CNVs) are known for the cases with ID/GDD, but unknown for those with exclusive ID/GDD-EP. Importantly, the known predictors are largely from the same ethnic group; hence, they lack replication. Purpose: We aimed to determine and investigate the diagnostic yield of CNV tests, new causative CNVs, and the independent predictors of significant CNVs in Chinese children with unexplained ID/GDD-EP. Materials and methods: A total of 100 pediatric patients with unexplained ID/GDD-EP and 1,000 healthy controls were recruited. The American College of Medical Genetics guideline was used to classify the CNVs. Additionally, clinical information was collected and compared between those with significant and non-significant CNVs. Results: Twenty-eight percent of the patients had significant CNVs, 16% had variants of unknown significance, and 56% had non-significant CNVs. In total, 31 CNVs were identified in 28% (28/100) of cases: 25 pathogenic and 6 likely pathogenic. Eighteen known syndromes were diagnosed in 17 cases. Thirteen rare CNVs (8 novel and 5 reported in literature) were identified, of which three spanned dosage-sensitive genes: 19q13.2 deletion (ATP1A3), Xp11.4-p11.3 deletion (CASK), and 6q25.3-q25.3 deletion (ARID1B). By comparing clinical features in patients with significant CNVs against those with non-significant CNVs, a statistically significant association was found between the presence of significant CNVs and speech and language delay for those aged above 2 years and for those with facial malformations, microcephaly, congenital heart disease, fair skin, eye malformations, and mega cisterna magna. Multivariate logistic regression analysis allowed the identification of two independent significant CNV predictors, which are eye malformations and facial malformations. Conclusion: Our study supports the performance of CNV tests in pediatric patients with unexplained ID/GDD-EP, as there is high diagnostic yield, which informs genetic counseling. It adds 13 rare CNVs (8 novel), which can be accountable for both conditions. Moreover, congenital eye and facial malformations are clinical markers that can aid clinicians to understand which patients can benefit from the CNV testing and which will not, thus helping patients to avoid unnecessary and expensive tests.
| S-EPMC6252327 | biostudies-literature
Project description:Estimates of children and adolescents with disabilities worldwide are needed to inform global intervention under the disability-inclusive provisions of the Sustainable Development Goals. We sought to update the most widely reported estimate of 93 million children <15 years with disabilities from the Global Burden of Disease Study 2004. We analyzed Global Burden of Disease Study 2017 data on the prevalence of childhood epilepsy, intellectual disability, and vision or hearing loss and on years lived with disability (YLD) derived from systematic reviews, health surveys, hospital and claims databases, cohort studies, and disease-specific registries. Point estimates of the prevalence and YLD and the 95% uncertainty intervals (UIs) around the estimates were assessed. Globally, 291.2 million (11.2%) of the 2.6 billion children and adolescents (95% UI: 249.9-335.4 million) were estimated to have 1 of the 4 specified disabilities in 2017. The prevalence of these disabilities increased with age from 6.1% among children aged <1 year to 13.9% among adolescents aged 15 to 19 years. A total of 275.2 million (94.5%) lived in low- and middle-income countries, predominantly in South Asia and sub-Saharan Africa. The top 10 countries accounted for 62.3% of all children and adolescents with disabilities. These disabilities accounted for 28.9 million YLD or 19.9% of the overall 145.3 million (95% UI: 106.9-189.7) YLD from all causes among children and adolescents. The number of children and adolescents with these 4 disabilities is far higher than the 2004 estimate, increases from infancy to adolescence, and accounts for a substantial proportion of all-cause YLD.
| S-EPMC7613313 | biostudies-literature
Project description:A number of rare copy number variants (CNVs), including both deletions and duplications, have been associated with developmental disorders, including schizophrenia, autism, intellectual disability, and epilepsy. Pathogenicity may derive from dosage sensitivity of one or more genes contained within the CNV locus. To understand pathophysiology, the specific disease-causing gene(s) within each CNV need to be identified. In the present study, we test the hypothesis that ohnologs (genes retained after ancestral whole-genome duplication events, which are frequently dosage sensitive) are overrepresented in pathogenic CNVs. We selected three sets of genes implicated in copy number pathogenicity: (i) genes mapping within rare disease-associated CNVs, (ii) genes within de novo CNVs under negative genetic selection, and (iii) genes identified by clinical array comparative genome hybridization studies as potentially pathogenic. We compared the proportion of ohnologs between these gene sets and control genes, mapping to CNVs not known to be disease associated. We found that ohnologs are significantly overrepresented in genes mapping to pathogenic CNVs, irrespective of how CNVs were identified, with over 90% containing an ohnolog, compared with control CNVs >100 kb, where only about 30% contained an ohnolog. In some CNVs, such as del15p11.2 (CYFIP1) and dup/del16p13.11 (NDE1), the most plausible prior candidate gene was also an ohnolog, as were the genes VIPR2 and NRXN1, each found in short CNVs containing no other genes. Our results support the hypothesis that ohnologs represent critical dosage-sensitive elements of the genome, possibly responsible for some of the deleterious phenotypes observed for pathogenic CNVs and as such are readily identifiable candidate genes for further study.
| S-EPMC3890797 | biostudies-other
Project description:ImportanceAt least 11 rare copy number variants (CNVs) have been shown to be major risk factors for schizophrenia (SZ). These CNVs also increase the risk for other neurodevelopmental disorders, such as intellectual disability. It is possible that additional intellectual disability-associated CNVs increase the risk for SZ but have not yet been implicated in SZ because of previous studies being underpowered.ObjectiveTo examine whether additional CNVs implicated in intellectual disability represent novel SZ risk loci.Design, setting, and participantsWe used single-nucleotide polymorphism (SNP) array data to evaluate a set of 51 CNVs implicated in intellectual disability (excluding the known SZ loci) in a large data set of patients with SZ and healthy persons serving as controls recruited in a variety of settings. We analyzed a new sample of 6934 individuals with SZ and 8751 controls and combined those data with previously published large data sets for a total of 20 403 cases of SZ and 26 628 controls.Main outcomes and measuresBurden analysis of CNVs implicated in intellectual disability (excluding known SZ CNVs) for association with SZ. Association of individual intellectual disability CNV loci with SZ.ResultsOf data on the 20 403 cases (6151 [30.15%] female) and 26 628 controls (14 252 [53.52%] female), 51 intellectual disability CNVs were analyzed. Collectively, intellectual disability CNVs were significantly enriched for SZ (P = 1.0 × 10-6; odds ratio [OR], 1.9 [95% CI, 1.46-2.49]). Of the 51 CNVs tested, 19 (37%) were more common in SZ cases; only 4 (8%) were more common in controls (no observations were made for the remaining 28 [55%] loci). One novel locus, deletion at 16p12.1, was significantly associated with SZ after correction for multiple testing (rate in SZ, 33 [0.16%]; rate in controls, 12 [0.05%]; corrected P = .017; OR, 3.3; 95% CI, 1.61-7.05), and 2 loci reached nominal levels of significance (deletions at 2q11.2: 6 [0.03%] vs 1 [0.004%]; OR, 9.3; 95% CI, 1.03-447.76; corrected P > .99; and duplications at 10q11.21q11.23: 5 [0.2%] vs 0 [0.03%]; OR, infinity; 95% CI, 1.26-infinity; corrected P = .71). Our new data set also provided independent support for the 11 SZ risk loci previously reported to be associated with the disorder and for the protective effect of 22q11.2 duplication.Conclusions and relevanceA large proportion of CNV loci implicated in intellectual disability are risk factors for SZ, but the available sample size precludes statistical confirmation for additional individual loci.
| S-EPMC5014093 | biostudies-literature
Project description:BACKGROUND:De novo mutations are a frequent cause of disorders related to brain development. We report the results of screening patients diagnosed with both epilepsy and intellectual disability (ID) using exome sequencing to identify known and new causative de novo mutations relevant to these conditions. METHODS:Exome sequencing was performed on 39 patient-parent trios to identify de novo mutations. Clinical significance of de novo mutations in genes was determined using the American College of Medical Genetics and Genomics standard guidelines for interpretation of coding variants. Variants in genes of unknown clinical significance were further analysed in the context of previous trio sequencing efforts in neurodevelopmental disorders. RESULTS:In 39 patient-parent trios we identified 29 de novo mutations in coding sequence. Analysis of de novo and inherited variants yielded a molecular diagnosis in 11 families (28.2%). In combination with previously published exome sequencing results in neurodevelopmental disorders, our analysis implicates HECW2 as a novel candidate gene in ID and epilepsy. CONCLUSIONS:Our results support the use of exome sequencing as a diagnostic approach for ID and epilepsy, and confirm previous results regarding the importance of de novo mutations in this patient group. The results also highlight the utility of network analysis and comparison to previous large-scale studies as strategies to prioritise candidate genes for further studies. This study adds knowledge to the increasingly growing list of causative and candidate genes in ID and epilepsy and highlights HECW2 as a new candidate gene for neurodevelopmental disorders.
| S-EPMC5099177 | biostudies-literature
Project description:BackgroundArray genomic hybridization is being used clinically to detect pathogenic copy number variants in children with intellectual disability and other birth defects. However, there is no agreement regarding the kind of array, the distribution of probes across the genome, or the resolution that is most appropriate for clinical use.ResultsWe performed 500 K Affymetrix GeneChip array genomic hybridization in 100 idiopathic intellectual disability trios, each comprised of a child with intellectual disability of unknown cause and both unaffected parents. We found pathogenic genomic imbalance in 16 of these 100 individuals with idiopathic intellectual disability. In comparison, we had found pathogenic genomic imbalance in 11 of 100 children with idiopathic intellectual disability in a previous cohort who had been studied by 100 K GeneChip array genomic hybridization. Among 54 intellectual disability trios selected from the previous cohort who were re-tested with 500 K GeneChip array genomic hybridization, we identified all 10 previously-detected pathogenic genomic alterations and at least one additional pathogenic copy number variant that had not been detected with 100 K GeneChip array genomic hybridization. Many benign copy number variants, including one that was de novo, were also detected with 500 K array genomic hybridization, but it was possible to distinguish the benign and pathogenic copy number variants with confidence in all but 3 (1.9%) of the 154 intellectual disability trios studied.ConclusionAffymetrix GeneChip 500 K array genomic hybridization detected pathogenic genomic imbalance in 10 of 10 patients with idiopathic developmental disability in whom 100 K GeneChip array genomic hybridization had found genomic imbalance, 1 of 44 patients in whom 100 K GeneChip array genomic hybridization had found no abnormality, and 16 of 100 patients who had not previously been tested. Effective clinical interpretation of these studies requires considerable skill and experience.
| S-EPMC2781027 | biostudies-literature
Project description:BackgroundArray comparative genomic hybridization (a-CGH) has become the first-tier investigation in patients with unexplained developmental delay/intellectual disability (DD/ID). Although the costs are progressively decreasing, a-CGH is still an expensive and labour-intensive technique: for this reason a definition of the categories of patients that can benefit the most of the analysis is needed. Aim of the study was to retrospectively analyze the clinical features of children with DD/ID attending the outpatient clinic of the Mother & Child Department of the University Hospital of Modena subjected to a-CGH, to verify by uni- and multivariate analysis the independent predictors of pathogenic CNVs.Methods116 patients were included in the study. Data relative to the CNVs and to the patients' clinical features were analyzed for genotype/phenotype correlations.Results and conclusions27 patients (23.3%) presented pathogenic CNVs (21 deletions, 3 duplications and 3 cases with both duplications and deletions). Univariate analysis showed a significant association of the pathogenic CNVs with the early onset of symptoms (before 1 yr of age) and the presence of malformations and dysmorphisms. Logistic regression analysis showed a significant independent predictive value for diagnosing a pathogenic CNV for malformations (P = 0.002) and dysmorphisms (P = 0.023), suggesting that those features should address a-CGH analysis as a high-priority test for diagnosis.
| S-EPMC4014206 | biostudies-literature
Project description:To identify novel epilepsy genes using a panel approach and describe the functional consequences of mutations.Using a panel approach, we screened 357 patients comprising a vast spectrum of epileptic disorders for defects in genes known to contribute to epilepsy and/or intellectual disability (ID). After detection of mutations in a novel epilepsy gene, we investigated functional effects in Xenopus laevis oocytes and screened a follow-up cohort.We revealed de novo mutations in GRIN2B encoding the NR2B subunit of the N-methyl-D-aspartate (NMDA) receptor in 2 individuals with West syndrome and severe developmental delay as well as 1 individual with ID and focal epilepsy. The patient with ID and focal epilepsy had a missense mutation in the extracellular glutamate-binding domain (p.Arg540His), whereas both West syndrome patients carried missense mutations within the NR2B ion channel-forming re-entrant loop (p.Asn615Ile, p.Val618Gly). Subsequent screening of 47 patients with unexplained infantile spasms did not reveal additional de novo mutations, but detected a carrier of a novel inherited GRIN2B splice site variant in close proximity (c.2011-5_2011-4delTC). Mutations p.Asn615Ile and p.Val618Gly cause a significantly reduced Mg(2+) block and higher Ca(2+) permeability, leading to a dramatically increased Ca(2+) influx, whereas p.Arg540His caused less severe disturbance of channel function, corresponding to the milder patient phenotype.We identified GRIN2B gain-of-function mutations as a cause of West syndrome with severe developmental delay as well as of ID with childhood onset focal epilepsy. Severely disturbed channel function corresponded to severe clinical phenotypes, underlining the important role of facilitated NMDA receptor signaling in epileptogenesis.
| S-EPMC4223934 | biostudies-literature