Rare Copy Number Variants Research Articles

Copy Number Variants Are Ovarian Cancer Risk Alleles at Known and Novel Risk Loci.

Known risk alleles for epithelial ovarian cancer (EOC) account for approximately 40% of the heritability for EOC. Copy number variants (CNVs) have not been investigated as EOC risk alleles in a large population cohort. Single nucleotide polymorphism array data from 13 071 EOC cases and 17 306 controls of White European ancestry were used to identify CNVs associated with EOC risk using a rare admixture maximum likelihood test for gene burden and a by-probe ratio test. We performed enrichment analysis of CNVs at known EOC risk loci and functional biofeatures in ovarian cancer-related cell types. We identified statistically significant risk associations with CNVs at known EOC risk genes; BRCA1 (PEOC = 1.60E-21; OREOC = 8.24), RAD51C (Phigh-grade serous ovarian cancer [HGSOC] = 5.5E-4; odds ratio [OR]HGSOC = 5.74 del), and BRCA2 (PHGSOC = 7.0E-4; ORHGSOC = 3.31 deletion). Four suggestive associations (P < .001) were identified for rare CNVs. Risk-associated CNVs were enriched (P < .05) at known EOC risk loci identified by genome-wide association study. Noncoding CNVs were enriched in active promoters and insulators in EOC-related cell types. CNVs in BRCA1 have been previously reported in smaller studies, but their observed frequency in this large population-based cohort, along with the CNVs observed at BRCA2 and RAD51C gene loci in EOC cases, suggests that these CNVs are potentially pathogenic and may contribute to the spectrum of disease-causing mutations in these genes. CNVs are likely to occur in a wider set of susceptibility regions, with potential implications for clinical genetic testing and disease prevention.

Investigation of Copy Number Variation in South African Patients With Congenital Heart Defects.

Congenital heart disease (CHD) is a leading non-infectious cause of pediatric morbidity and mortality worldwide. Although the etiology of CHD is poorly understood, genetic factors including copy number variants (CNVs) contribute to the risk of CHD in individuals of European ancestry. The presence of rare CNVs in African CHD populations is unknown. This study aimed to identify pathogenic and likely pathogenic CNVs in South African patients with CHD. Genotyping was performed on 90 patients with nonsyndromic CHD using the Affymetrix CytoScan HD platform. These data were used to identify large, rare CNVs in known CHD-associated genes and candidate genes. We identified eight CNVs overlapping known CHD-associated genes (GATA4, CRKL, TBX1, FLT4, B3GAT3, NSD1) in six patients. The analysis also revealed CNVs encompassing five candidate genes likely to play a role in the development of CHD (DGCR8, KDM2A, JARID2, FSTL1, CYFIP1) in five patients. One patient was found to have 47, XXY karyotype. We report a total discovery yield of 6.7%, with 5.6% of the cohort carrying pathogenic or likely pathogenic CNVs expected to cause the observed phenotypes. In this study, we show that chromosomal microarray is an effective technique for identifying CNVs in African patients diagnosed with CHD and have demonstrated results similar to previous CHD genetic studies in Europeans. Novel potential CHD genes were also identified, indicating the value of genetic studies of CHD in ancestrally diverse populations.

Investigating the contributions of circadian pathway and insomnia risk genes to autism and sleep disturbances

Sleep disturbance is prevalent in youth with Autism Spectrum Disorder (ASD). Researchers have posited that circadian dysfunction may contribute to sleep problems or exacerbate ASD symptomatology. However, there is limited genetic evidence of this. It is also unclear how insomnia risk genes identified through GWAS in general populations are related to ASD and common sleep problems like insomnia traits in ASD. We investigated the contribution of copy number variants (CNVs) encompassing circadian pathway genes and insomnia risk genes to ASD risk as well as sleep disturbances in children with ASD. We studied 5860 ASD probands and 2092 unaffected siblings from the Simons Simplex Collection (SSC) and MSSNG database, as well as 7509 individuals from two unselected populations (IMAGEN and Generation Scotland). Sleep duration and insomnia symptoms were parent reported for SSC probands. We identified 335 and 616 rare CNVs encompassing circadian and insomnia risk genes respectively. Deletions and duplications with circadian genes were overrepresented in ASD probands compared to siblings and unselected controls. For insomnia-risk genes, deletions (not duplications) were associated with ASD in both cohorts. Results remained significant after adjusting for cognitive ability. CNVs containing circadian pathway and insomnia risk genes showed a stronger association with ASD, compared to CNVs containing other genes. Circadian genes did not influence sleep duration or insomnia traits in ASD. Insomnia risk genes intolerant to haploinsufficiency increased risk for insomnia when duplicated. CNVs encompassing circadian and insomnia risk genes increase ASD liability with little to no observable impacts on sleep disturbances.

5.4 Exploring Gene Dosage Disorders in the Healthcare Setting

ObjectivesASD, schizophrenia, and other clinically distinct neurodevelopmental/psychiatric disorders (NPDs) have shared genetic etiologies, including copy number variants (CNVs) and single gene disorders. To date, rare variants that cause NPDs have primarily been investigated in clinically ascertained cohorts, therefore population-based estimates of their prevalence and penetrance are lacking. Here, we explored the prevalence, penetrance, and personal utility of NPD CNVs and single gene variants in a large healthcare system population.MethodsWe analyzed linked genomic and electronic health record (EHR) data from 90,595 participants in Geisinger’s MyCode® Community Health Initiative. Pathogenic variants involving 31 recurrent NPD CNVs and loss-of-function variants in 94 high-confidence NPD genes were identified through exome sequencing. NPD penetrance was calculated using preselected EHR diagnosis codes. We examined the personal utility of receiving these results in a selected set of NPD CNVs by evaluating the participants’ psychosocial reactions using a mixed-methods approach.ResultsIn this healthcare system population, CNVs and single gene variants that cause NPDs were prevalent (∼1.1% of participants) and penetrant. Participant responses to receiving these genomic results were positive overall, suggesting personal utility in learning this information and incorporating it into their health care.ConclusionsCollectively, rare NPD CNVs and single gene variants play an important contributory role in mental health disorders. Population screening for pathogenic variants to identify high-risk groups could improve clinical outcomes through early intervention and anticipatory therapeutic support.GS, ND, OTH ObjectivesASD, schizophrenia, and other clinically distinct neurodevelopmental/psychiatric disorders (NPDs) have shared genetic etiologies, including copy number variants (CNVs) and single gene disorders. To date, rare variants that cause NPDs have primarily been investigated in clinically ascertained cohorts, therefore population-based estimates of their prevalence and penetrance are lacking. Here, we explored the prevalence, penetrance, and personal utility of NPD CNVs and single gene variants in a large healthcare system population. ASD, schizophrenia, and other clinically distinct neurodevelopmental/psychiatric disorders (NPDs) have shared genetic etiologies, including copy number variants (CNVs) and single gene disorders. To date, rare variants that cause NPDs have primarily been investigated in clinically ascertained cohorts, therefore population-based estimates of their prevalence and penetrance are lacking. Here, we explored the prevalence, penetrance, and personal utility of NPD CNVs and single gene variants in a large healthcare system population. MethodsWe analyzed linked genomic and electronic health record (EHR) data from 90,595 participants in Geisinger’s MyCode® Community Health Initiative. Pathogenic variants involving 31 recurrent NPD CNVs and loss-of-function variants in 94 high-confidence NPD genes were identified through exome sequencing. NPD penetrance was calculated using preselected EHR diagnosis codes. We examined the personal utility of receiving these results in a selected set of NPD CNVs by evaluating the participants’ psychosocial reactions using a mixed-methods approach. We analyzed linked genomic and electronic health record (EHR) data from 90,595 participants in Geisinger’s MyCode® Community Health Initiative. Pathogenic variants involving 31 recurrent NPD CNVs and loss-of-function variants in 94 high-confidence NPD genes were identified through exome sequencing. NPD penetrance was calculated using preselected EHR diagnosis codes. We examined the personal utility of receiving these results in a selected set of NPD CNVs by evaluating the participants’ psychosocial reactions using a mixed-methods approach. ResultsIn this healthcare system population, CNVs and single gene variants that cause NPDs were prevalent (∼1.1% of participants) and penetrant. Participant responses to receiving these genomic results were positive overall, suggesting personal utility in learning this information and incorporating it into their health care. In this healthcare system population, CNVs and single gene variants that cause NPDs were prevalent (∼1.1% of participants) and penetrant. Participant responses to receiving these genomic results were positive overall, suggesting personal utility in learning this information and incorporating it into their health care. ConclusionsCollectively, rare NPD CNVs and single gene variants play an important contributory role in mental health disorders. Population screening for pathogenic variants to identify high-risk groups could improve clinical outcomes through early intervention and anticipatory therapeutic support.GS, ND, OTH Collectively, rare NPD CNVs and single gene variants play an important contributory role in mental health disorders. Population screening for pathogenic variants to identify high-risk groups could improve clinical outcomes through early intervention and anticipatory therapeutic support.

22.1 Gene Copy Number Variation in Pediatric Mental Health

Rare copy number variants (CNVs) likely play an important role in common childhood neuropsychiatric disorders such as ADHD and OCD. These disorders represent the extremes of broadly distributed behavioral traits that are influenced by underlying variation in fundamental cognitive processes such as response inhibition. Trait-based approaches in a population sample can help reduce heterogeneity and improve the power to detect rare CNVs associated with these disorders. Currently, we do not know the prevalence of CNVs related to neuropsychiatric disorders in youth in the general population.

5.2 Copy Number Variants (CNVs) in General Adult Psychiatry and Their Translation to the Clinic

Large, rare copy number variants (CNVs) are established risk factors for disorders on the neurodevelopmental spectrum including intellectual disability, ASD, and schizophrenia. However, it is possible to carry a neurodevelopmental disorder–associated CNV (neurodevelopmental CNV) and to not develop one of these disorders, and perhaps even to appear unaffected. The aims of my presentation are to: 1) explain the effects of neurodevelopmental CNVs outside of the neurodevelopmental spectrum; and 2) explore the implications of phenotypic associations with neurodevelopmental CNVs for clinical practice in general adult psychiatry.

Rates of rare copy number variants in different circumstances among patients with genetic developmental and epileptic encephalopathy.

Most patients with developmental and epileptic encephalopathy (DEE) have genetic etiology, which has been uncovered with different methods. Although chromosomal microarray analysis (CMA) has been broadly used in patients with DEE, data is still limited. Among 560 children (<18 years) who underwent CMA in our hospital between January 2013 and June 2021, 146 patients with developmental delay and recurrent seizures were screened. Patients with major brain abnormalities, metabolic abnormalities, and specific syndromes were excluded. The rate of rare copy number variants (CNVs) was estimated in total and according to seizure-onset age, relation to first seizure with the diagnosis of developmental delay, epilepsy syndromes, and organ anomalies. Among the 110 patients enrolled, the rate of rare CNVs was 16.4%, varying by seizure-onset age: 33.3% in three neonates, 21.2% in 33 infants, 13.3% in 45 early childhood patients, 5.3% in 19 late childhood patients, and 30.0% in 10 adolescents. In relation to the first seizure with the diagnosis of developmental delay, the rates were 3.7%, 22.2%, and 12.5% in "before", "after", and "concurrent" subclasses, respectively. The rates of rare CNVs were 16.7% in "other predominantly focal or multifocal epilepsy", 28.6% in "other predominantly generalized epilepsy (PGE)", and 15.4% in West syndrome. The rates were 27.8% in minor brain anomalies, 37.5% in facial dysmorphism, and 22.2%, 20.0%, and 57.1% in endocrine, genitourinary and cardiovascular anomalies, respectively. The rate of rare CNVs in patients with genetic DEE was 16.4% in total, which was higher in seizures occurring below the infantile period or after the diagnosis of developmental delay, in PGE, and in the presence of facial dysmorphism or cardiovascular anomalies.

Influences of rare copy-number variation on human complex traits

The human genome contains hundreds of thousands of regions harboring copy-number variants (CNV). However, the phenotypic effects of most such polymorphisms are unknown because only larger CNVs have been ascertainable from SNP-array data generated by large biobanks. We developed a computational approach leveraging haplotype sharing in biobank cohorts to more sensitively detect CNVs. Applied to UKBiobank, this approach accounted for approximately half of all rare gene inactivation events produced by genomic structural variation. This CNV call set enabled a detailed analysis of associations between CNVs and 56 quantitative traits, identifying 269 independent associations (p<5×10-8) likely to be causally driven by CNVs. Putative target genes were identifiable for nearly half of the loci, enabling insights intodosage sensitivity of these genes and uncovering several gene-trait relationships. These results demonstrate the ability of haplotype-informed analysis to provide insights into the genetic basis of human complex traits.

Accurate in silico confirmation of rare copy number variant calls from exome sequencing data using transfer learning.

Exome sequencing is widely used in genetic studies of human diseases and clinical genetic diagnosis. Accurate detection of copy number variants (CNVs) is important to fully utilize exome sequencing data. However, exome data are noisy. None of the existing methods alone can achieve both high precision and recall rate. A common practice is to perform heuristic filtration followed by manual inspection of read depth of putative CNVs. This approach does not scale in large studies. To address this issue, we developed a transfer learning method, CNV-espresso, for in silico confirming rare CNVs from exome sequencing data. CNV-espresso encodes candidate CNVs from exome data as images and uses pretrained convolutional neural network models to classify copy number states. We trained CNV-espresso using an offspring-parents trio exome sequencing dataset, with inherited CNVs as positives and CNVs with Mendelian errors as negatives. We evaluated the performance using additional samples that have both exome and whole-genome sequencing (WGS) data. Assuming the CNVs detected from WGS data as a proxy of ground truth, CNV-espresso significantly improves precision while keeping recall almost intact, especially for CNVs that span a small number of exons. CNV-espresso can effectively replace manual inspection of CNVs in large-scale exome sequencing studies.

Multisite assessment of the impact of cell-free DNA-based screening for rare autosomal aneuploidies on pregnancy management and outcomes.

Cell-free (cf) DNA screening is a noninvasive prenatal screening approach that is typically used to screen for common fetal trisomies, with optional screening for sex chromosomal aneuploidies and fetal sex. Genome-wide cfDNA screening can screen for a wide variety of additional anomalies, including rare autosomal aneuploidies (RAAs) and copy number variants. Here, we describe a multi-cohort, global retrospective study that looked at the clinical outcomes of cases with a high-risk cfDNA screening result for a RAA. Our study cohort included a total of 109 cases from five different sites, with diagnostic outcome information available for 68% (74/109) of patients. Based on confirmatory diagnostic testing, we found a concordance rate of 20.3% for presence of a RAA (15/74) in our study population. Pregnancy outcome was also available for 77% (84/109) of cases in our cohort. Many of the patients experienced adverse pregnancy outcomes, including intrauterine fetal demise, fetal growth restriction, and preterm birth. These adverse outcomes were observed both in patients with fetal or placental confirmation of the presence of a RAA, as well as patients that did not undergo fetal and/or placental diagnostic testing. In addition, we have proposed some suggestions for pregnancy management and counseling considerations for situations where a RAA is noted on a cfDNA screen. In conclusion, our study has shown that genome-wide cfDNA screening for the presence of rare autosomal aneuploidies can be beneficial for both patients and their healthcare practitioners. This can provide a possible explanation for an adverse pregnancy outcome or result in a change in pregnancy management, such as increased monitoring for adverse outcomes.

Phenotype and Genotype in a Taiwanese Girl with Sotos Syndrome

Rare copy number variations have been linked to an important source of mutation in many psychopathological traits and neurodevelopmental disorders. In this study, we describe a Taiwanese girl with mental retardation and mild macrocephaly who underwent a childhood psychological evaluation for several years first. When she was 5 years old, she came to our hospital for further diagnosis. We conducted molecular cytogenetic tests and confirmed she actually has Sotos syndrome. We compared our case with two others with very similar deletion regions, but their phenotypes were heterogeneous. Sotos syndrome is very rare in Taiwan, and it is suggested that genetic analysis should be considered early if symptoms of this case are observed.

Next-Generation Sequencing Highlights of Diffuse Large B-cell Lymphoma in a Tertiary Care Hospital in North India.

Introduction: Next-generation sequencing (NGS) elucidates the diffuse large B-cell lymphoma (DLBCL) genetic characteristics by finding recurrent and novel somatic mutations. This observational study attempted to create an NGS panel with a focus on identifying novel somatic mutations which could have potential clinical and therapeutic implications. This panel was created to look for mutations in 133 genes chosen on basis of a literature review and it was used to sequence the tumor DNA of 20 DLBCL patients after a centralized histopathologic review.Methods: The study included 20 patients having DLBCL. The quality and quantity of tumor cells were accessed by H&E staining and correlated with histopathology and Immunohistochemistry (IHC) status. Patients were grouped as ABC (activated B-cell), PMBL (primary mediastinal large B-cell lymphoma), and other or unclassified subtypes. The lymphoma panel of 133 was designed on targeted sequencing of multiple genes for the coding regions through NGS. The libraries were prepared and sequenced using the Illumina platform. The alignment of obtained sequences was performed using Burrows-Wheeler Aligner and identification of somatic mutations was done using LoFreq (version 2) variant caller. The mutations were annotated using an annotation pipeline (VariMAT). Previously published literature and databases were used for the annotation of clinically relevant mutations. The common variants were filtered for reporting based on the presence in various population databases (1000G, ExAC, EVS, 1000Japanese, dbSNP, UK10K, MedVarDb). A custom read-depth-based algorithm was used to determine CNV (Copy Number Variants) from targeted sequencing experiments. Rare CNVs were detected using a comparison of the test data read-depths with the matched reference dataset. Reportable mutations were prioritized and prepared based on AMP-ASCO-CAP (Association for Molecular Pathology-American Society of Clinical Oncology-College of American Pathologists), WHO guidelines, and also based on annotation metrics from OncoMD (a knowledge base of genomic alterations).Results: The informativity of the panel was 95 percent. NOTCH 1 was the most frequently mutated gene in 16.1% of patients followed by 12.9% who had ARID1A mutations. MYD88 and TP53 mutations were detected in 9.6% of the patient while 6.4% of patients had CSF3R mutations. NOTCH 1 and TP 53 are the most frequently reported gene in the middle age group (40-60). Mutation in MYD88 is reported in every age group. MYD88 (51%) is the most common mutation in ABC subtypes of DLBCL, followed by NOTCH 1 (44%) and SOCS 1 (33%) according to our findings. NOTCH 1 mutations are frequent in ABC and PMBL subtypes. Closer investigation reveals missense mutation is the most frequent mutation observed in the total cohort targeting 68.4% followed by frameshift deletion reported in 26.3%. Six novel variants have been discovered in this study.Conclusions: This study demonstrates the high yield of information in DLBCL using the NGS Lymphoma panel. Results also highlight the molecular heterogeneity of DLBCL subtypes which indicates the need for further studies to make the results of the NGS more clinically relevant.

Rare coding variation provides insight into the genetic architecture and phenotypic context of autism.

Some individuals with autism spectrum disorder (ASD) carry functional mutations rarely observed in the general population. We explored the genes disrupted by these variants from joint analysis of protein-truncating variants (PTVs), missense variants and copy number variants (CNVs) in a cohort of 63,237 individuals. We discovered 72 genes associated with ASD at false discovery rate (FDR) ≤ 0.001 (185 at FDR ≤ 0.05). De novo PTVs, damaging missense variants and CNVs represented 57.5%, 21.1% and 8.44% of association evidence, while CNVs conferred greatest relative risk. Meta-analysis with cohorts ascertained for developmental delay (DD) (n = 91,605) yielded 373 genes associated with ASD/DD at FDR ≤ 0.001 (664 at FDR ≤ 0.05), some of which differed in relative frequency of mutation between ASD and DD cohorts. The DD-associated genes were enriched in transcriptomes of progenitor and immature neuronal cells, whereas genes showing stronger evidence in ASD were more enriched in maturing neurons and overlapped with schizophrenia-associated genes, emphasizing that these neuropsychiatric disorders may share common pathways to risk.

Identification of novel rare copy number variants associated with sporadic tetralogy of Fallot and clinical implications

Tetralogy of Fallot (TOF) is the most common cyanotic congenital heart disease. Highly penetrant copy number variants (CNVs) and genes related to the etiology of TOF likely exist with differences among populations. We aimed to identify CNV contributions to sporadic TOF cases in Han Chinese. Genomic DNA was extracted from peripheral blood in 605 subjects (303 sporadic TOF and 302 unaffected Han Chinese [Control] from cardiac centers in China) and analyzed by genome-wide association study (GWAS). The GWAS results were compared with existing Database of Genetic Variants. These CNVs were further validated by qPCR. Bioinformatics analyses were performed with protein-protein interaction (PPI) network and KEGG pathway enrichment. Across all chromosomes 119 novel "TOF-specific CNVs" were identified with prevalence of CNVs of 21.5% in chromosomes 1-20 and 37.0% including Chr21/22. In chromosomes 1-20, CNVs on 11q25 (encompasses genes ACAD8, B3GAT1, GLB1L2, GLB1L3, IGSF9B, JAM3, LOC100128239, LOC283177, MIR4697, MIR4697HG, NCAPD3, OPCML, SPATA19, THYN1, and VPS26B) and 14q32.33 (encompasses genes THYN1, OPCML, and NCAPD3) encompass genes most likely to be associated with TOF. Specific CNVs found on the chromosome 21 (6.3%) and 22(11.9%) were also identified in details. PPI network analysis identified the genes covering the specific CNVs related to TOF and the signaling pathways. This study for first time identified novel TOF-specific CNVs in the Han Chinese with higher frequency than in Caucasians and with 11q25 and 14q32.33 not reported in TOF of Caucasians. These novel CNVs identify new candidate genes for TOF and provide new insights into genetic basis of TOF.

A cross-disorder dosage sensitivity map of the human genome

Rare copy-number variants (rCNVs) include deletions and duplications that occur infrequently in the global human population and can confer substantial risk for disease. In this study, we aimed to quantify the properties of haploinsufficiency (i.e., deletion intolerance) and triplosensitivity (i.e., duplication intolerance) throughout the human genome. We harmonized and meta-analyzed rCNVs from nearly one million individuals to construct a genome-wide catalog of dosage sensitivity across 54 disorders, which defined 163 dosage sensitive segments associated with at least one disorder. These segments were typically gene dense and often harbored dominant dosage sensitive driver genes, which we were able to prioritize using statistical fine-mapping. Finally, we designed an ensemble machine-learning model to predict probabilities of dosage sensitivity (pHaplo & pTriplo) for all autosomal genes, which identified 2,987 haploinsufficient and 1,559 triplosensitive genes, including 648 that were uniquely triplosensitive. This dosage sensitivity resource will provide broad utility for human disease research and clinical genetics.

Chromosome 2q12.3-q13 copy number variants in patients with neurodevelopmental disorders: genotype-phenotype correlation and new hotspots.

The complex structure of the chromosome 2q12.3-q13 region provides a high chance of recombination events between various low copy repeats (LCRs). Copy number variants (CNV) in this region are present in both healthy populations and individuals affected with developmental delay, autism and congenital anomalies. Variable expressivity, reduced penetrance and limited characterization of the affected genes have complicated the classification of the CNVs clinical significance. Chromosomal microarray analysis data were reviewed for 10 298 patients with neurodevelopmental disorders referred to the UPMC Medical Genetics and Genomics Laboratories. A genotype-phenotype correlation was performed among the patients harboring the 2q12.3-q13 CNVs with overlapping genomic intervals. We identified 17 (1 in ~600) individuals with rare CNVs in the 2q12.3-q13 region, including nine patients with deletions, seven individuals with duplications and one patient who had both a deletion and a duplication. Likely pathogenic CNVs with the breakpoints between LCRs encompassing the potential dosage-sensitive genes BCL2L11, BUB1, FBLN7 and TMEM87B were the most common. CNVs were also observed between LCRs surrounding the RANBP2 and LIMS1 genes. Our study provides evidence for pathogenic CNV hotspots within the chromosome 2q12.3-q13 region. We suggest CNV classification based on the affected interval and the involvement of potential dosage-sensitive genes in these patients.

The genetic architecture of schizophrenia: review of large-scale genetic studies.

Schizophrenia is a complex and often chronic psychiatric disorder with high heritability. Diagnosis of schizophrenia is still made clinically based on psychiatric symptoms; no diagnostic tests or biomarkers are available. Pathophysiology-based diagnostic scheme and treatments are also not available. Elucidation of the pathogenesis is needed for development of pathology-based diagnostics and treatments. In the past few decades, genetic research has made substantial advances in our understanding of the genetic architecture of schizophrenia. Rare copy number variations (CNVs) and rare single-nucleotide variants (SNVs) detected by whole-genome CNV analysis and whole-genome/-exome sequencing analysis have provided the great advances. Common single-nucleotide polymorphisms (SNPs) detected by large-scale genome-wide association studies have also provided important information. Large-scale genetic studies have been revealed that both rare and common genetic variants play crucial roles in this disorder. In this review, we focused on CNVs, SNVs, and SNPs, and discuss the latest research findings on the pathogenesis of schizophrenia based on these genetic variants. Rare variants with large effect sizes can provide mechanistic hypotheses. CRISPR-based genetics approaches and induced pluripotent stem cell technology can facilitate the functional analysis of these variants detected in patients with schizophrenia. Recent advances in long-read sequence technology are expected to detect variants that cannot be detected by short-read sequence technology. Various studies that bring together data from common variant and transcriptomic datasets provide biological insight. These new approaches will provide additional insight into the pathophysiology of schizophrenia and facilitate the development of pathology-based therapeutics.

SHANK3 genetic polymorphism and susceptibility to ASD: evidence from molecular, in silico, and meta-analysis approaches.

The SHANK3 gene encodes a master synaptic scaffolding protein at the excitatory synapse's postsynaptic density, which is predominantly responsible for constructing a synapse, maintaining synaptic structure, and functions. Recently, evidence from rare mutations and copy number variation provided an important clue about SHANK3 which acts as a strong candidate gene in the pathogenesis of Autism Spectrum Disorder (ASD). To investigate potential allelic variants for the SHANK3 (rs9616915) gene as a genetic risk factor, we performed PCR-RFLP analysis and Sanger sequencing for 90 ASD and 90 healthy subjects. Moreover, to understand the functional and structural impacts of our selected non-synonymous SHANK3 SNP rs9616915, we have performed an in silico analysis. Subsequently, a meta-analysis of rs9616915 with a total of 6 eligible studies (including the present study) containing a total of 795 cases and 12,947 controls was obtained from a comprehensive online database search to evaluate the overall association with ASD. Our retrieved data, such as Pearson's chi-square test (p = 0.081) as well as logistic regression analysis of co-dominant (p = 0.1131), dominant (p = 0.3656) and recessive models (p = 0.0569) speculated no significant association between rs9616915 and our studied sample. Interestingly, by in silico analysis, we have observed two hydrogen bonds between amino acids instead of one hydrogen bond in the protein structure of rs9616915, which indicates this mutant structure could affect the proteins' stability. The findings of the meta-analysis revealed that four genetic association models were associated with ASD susceptibility. Our study suggested that targeted SHANK3 SNP of interest rs9616915 might not be associated with ASD in the southern part of the Bangladeshi population.

Positive predictive value estimates for noninvasive prenatal testing from data of a prenatal diagnosis laboratory and literature review

ObjectiveSince 2011, noninvasive prenatal testing (NIPT) has undergone rapid expansion, with both utilization and coverage. However, conclusive data regarding the clinical validity and utility of this testing tool are lacking. Thus, there is a continued need to educate clinicians and patients about the current benefits and limitations in order to inform pre- and post-test counseling, pre/perinatal decision making, and medical risk assessment/management.MethodsThis retrospective study included women referred for invasive prenatal diagnosis to confirm positive NIPT results between January 2017 and December 2020. Prenatal diagnosis testing, including karyotyping, chromosomal microarray analysis (CMA) were performed. Positive predictive values (PPVs) were calculated.ResultsIn total, 468 women were recruited. The PPVs for trisomies 21, 18, and 13 were 86.1%, 57.8%, and 25.0%, respectively. The PPVs for rare chromosomal abnormalities (RCAs) and copy number variants (CNVs) were 17.0% and 40.4%, respectively. The detection of sex chromosomal aneuploidies (SCAs) had a PPV of 20% for monosomy X, 23.5% for 47,XXX, 68.8% for 47,XXY, and 62.5% for 47,XYY. The high-risk groups had a significant increase in the number of true positive cases compared to the low- and moderate-risk groups.ConclusionsT13, monosomy X, and RCA were associated with lower PPVs. The improvement of cell-free fetal DNA screening technology and continued monitoring of its performance are important.

Exonic deletions in IMMP2L in schizophrenia with enhanced glycation stress subtype.

We previously identified a subtype of schizophrenia (SCZ) characterized by increased plasma pentosidine, a marker of glycation and oxidative stress (PEN-SCZ). However, the genetic factors associated with PEN-SCZ have not been fully clarified. We performed a genome-wide copy number variation (CNV) analysis to identify CNVs associated with PEN-SCZ to provide an insight into the novel therapeutic targets for PEN-SCZ. Plasma pentosidine was measured by high-performance liquid chromatography in 185 patients with SCZ harboring rare CNVs detected by array comparative genomic hybridization. In three patients with PEN-SCZ showing additional autistic features, we detected a novel deletion at 7q31.1 within exons 2 and 3 of IMMP2L, which encodes the inner mitochondrial membrane peptidase subunit 2. The deletion was neither observed in non-PEN-SCZ nor in public database of control subjects. IMMP2L is one of the SCZ risk loci genes identified in a previous SCZ genome-wide association study, and its trans-populational association was recently described. Interestingly, deletions in IMMP2L have been previously linked with autism spectrum disorder. Disrupted IMMP2L function has been shown to cause glycation/oxidative stress in neuronal cells in an age-dependent manner. To our knowledge, this is the first genome-wide CNV study to suggest the involvement of IMMP2L exons 2 and 3 in the etiology of PEN-SCZ. The combination of genomic information with plasma pentosidine levels may contribute to the classification of biological SCZ subtypes that show additional autistic features. Modifying IMMP2L functions may be useful for treating PEN-SCZ if the underlying biological mechanism can be clarified in further studies.