Novel and Recurrent Copy Number Variants in ABCA4-Associated Retinopathy.
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ABSTRACT:
SUBMITTER: Corradi Z
PROVIDER: S-EPMC11173210 | biostudies-literature | 2024 May
REPOSITORIES: biostudies-literature
Publications
Novel and Recurrent Copy Number Variants in <i>ABCA4</i>-Associated Retinopathy.
Corradi Zelia Z Dhaenens Claire-Marie CM Grunewald Olivier O Kocabaş Ipek Selen IS Meunier Isabelle I Banfi Sandro S Karali Marianthi M Cremers Frans P M FPM Hitti-Malin Rebekkah J RJ
International journal of molecular sciences 20240529 11
<i>ABCA4</i> is the most frequently mutated gene leading to inherited retinal disease (IRD) with over 2200 pathogenic variants reported to date. Of these, ~1% are copy number variants (CNVs) involving the deletion or duplication of genomic regions, typically >50 nucleotides in length. An in-depth assessment of the current literature based on the public database LOVD, regarding the presence of known CNVs and structural variants in <i>ABCA4</i>, and additional sequencing analysis of <i>ABCA4</i> u ...[more]
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Project description:PurposeTo identify the missing heritability of ABCA4-related retinopathy in a Chinese cohort.MethodsWe recruited 33 unrelated patients with ABCA4-related retinopathy carrying a monoallelic variant in ABCA4. All patients underwent ophthalmic examinations. Next-generation sequencing of the whole ABCA4 sequence, including coding and noncoding regions, was performed to detect deep intronic variants (DIVs) and copy number variations (CNVs).ResultsWe identified eight missing pathogenic ABCA4 variants in 60.6% of the patients (20/33), which comprised five DIVs and three CNVs. The five DIVs, including four novel (c.1555-816T>G, c.2919-169T>G, c.2919-884G>T, and c.5461-1321A>G) and one reported (c.4539+1100A>G), accounted for the missing alleles in 51.5% of the patients. Minigene assays showed that four novel DIVs activated cryptic splice sites leading to the insertions of pseudoexons. The three novel CNVs consisted of one gross deletion of 1273 bp (exon 2) and two gross duplications covering 25.2 kb (exons 28-43) and 9.4 kb (exons 38-44). The microhomology domains were identified at the breakpoints and revealed the potential mechanisms of CNV formation.ConclusionsDIVs and CNVs explained approximately two-thirds of the unresolved Chinese cases with ABCA4-related retinopathy. Combining results from phenotypic-directed screening, targeting the whole ABCA4 sequencing and in silico tools can help to identify the missing heritability.
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Project description:BackgroundMultiple rare copy number variants (CNVs) including genomic deletions and duplications play a prominent role in neurodevelopmental disorders such as mental retardation, autism, and schizophrenia, but have not been systematically studied in Tourette syndrome (TS).MethodsWe performed a genome-wide screening of single nucleotide polymorphism (SNP) genotyping microarray data to identify recurrent or de novo rare exonic CNVs in a case-control association study of patients with TS.ResultsWe identified 5 exon-affecting rare CNVs that are either de novo or recurrent in 10 out of 111 patients with TS but were not found in 73 ethnically matched controls or in the entries of the Database of Genomic Variants (containing 21,178 CNVs at 6,558 loci). Three out of the 5 CNVs have been implicated previously by other studies in schizophrenia, autism, and attention-deficit hyperactivity disorder, suggesting that these CNVs produce a continuum of neuropsychiatric disturbances that manifest in different ways depending on other genetic, environmental, or stochastic factors.ConclusionsRare, recurrent exonic copy number variants are associated in a subset of patients with Tourette syndrome.
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Project description:ImportanceRecurrent copy number variants (rCNVs) have been associated with increased risk of psychiatric disorders in case-control studies, but their population-level impact is unknown.ObjectiveTo provide unbiased population-based estimates of prevalence and risk associated with psychiatric disorders for rCNVs and to compare risks across outcomes, rCNV dosage type (deletions or duplications), and locus features.Design, setting, and participantsThis genetic association study is an analysis of data from the Lundbeck Foundation Initiative for Integrative Psychiatric Research (iPSYCH) case-cohort sample of individuals born in Denmark in 1981-2008 and followed up until 2015, including (1) all individuals (n = 92 531) with a hospital discharge diagnosis of attention-deficit/hyperactivity disorder (ADHD), autism spectrum disorder (ASD), bipolar disorder, major depressive disorder (MDD), or schizophrenia spectrum disorder (SSD) and (2) a subcohort (n = 50 625) randomly drawn from the source population. Data were analyzed from January 2021 to August 2023.ExposuresCarrier status of deletions and duplications at 27 autosomal rCNV loci was determined from neonatal blood samples genotyped on single-nucleotide variant microarrays.Main outcomes and measuresPopulation-based rCNV prevalence was estimated with a survey model using finite population correction to account for oversampling of cases. Hazard ratio (HR) estimates and 95% CIs for psychiatric disorders were derived using weighted Cox proportional hazard models. Risks were compared across outcomes, dosage type, and locus features using generalized estimating equation models.ResultsA total of 3547 rCNVs were identified in 64 735 individuals assigned male at birth (53.8%) and 55 512 individuals assigned female at birth (46.2%) whose age at the end of follow-up ranged from 7.0 to 34.7 years (mean, 21.8 years). Most observed increases in rCNV-associated risk for ADHD, ASD, or SSD were moderate, and risk estimates were highly correlated across these disorders. Notable exceptions included high ASD-associated risk observed for Prader-Willi/Angelman syndrome duplications (HR, 20.8; 95% CI, 7.9-55). No rCNV was associated with increased MDD risk. Also, rCNV-associated risk was positively correlated with locus size and gene constraint but not with dosage type. Comparison with published case-control and community-based studies revealed a higher prevalence of deletions and lower associated increase in risk for several rCNVs in iPSYCH2015.Conclusions and relevanceThis study found that several rCNVs were more prevalent and conferred less risk of psychiatric disorders than estimated previously. Most case-control studies overestimate rCNV-associated risk of psychiatric disorders, likely because of selection bias. In an era where genetics is increasingly being clinically applied, these results highlight the importance of population-based risk estimates for genetics-based predictions.
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Project description:PurposeTo determine whether rare copy number variants (CNVs) increase risk for comitant esotropia.MethodsCNVs were identified in 1614 Caucasian individuals with comitant esotropia and 3922 Caucasian controls from Illumina SNP genotyping using two Hidden Markov model (HMM) algorithms, PennCNV and QuantiSNP, which call CNVs based on logR ratio and B allele frequency. Deletions and duplications greater than 10 kb were included. Common CNVs were excluded. Association testing was performed with 1 million permutations in PLINK. Significant CNVs were confirmed with digital droplet polymerase chain reaction (ddPCR). Whole genome sequencing was performed to determine insertion location and breakpoints.ResultsEsotropia patients have similar rates and proportions of CNVs compared with controls but greater total length and average size of both deletions and duplications. Three recurrent rare duplications significantly (P = 1 × 10-6) increase the risk of esotropia: chromosome 2p11.2 (hg19, 2:87428677-87965359), spanning one long noncoding RNA (lncRNA) and two microRNAs (OR 14.16; 95% confidence interval [CI] 5.4-38.1); chromosome 4p15.2 (hg19, 4:25554332-25577184), spanning one lncRNA (OR 11.1; 95% CI 4.6-25.2); chromosome 10q11.22 (hg19, 10:47049547-47703870) spanning seven protein-coding genes, one lncRNA, and four pseudogenes (OR 8.96; 95% CI 5.4-14.9). Overall, 114 cases (7%) and only 28 controls (0.7%) had one of the three rare duplications. No case nor control had more than one of these three duplications.ConclusionsRare CNVs are a source of genetic variation that contribute to the genetic risk for comitant esotropia, which is likely polygenic. Future research into the functional consequences of these recurrent duplications may shed light on the pathophysiology of esotropia.
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Project description:BACKGROUND: Algorithms and software for CNV detection have been developed, but they detect the CNV regions sample-by-sample with individual-specific breakpoints, while common CNV regions are likely to occur at the same genomic locations across different individuals in a homogenous population. Current algorithms to detect common CNV regions do not account for the varying reliability of the individual CNVs, typically reported as confidence scores by SNP-based CNV detection algorithms. General methodologies for identifying these recurrent regions, especially those directed at SNP arrays, are still needed. RESULTS: In this paper, we describe two new approaches for identifying common CNV regions based on (i) the frequency of occurrence of reliable CNVs, where reliability is determined by high confidence scores, and (ii) a weighted frequency of occurrence of CNVs, where the weights are determined by the confidence scores. In addition, motivated by the fact that we often observe partially overlapping CNV regions as a mixture of two or more distinct subregions, regions identified using the two approaches can be fine-tuned to smaller sub-regions using a clustering algorithm. We compared the performance of the methods with sequencing-based results in terms of discordance rates, rates of departure from Hardy-Weinberg equilibrium (HWE) and average frequency and size of the identified regions. The discordance rates as well as the rates of departure from HWE decrease when we select CNVs with higher confidence scores. We also performed comparisons with two previously published methods, STAC and GISTIC, and showed that the methods we consider are better at identifying low-frequency but high-confidence CNV regions. CONCLUSIONS: The proposed methods for identifying common CNV regions in multiple individuals perform well compared to existing methods. The identified common regions can be used for downstream analyses such as group comparisons in association studies.
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