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Genetic epilepsy diagnosis is increasing due to technological advancements. Although the use of molecular diagnosis is increasing, chromosomal microarray analysis (CMA) remains an important diagnostic tool for many patients. We aim to explore the role and indications of CMA in epilepsy, given the current genomic advances. We obtained data from 378 epileptic described patients, who underwent CMA between 2015 and 2021. Different types of syndromic or nonsyndromic epilepsy were represented. After excluding patients who were undertreated or had missing data, we included 250 patients with treated epilepsy and relevant clinical information. These patients mostly had focal epilepsy or developmental and epileptic encephalopathy, with a median start age of 2 years. Ninety percent of the patients had intellectual disability, more than two thirds had normal head size, and 60% had an abnormal magnetic resonance imaging. We also included 10 patients with epilepsy without comorbidities. In our cohort, we identified 35 pathogenic copy number variations (CNVs) explaining epilepsy with nine recurrent CNVs enriched in patients with epilepsy, 12 CNVs related to neurodevelopmental disorder phenotype with possible epilepsy, five CNVs including a gene already known in epilepsy, and nine CNVs based on size combined with de novo occurrence. The diagnosis rate in our study reached 14% (35 of 250) with first-line CMA, as previously reported. Although targeted gene panel sequencing could potentially diagnose some of the reported epilepsy CNVs (34% [12 of 35]). CMA remains a viable option as the first-line genetic test in cases where other genetic tests are not available and as a second-line diagnostic technique if gene panel or exome sequencing yields negative results. [ABSTRACT FROM AUTHOR]

Mosaic chromosomal alterations are implicated in neuropsychiatric disorders, but the contribution to schizophrenia (SCZ) risk for somatic copy number variations (sCNVs) emerging in early developmental stages has not been fully established. We analyzed blood-derived genotype arrays from 9715 patients with SCZ and 28,822 control participants of Chinese descent using a computational tool (MoChA) based on long-range chromosomal information to detect mosaic chromosomal alterations. We focused on probable early developmental sCNVs through stringent filtering. We assessed the burden of sCNVs across varying cell fraction cutoffs, as well as the frequency with which genes were involved in sCNVs. We integrated this data with the PGC (Psychiatric Genomics Consortium) dataset, which comprises 12,834 SCZ cases and 11,648 controls of European descent, and complemented it with genotyping data from postmortem brain tissue of 936 participants (449 cases and 487 controls). Patients with SCZ had a significantly higher somatic losses detection rate than control participants (1.00% vs. 0.52%; odds ratio = 1.91; 95% CI, 1.47–2.49; two-sided Fisher's exact test, p = 1.49 × 10−6). Further analysis indicated that the odds ratios escalated proportionately (from 1.91 to 2.78) with the increment in cell fraction cutoffs. Recurrent sCNVs associated with SCZ (odds ratio > 8; Fisher's exact test, p <.05) were identified, including notable regions at 10q21.1 (ZWINT), 3q26.1 (SLITRK3), 1q31.1 (BRINP3) and 12q21.31-21.32 (MGAT4C and NTS) in the Chinese cohort, and some regions were validated with PGC data. Cross-tissue validation pinpointed somatic losses at loci like 1p35.3-35.2 and 19p13.3-13.2. The study highlights the significant impact of mosaic chromosomal alterations on SCZ, suggesting their pivotal role in the disorder's genetic etiology. [ABSTRACT FROM AUTHOR]

Copy number variations (CNV) contribute significantly to genetic variations. Numerous studies have shown that CNV affects phenotypic traits in livestock. The SMAD family member 2 (SMAD2) is a leading candidate gene in reproduction and has a crucial effect on litter size. Additionally, SMAD2 is also required for male reproduction and influences male germ cell development. However, there are no reports on investigating the effect of CNVs in the SMAD2 gene on reproductive traits in goat. Therefore, the goal of this study was to explore associations between CNV of the SMAD2 gene and litter size and semen quality in Shaanbei white cashmere (SBWC) goats. In this study, two CNVs within the SMAD2 were identified in 352 SBWC goats (50 males and 302 females). The association analysis revealed that only CNV2 was significantly associated with female goat first-born litter size (P = 3.59 × 10−4), male semen concentration (P < 0.01), ejaculation volume, live sperm count, and sperm deformity rate (P < 0.05). In terms of phenotypic performance, the individuals with loss genotypes outperformed those with other genotypes. CNV1 and CNV2 genotype combinations containing their dominant genotypes were also associated with goat litter size (P = 1.7 × 10−5), but no differences in semen quality were found. In summary, CNV2 of the SMAD2 gene is useful for molecular marker-assisted selection breeding, as it is associated with essential goat reproductive traits. • Two CNV loci within the SMAD2 gene were identified in SBWC goats. • CNV2 was significantly associated with litter size in female goats (P < 0.01). • In male goats, CNV2 had a significant effect on semen quality traits (P < 0.05). • Therefore, CNV2 in the SMAD2 gene could be an effective DNA marker for breeding. [ABSTRACT FROM AUTHOR]

• Induction chemo-immunotherapy promote surgery conversion rate (74.4%) in unresectable stage IIIA-IIIB lung cancer. • The major pathological response (MPR) rate for induction chemo-immunotherapy was 65.6%. • 73% of patients with N2 disease demonstrated down-staging to N0 after chemo-immunotherapy. • Copy number variation (CNV) ploidy serve as a predictive biomarker for patients achieved MPR. Non-small cell lung cancer (NSCLC) is the most common type of lung cancer. Despite this, evidence supporting optimal management of certain stages remains a topic of debate. In this retrospective study we examine the efficacy and safety, as well as exploring the biomarkers of neoadjuvant induction immuno-chemotherapy, in Chinese patients with unresectable stage III NSCLC. Patients with unresectable stage III NSCLC who were identified as driver mutation-negative and who received neoadjuvant chemo-immunotherapy were enrolled from three Chinese hospitals between Jan. 17, 2019, and Jan.17, 2022. Perioperative outcomes and survival data were collected. Retrospective biomarker exploration was performed in available baseline tumor samples and surgical specimens. 94 patients were enrolled and received chemo-immunotherapy as neoadjuvant treatment. 80 patients had squamous cell carcinoma, and 26 had stage IIIB disease. Surgery conversion rate was 74.4%, R0 resection rate was 98.4%. Of 64 patients who underwent surgery, major pathological response (MPR) rate was 65.6% and pathologic complete response (pCR) rate was 42.2%. 73% of patients with N2 disease demonstrated down-staging to N0. Treatment-related adverse events (TRAEs) occurred in 43 patients (45.7%) with anemia was the most common. The Grade ≥ 3 TRAEs rate was 3.2% (3/94). A significant association between copy number variation (CNV) ploidy was also found. The combination treatment of immuno-chemotherapy for unresectable stage III NSCLC is not only effective but also has a favourable safety profile. For the first time we provide evidence that CNV status may be a predictive biomarker of MPR. [ABSTRACT FROM AUTHOR]

• HRD test is widely used for administrating PARPi chemotherapy in breast cancer. • Existing methods are either experimentally complicated or commercially expensive. • Low-pass WGS based HRD detection method performs well in breast cancer. • Present an HRD test with high accuracy, ease of operation, and acceptable cost. Homologous recombination repair deficiency (HRD) results in a defect in DNA repair and is a frequent driver of tumorigenesis. Poly(ADP-ribose) polymerase inhibitors (PARPi) or platinum-based therapies have increased theraputic effectiveness when treating HRD positive cancers. For breast cancer and ovairan cancer HRD companion diagnostic tests are commonly used. However, the currently used HRD tests are based on high-depth genome sequencing or hybridization-based capture sequencing, which are technically complex and costly. In this study, we modified an existing method named shallowHRD, which uses low-pass whole genome sequencing (WGS) for HRD detection, and estimated the performance of the modified shallowHRD pipeline. Our shallowHRD pipeline achieved an AUC of 0.997 in simulated low-pass WGS data, with a sensitivity of 0.981 and a specificity of 0.964; and achieved a higher HRD risk score in clinical BRCA-deficient breast cancer samples (p = 5.5 × 10−5, compared with BRCA-intact breast cancer samples). We also estimated the limit of detection the shallowHRD pipeline could accurately predict HRD status with a minimum sequencing depth of 0.1 ×, a tumor purity of > 20%, and an input DNA amount of 1 ng. Our study demostrates using low-pass sequencing, HRD status can be determined with high accuracy using a simple approach with greatly reduced cost. [ABSTRACT FROM AUTHOR]

• 16p11.2 CNVs were identified in 0.35% (30/8578) of prenatal SNP array results. • 16p11.2 CNVs have variable prenatal phenotypic features. • 16p11.2 CNVs are frequently inherited from parents with a milder or normal phenotype. • Vertebral deformities were frequent in cases of 16p11.2 proximal deletion. The 16p11.2 copy number variations (CNVs) are increasingly recognized as one of the most frequent genomic disorders, with a broad spectrum of phenotypes. The fetal phenotype associated with 16p11.2 CNVs is poorly described. The current study presents prenatal series of 16p11.2 CNVs and provides a better understanding of this submicroscopic imbalance in prenatal diagnosis. Retrospective case series were extracted from a single tertiary referral center performing prenatal single nucleotide polymorphism (SNP) array from April 2017 to December 2021. The maternal demographics, indication for amniocentesis, ultrasound findings, SNP array results, inheritance of the CNVs, and pregnancy outcomes were studied. We indentified 30 fetuses carrying 16p11.2 CNVs, representing 0.35% (30/8578) of prenatal SNP array results. The series included 17 fetuses with a proximal deletion, 7 with a distal deletion, 4 with a proximal duplication, and 2 with a distal duplication. Prenatal ultrasound anomalies were reported in 80% of these cases. The most common presentation was vertebral anomalies (9/30). Other features noted in more than one fetus were increased nuchal translucency/nuchal fold (NT/NF) (5/30), absent/hypoplastic nasal bone (3/30), polyhydramnios (3/30), ventricular septal defect (VSD) (2/30), unilateral mild ventriculomegaly (2/30), fetal growth restriction (FGR) (2/30), right aortic arch (2/30). All the 9 vertebral anomalies were present in fetuses harboring proximal deletion (9/17). Familial transmission was confirmed in 44% of cases (11/25) and termination of pregnancy was requested in 62.1% (18/29) of cases. The 16p11.2 CNVs can have variable prenatal phenotypes and these CNVs are frequently inherited from parents with a milder or normal phenotype. Our results underline that vertebral deformities were frequent in cases of 16p11.2 proximal deletion, and further demonstrate the incomplete penetrance of the CNVs. [ABSTRACT FROM AUTHOR]

Genomic copy number variations (CNVs) are considered as a significant source of genetic diversity and widely involved in gene expression and regulatory mechanism, genetic disorders and disease risk, susceptibility to certain diseases and conditions, and resistance to medical drugs. Many studies have targeted the identification, profiling, analysis, and associations of genetic CNVs. We propose herein two new fuzzy methods, taht is, one based on the fuzzy inference from the pre-processed input, and another based on fuzzy C-means clustering. Our solutions present a higher true positive rate and a lower false negative with no false positive, efficient performance and consumption of least resources. [ABSTRACT FROM AUTHOR]

• The frequency of nonsecretors was relative low in the studied populations. • 235G > A and 304G > A did not impair the enzyme activity by transient expression study. • FUT2 variations suggested that the studied populations were formed by admixture. The secretor type α(1,2)fucosyltransferase gene (FUT2) is known to be rich in population-specific polymorphisms. However, genetic variations of FUT2 have not been well examined in Latin American populations in which nonsecretors are rare. Conventional polymerase chain reactions and direct sequencing were performed to detect single nucleotide polymorphisms (SNPs) and copy number variations (CNVs) of FUT2 in Mexicans including Americans of Mexican ancestry, Puerto Ricans, Caribbeans, and Colombians. FUT2 alleles were determined by cloning into plasmids or PHASE software. The impact of uncharacterized missense SNPs on the enzyme activity were examined by transient transfection assays and estimated by several software programs. Three alleles, Se357 , Se , and se428 , were common, and the frequency of nonsecretors was relatively low in the studied populations. We also encountered several alleles specific to Africans, Europeans, and South and East Asians including a South Asian-specific sedel. In contrast to the in silico prediction, a transient expression study suggested that both of two missense SNPs, 235G > A and 304G > A, did not impair the enzyme activity. The allelic polymorphism of FUT2 suggests that the modern Latin American populations were formed via genetic admixture among Native Americans and populations whose ancestors migrated from other continents. In this study, we have observed a discrepancy between in silico and functional analyses for FUT2 for the first time. Therefore, experimental functional analysis is required for evaluation of SNPs of FUT2. [ABSTRACT FROM AUTHOR]

The pangenome provides genomic variations in the cultivated gene pool for a given species. However, as the crop's gene pool comprises many species, especially wild relatives with diverse genetic stock, here we suggest using accessions from all available species of a given genus for the development of a more comprehensive and complete pangenome, which we refer to as a super-pangenome. The super-pangenome provides a complete genomic variation repertoire of a genus and offers unprecedented opportunities for crop improvement. This opinion article focuses on recent developments in crop pangenomics, the need for a super-pangenome that should include wild species, and its application for crop improvement. Pangenome studies conducted so far have been limited mainly to one species and mostly cultivated accessions. The challenge with the current pangenomes is lack of representation of genomic diversity at the genus level. Crop wild relatives possess unearthed genetic diversity that has been lost during domestication and breeding. Pangenomics of crop wild relatives is the way forward to catalogue the complete gene repertoire of a genus. The super-pangenome is the approach of developing a pangenome of the pangenomes of different species for a given genus. Currently available methods and tools to develop pangenomes are mainly restricted to bacterial (prokaryotic) genomes. It is important now to develop novel, effective, and user-friendly tools for the development of super-pangenomes for crop (eukaryotic) genomes. [ABSTRACT FROM AUTHOR]

Cardiovascular disease is the leading cause of death in the United States. Consequently, individuals who are genetically predisposed for high risk of cardiovascular disease would benefit most from prevention and early intervention approaches. Among common health risk factors affecting adult populations, we evaluated 23 cardiovascular disease-related traits, including BMI, glucose levels and lipid profiling to determine their associations with low-frequency recurrent copy number variations (CNV) (population frequency < 5%). We examined 10,619 unrelated subjects of European ancestry from the Electronic Medical Records and Genomics (eMERGE) Network who were genotyped with 657,366 markers genome-wide on the Illumina Infinium Quad 660 array. We performed CNV calling based on array marker intensity and evaluated data quality, ancestry stratification, and relatedness to ensure unbiased association discovery. Using a segment-based scoring approach, we assessed the association of all CNVs with each trait. In this large genome-wide analysis of low-frequency CNVs, we observed 11 novel genome-wide significant associations of low-frequency CNVs with major cardiovascular disease traits. In one of the largest genome-wide studies for low-frequency recurrent CNVs, we identified 11 loci associated with cardiovascular disease and related traits at the genome-wide significance level that may serve as biomarkers for prevention and early intervention studies in subjects who are at elevated risk. Our study further supports the role of low-frequency recurrent CNVs in the pathogenesis of common complex disease traits. • A genome-wide low-frequency CNV association analysis including 10,619 subjects. • A total of 23 clinical variables were examined. • 47 unique CNVRs are significantly associated with 12 traits. • Pathway "Retinol metabolism" is significantly enriched in the 47 CNVR intervals. • Six homozygous deletion regions are significantly associated with 4 traits. • Potential role of low-frequency recurrent CNVs in the pathogenesis of common complex disease traits. [ABSTRACT FROM AUTHOR]

Abstract Early work from about two decades ago implicated DNA double-strand break (DSB) formation and repair in neuronal development. Findings emerging from recent studies of DSBs in proliferating neural progenitors and in mature, non-dividing neurons suggest important roles of DSBs in brain physiology, aging, cancer, psychiatric and neurodegenerative disorders. We provide an overview of some findings and speculate on what may lie ahead. [ABSTRACT FROM AUTHOR]

During the last few years multiplex real-time or quantitative polymerase chain reaction PCR (qPCR) has become the method of choice for multiplex gene expression changes and gene copy number variations (CNVs) analysis. However, such determinations require the use of different fluorescent labels for the different amplified sequences, which increases significantly the costs of the analysis and limits the applicability of the technique for simultaneous amplification of many targets of interest in a single reaction. In this regard, the use of the coupling between gel electrophoresis (GE) separation with inductively coupled plasma mass spectrometry (ICP-MS) detection allows the label-free determination of multiplex PCR-amplified sequences (amplicons) by monitoring the P present in the DNA backbone. The quantitative dimension is obtained since under optimal and controlled multiplex PCR conditions the peak areas of the separated amplicons are directly proportional to the amount of DNA template in the original sample. Moreover, the calibration of the GE-ICP-MS system with a DNA ladder permits direct estimation of the size (bp) of the PCR products. The suitability of the proposed multiplex strategy has been evaluated addressing two different situations: determination of CNVs and gene expression changes in human ovarian cancer cells. In the first case, the results obtained for the simultaneous quantitation of CNVs of four genes ( HER2 , CCNE1 , GSTM1 , ACTB ) on DNA obtained from OVCAR-3 cells were in accordance with the literature data, and also with the results obtained by conventional simplex qPCR. In the second case, multiplex gene expression changes of BAX , ERCC1 and CTR1 genes, using ACTB as constitutive gene, on A2780cis respect to A2780 cells, resistant and sensitive to cisplatin, respectively, provided the same information as single reaction reverse transcription (RT)-qPCR. [ABSTRACT FROM AUTHOR]

The 22q11.2 deletion syndrome (22q11DS), the most common survivable human genetic deletion disorder, is caused by a hemizygous deletion of 30–40 contiguous genes on chromosome 22, many of which have not been well characterized. Clinical features seen in patients with this deletion, including intellectual disability, are not completely penetrant and vary in severity between patients, suggesting the involvement of variants elsewhere in the genome in the manifestation of the phenotype. Given that it is a relatively rare disorder (1/2000-6000 in humans), limited research has shed light into the contribution of these second-site variants to the developmental pathogenesis that underlies 22q11DS. As CNVs throughout the genome might constitute such a genetic risk factor for variability in the 22q11DS phenotypes such as intellectual disability, we sought to determine if the overall burden of rare CNVs in the genetic background influenced the phenotypic variability. We analyzed CNV and clinical data from 66 individuals with 22q11DS, and found that 77% (51/66) of individuals with the 22q11DS also carry additional rare CNVs (<0.1% frequency). We observed several trends between CNV burden and phenotype, including that the burden of large rare CNVs (>200 Kb in size) was significantly higher in 22q11DS individuals with intellectual disability than with normal IQ. Our analysis shows that rare CNVs may contribute to intellectual disability 22q11DS, and further analysis on larger 22q11DS cohorts should be performed to confirm this correlation. [ABSTRACT FROM AUTHOR]

Only a few subjects carrying supernumerary marker chromosomes derived from 19 chromosome (sSMC(19)) have been described to date and for a small portion of them the genic content has been defined at the molecular level. We present seven new different sSMCs(19) identified in eight individuals, seven of whom unrelated. The presence of the sSMC is associated with a clinical phenotype in five subjects, while the other three carriers, two of whom related, are normal. All sSMCs(19) have been characterized by means of conventional and molecular cytogenetics. We compare the sSMCs(19) carriers with a clinical phenotype to already described patients with gains (sSMCs or microduplications) of overlapping genomic regions with the aim to deepen the pathogenicity of the encountered imbalances and to assess the role of the involved genes on the phenotype. The present work supports the correlation between the gain of some chromosome 19 critical regions and specific phenotypes. [ABSTRACT FROM AUTHOR]

Purpose: To characterize the electroclinical features of epilepsy associated with intellectual disability and pathogenic copy number variations (CNVs) METHODS: we prospectively investigated 61 adult patients with epilepsy and intellectual disability or other neurodevelopmental disorders. We performed high resolution SNP-Array analysis in order to detect clinical relevant chromosomal microdeletions and microduplications. An ordinal logistic regression model was fitted with 34 demographic, clinical and EEG-related variables in order to identify the epilepsy phenotype of patients with pathogenic CNVs.Results: chromosome microarray analysis identify non-polymorphic CNVs in 33 patients analyzed: 11 had an established pathogenic microdeletion/microduplication, 22 were carriers of CNVs of unknown clinical significance. Univariate analysis revealed a significant association between pathogenic CNVs and 3 electroclinical variables considered, specifically atypical absence seizures (p<0.05), tonic seizures (p<0.05), epileptic spasms (p<0.01).Conclusions: high resolution SNP-Array analysis should be evaluated in adult patients with intellectual disability and epilepsy with peculiar electroclinical features, specifically atypical absence seizures, tonic seizures, and epileptic spasms, resembling a Lennox-Gastaut syndrome without a clear structural lesion. [ABSTRACT FROM AUTHOR]

Inherited and acquired genomic abnormalities are known to cause genetic diseases and contribute to cancer formation. Recent studies demonstrated a substantial mutational load in mouse and human embryonic and induced pluripotent stem cells (ESCs and iPSCs). Single nucleotide variants, copy number variations, and larger chromosomal abnormalities may influence the differentiation capacity of pluripotent stem cells and the functionality of their derivatives in disease modeling and drug screening, and are considered a serious risk for cellular therapies based on ESC or iPSC derivatives. This review discusses the types and origins of different genetic abnormalities in pluripotent stem cells, methods for their detection, and the mechanisms of development and enrichment during reprogramming and culture expansion. [ABSTRACT FROM AUTHOR]

The missense mutation V717I in amyloid precursor protein ( APP ) gene has been reported in many early-onset familial Alzheimer's disease (EOFAD) families. However, no detailed clinical picture regarding this mutation has ever been described for Chinese EOFAD. We investigate the age at onset (AAO), initial clinical features and non-cognitive neurological symptoms in 34 affected subjects from five Han Chinese EOFAD families with the APP V717I mutation to characterize the clinical phenotype. The AAO was 54.7 ± 4.9 years ( n = 34), with the APOE ɛ4 allele correlating with a decreased AAO. Prominent early affective symptoms, executive dysfunction and disorientation at onset were exhibited in 26 (76.5%), 18 (52.9%) and 16 (47%) cases, respectively. Spastic paraparesis and cerebellar ataxia occurred frequently in 13 (38.2%) and 12 (35.3%) cases, respectively, during the late stages of disease. The specific clinical phenotype of the APP V717I mutation for Chinese families is characterized by prominent early affective symptoms, executive dysfunction and disorientation as well as frequent late spastic paraparesis and cerebellar ataxia as compared to Western reports. We conclude that ethnic differences, environment or additional unknown factors may challenge the homogeneity of EOFAD with identical APP mutations. [ABSTRACT FROM AUTHOR]

Whole exome sequencing is recommended as the first tier test for neurodevelopmental disorders (NDDs) with trio being an ideal option for the detection of de novo variants. Cost constraints have led to adoption of sequential testing i.e. proband-only whole exome followed by targeted testing of parents. The reported diagnostic yield for proband exome approach ranges between 31 and 53%. Typically, these study designs have aptly incorporated targeted parental segregation before concluding a genetic diagnosis to be confirmed. The reported estimates however do not accurately reflect the yield of proband only standalone whole -exome, a question commonly posed to the referring clinician in self pay medical systems like India. To assess the utility of standalone proband exome (without follow up targeted parental testing), we retrospectively evaluated 403 cases of neurodevelopmental disorders referred for proband-only whole exome sequencing at Neuberg Centre for Genomic Medicine (NCGM), Ahmedabad during the period of January 2019 and December 2021. A diagnosis was considered confirmed only upon the detection of Pathogenic/Likely Pathogenic variants in concordance with patient's phenotype as well as established inheritance pattern. Targeted parental/familial segregation analysis was recommended as a follow up test where applicable. The diagnostic yield of the proband-only standalone whole exome was 31.5%. Only 20 families submitted samples for follow up targeted testing, and a genetic diagnosis was confirmed in twelve cases increasing the yield to 34.5%. To understand factors leading to poor uptake of sequential parental testing, we focused on cases where an ultra-rare variant was detected in hitherto described de novo dominant neurodevelopmental disorder. A total of 40 novel variants in genes associated with de novo autosomal dominant disorders could not be reclassified as parental segregation was denied. Semi-structured telephonic interviews were conducted upon informed consent to comprehend reasons for denial. Major factors influencing decision making included lack of definitive cure in the detected disorders; especially when couples not planning further conception and financial constraints to fund further targeted testing. Our study thus depicts the utility and challenges of proband-only exome approach and highlights the need for larger studies to understand factors influencing decision making in sequential testing. [ABSTRACT FROM AUTHOR]

Single nucleotide polymorphisms (SNPs)-based genotyping using microarray platform is now frequently used to detect copy number variants (CNVs) in the human genome. Here, we report CNVs identified using Illumina Human Omni 2.5 M oligonucleotide microarrays in 11 multiplex families with autism spectrum disorder (ASD) referred to Autism Research and Treatment Center (ART) and Madinah Maternity and Children Hospital (MMCH). Of the 11 families, 22 patients with ASD (all males) and their parents, were recruited for the present study. In total, 43 individuals were genotyped with high-resolution array. Abnormal microarray results were seen in all 22 patients with ASD. A total of 17 shared CNVs were selected for further analysis. Out of these 17 CNVs, we discovered one novel CNV, previously not described, and 16 recurrent CNVs that overlap with the genomic imbalances defined in the autism database, autism chromosome rearrangement database and database of genomic variants. Recurrent CNVs include 11 common and 5 rare CNVs. All rare CNVs are duplications except a 16-kb deletion on chr2q36.3. Rare gain of copy numbers includes a 2-kb duplication on chr9q21.13, overlapping duplications of 107 kb and 181 kb on chrXp22.33 in 2 different families and a 10-kb duplication on chr18q21.13. A novel loss of copy number on chr3q23 was found in four ASD cases. This CNV results in deletion of intron 2 of calsyntenin 2 ( CLSTN2 ) encoding synaptic protein calsyntenin 2. CLSTN2 is expressed exclusively in the brain, with high levels occurring in cortical gamma-aminobutyric acid (GABA)ergic interneurons and in medial temporal lobe regions. These results verify the diagnostic relevance of genome-wide small common and rare CNVs and provide further evidence of the high diagnostic yield of microarray for genetic testing in children with ASD. [ABSTRACT FROM AUTHOR]

• Copy Number Variations Regions (CNVR) were subject to pedigree analysis using 61 families of Gochu Asturcelta pig (492 individuals) and 478 different parents-offspring trios. • Pedigree analysis showed that most CNVR do not segregate from parents to offspring and that segregating CNVR do not conform to strict Mendelian inheritance patterns. • As CNVR showing Mendelian inheritance across generations are unlikely to be artifacts or false positives their use in genomic studies is suggested. Copy Number Variation Regions (CNVR) were subjected to pedigree analysis to contribute to the understanding of their segregation patterns. Up to 492 Gochu Asturcelta pig individuals forming 478 different parents-offspring trios (61 different families) were genotyped using the Axiom_PigHDv1 Array (658,692 SNPs). CNVR calling, performed using two different platforms (PennCNV and QuantiSNP), allowed to identify a total of 344 candidate CNVR on the 18 porcine autosomes covering about 106.8 Mb of the pig genome. Sixty-nine CNVR were identified, to some extent, in both the parents and the offspring and were classified as segregating CNVR. The other candidate CNVR were called in one or more progeny but in neither parent and classified either as singleton or recurrent de novo CNVR. Segregating CNVR were, on average, larger and more frequent than the recurrent de novo CNVR (444.8 kb vs 287.9 kb long and 34 vs 5 individuals, respectively). In any case, segregating CNVR did not conform to strict Mendelian inheritance patterns: estimates of average paternal and maternal transmission rates ranged from 11.0 % to 13.4 % and mean inheritance rate was below 21 %. This issue should be carefully considered when interpreting the results of CNV studies. Segregating CNVR, present across generations, are unlikely to be artifacts or false positives and can be hypothesized to be important at the population level. [ABSTRACT FROM AUTHOR]

• MUC19 CNVs had significant effects on cattle growth traits. • There were significant differences in individual growth traits of different CNV types. • The MCU19-CNV could be used as a molecular marker for cattle breeding. Copy number variation (CNV), as one of the important variations in the biological genome, refers to the deletion and duplication of genomic segments between 1 kb and 50 kb caused by genomic rearrangements. Currently, many copy number variations have been found to be significantly associated with important economic traits such as growth, development and reproduction of cattle. However, the study of MUC19 gene has not been reported. In this study, we detected an appropriate correlation between MUC19 gene and growth traits of Chinese cattle. We detected the distribution of MUC19 -CNV across Qinchuan cattle (QC), Pinan cattle (PN), Xianan cattle (XN), Yunling cattle (YL), Guyuan cattle (GY), Jiaxian cattle (JX), and analyzed the association between types of MUC19 -CNV and growth traits through SPSS20.0 software and method of ANOVA. The results showed that various types of CNV were present in each breed of cattle, but there were discrepancies in the distribution of copy number variant types. The Association analysis result showed that CNV of MUC19 gene showed a postive effect in cattle growth traits: the copy number of MUC19 was significantly correlated with hip width of PN cattle (P < 0.01), height at hip cross and withers height of PN cattle (P < 0.05), hip width and body length of JX cattle (P < 0.05), Huckle bone width of YL cattle (P < 0.05). [ABSTRACT FROM AUTHOR]

Autism spectrum disorders denote a series of lifelong neurodevelopmental conditions characterized by an impaired social communication profile and often repetitive, stereotyped behavior. Recent years have seen the complex genetic architecture of the disease being progressively unraveled with advancements in gene finding technology and next generation sequencing methods. However, a complete elucidation of the molecular mechanisms behind autism is necessary for potential diagnostic and therapeutic applications. A multidisciplinary approach should be adopted where the focus is not only on the ‘genetics’ of autism but also on the combinational roles of epigenetics, transcriptomics, immune system disruption and environmental factors that could all influence the etiopathogenesis of the disease. ASD is a clinically heterogeneous disorder with great genetic complexity; only through an integrated multidimensional effort can modern autism research progress further. [ABSTRACT FROM AUTHOR]

Aims: To identify the role of copy number variations (CNVs) on disease risk genes and its effect on disease phenotypes in type 2 diabetes mellitus (T2DM) in 12 random populations using high throughput arrays.Methods: CNV analysis was carried out on a total of 1715 individuals from 12 populations, from ArrayExpress Archive of the European Bioinformatics Institute along with our subjects using Affymetrix Genome Wide SNP 6.0 array. CNV effect on T2DM genes were analyzed using several bioinformatics tools and a molecular protein interaction network was constructed to identify the disease mechanism altered by the CNVs.Results: Analysis showed 34.4% of the total population to be under CNV burden for T2DM, with 83 disease causal and associated genes being under CNV influence. Hotspots were identified on chromosomes 22, 12, 6, 19 and 11.Overlap studies with case cohorts revealed significant disease risk genes such as EGFR, E2F1, PPP1R3A, HLA and TSPAN8.Conclusions: CNVs play a significant role in predisposing T2DM in normal cohorts and contribute to the phenotypic effects. Thus, CNVs should be considered as one of the major contributors in predisposition of the disease. [ABSTRACT FROM AUTHOR]

Copy number variations (CNVs) are one of the major sources of human genetic diversity and are associated with rare genomic disorders as well as complex traits and diseases. A copy number variation was observed at the D8S1179 locus during routine STR based parentage testing, in which the child exhibited three alleles, “13, 15, 16”, with the putative father a homozygous “15” and the mother homozygous “13”. In addition, in the same testing case, there was a one-step mutation at the STR locus FGA, in which the putative father was a “22, 24”, the mother was a “22, 25”, and the child was a “22, 23”. After further investigations by re-amplified with different primer sets, clone-based sequencing, karyotype analysis and whole-genome SNP analysis, the results showed that the child had the CNVs at chromosome 8q24.3 and 22q11.21. In conclusion, for parentage testing cases encountered with tri-allele patterns, more testings, such as cloning sequencing, karyotyping, or even whole genome analysis, as well as more appropriate statistical estimations might be conducted to further confirm or exclude the relationship. [ABSTRACT FROM AUTHOR]

Objectives Cell free tumor DNA (cfDNA) circulating in blood has a great potential as biomarker for cancer clinical management. The objective of this study is to evaluate if cfDNA in blood plasma is detectable in early stage lung cancer patients. Materials and methods We extracted cfDNAs and tumor tissue DNAs from 8 lung adenocarcinoma patients. We also extracted cfDNAs from 8 normal controls. To evaluate copy number variations (CNV) and identify potential mutations, we performed low pass whole genome sequencing and targeted sequencing of 50 cancer genes. To accurately reflect the tumor-associated genomic abnormality burden in plasma, we developed a new scoring algorithm, plasma genomic abnormality (PGA) score, by summarizing absolute log2 ratios in most variable genomic regions. We performed digital PCR and allele-specific PCR to validate mutations detected by targeted sequencing. Results and conclusions The median yield of cfDNA in 400ul plasma was 4.9ng (range 2.25–26.98 ng) in patients and 2.32 ng (range 1.30–2.81 ng) in controls ( p = 0.003). The whole genome sequencing generated approximately 20 million mappable sequence reads per subject and 5303 read counts per 1 Mb genomic region. Log2 ratio-based CNV analysis showed significant chromosomal abnormality in cancer tissue DNAs and subtle but detectable differences in cfDNAs between patients and controls. Genomic abnormality analysis showed that median PGA score was 9.28 (7.38–11.08) in the 8 controls and 19.50 (5.89–64.47) in the 8 patients ( p = 0.01). Targeted deep sequencing in tumor tissues derived from the 8 patients identified 14 mutations in 12 different genes. The PCR-based assay confirmed 3 of 6 selected mutations in cfDNAs. These results demonstrated that the PGA score and cfDNA mutational analysis could be useful tool for the early detection of lung cancer. These blood-based genomic and genetic assays are noninvasive and may sensitively distinguish early stage disease when combined with other existing screening strategies including low-dose CT scanning. [ABSTRACT FROM AUTHOR]

The present study was designed to determine the effects of copy number variations (CNVs) of squalene synthase 1( SQS 1) gene on the mevalonate (MVA) pathway. SQS 1 gene from G. uralensis ( Gu SQS1) was cloned and over-expressed in Pichia pastoris GS115. Six recombinant P. pastoris strains containing different copy number of Gu SQS1 were constructed. HPLC was used to assay the level of ergosterol in all transgenic P. pastoris strains containing Gu SQS1. HPLC analysis showed that the contents of ergosterol in all of the transgenic P. pastoris containing Gu SQS1 were higher than that in the negative control. And with the increase of copy number of Gu SQS1, the content of ergosterol showed an increasing-decreasing-increasing pattern. The contents of ergosterol in 10-copy- Gu SQS1 P. pastoris and 47-copy- Gu SQS1 P. pastoris were significantly higher than that in the rest recombinant P. pastoris strains. In conclusion, the CNVs of Gu SQS1 influence the content of secondary metabolites in the MVA pathway. The present study provides a basis for over-expressing Gu SQS1 and increasing the content of glycyrrhizin in G. uralensis cultivars. [ABSTRACT FROM AUTHOR]

Background and purpose We explore analytical and data-driven approaches to investigate the integration of genetic variations (single nucleotide polymorphisms [SNPs] and copy number variations [CNVs]) with dosimetric and clinical variables in modeling radiation-induced rectal bleeding (RB) and erectile dysfunction (ED) in prostate cancer patients. Materials and methods Sixty-two patients who underwent curative hypofractionated radiotherapy (66 Gy in 22 fractions) between 2002 and 2010 were retrospectively genotyped for CNV and SNP rs5489 in the xrcc1 DNA repair gene. Fifty-four patients had full dosimetric profiles. Two parallel modeling approaches were compared to assess the risk of severe RB (Grade ⩾3) and ED (Grade ⩾1); Maximum likelihood estimated generalized Lyman–Kutcher–Burman (LKB) and logistic regression. Statistical resampling based on cross-validation was used to evaluate model predictive power and generalizability to unseen data. Results Integration of biological variables xrcc1 CNV and SNP improved the fit of the RB and ED analytical and data-driven models. Cross-validation of the generalized LKB models yielded increases in classification performance of 27.4% for RB and 14.6% for ED when xrcc1 CNV and SNP were included, respectively. Biological variables added to logistic regression modeling improved classification performance over standard dosimetric models by 33.5% for RB and 21.2% for ED models. Conclusion As a proof-of-concept, we demonstrated that the combination of genetic and dosimetric variables can provide significant improvement in NTCP prediction using analytical and data-driven approaches. The improvement in prediction performance was more pronounced in the data driven approaches. Moreover, we have shown that CNVs, in addition to SNPs, may be useful structural genetic variants in predicting radiation toxicities. [ABSTRACT FROM AUTHOR]

Background Cerebral visual impairment (CVI) is a disorder in projection and/or interpretation of the visual input in the brain and accounts for 27% of the visually impaired children. Aim A large cohort of patients with CVI was investigated in order to ascertain the relevance of chromosomal aberrations in the etiology of this disorder. Methods 607 patients with CVI and a visual acuity ≤0.3 were assessed for the presence of a chromosomal aberration retrospectively. The observed aberrations were classified for pathogenicity. Results A total of 98 chromosomal aberrations were found in 79 persons (13%) of the cohort. In nine persons it was not possible to classify the clinical implication of the aberration, due to lack of detailed information. In 70 persons it was possible to classify the aberration for causality: in 41 patients the aberration was associated with CVI, in 16 it was unknown and in 13 the aberration was unlikely to be associated with CVI. For four aberrations, present in 26 patients, the association with CVI has been reported before: trisomy 21, 1p36 deletion syndrome, 17p13.3 deletion syndrome (Miller-Dieker syndrome) and 22q13.3 deletion syndrome (Phelan-McDermid syndrome). The chromosomal aberrations in another 15 patients were for the first time associated with CVI. Conclusions Chromosomal aberrations associated with CVI were found in 7% (41/607) of patients, of which 37% (15/41) have not been reported before in association with CVI. Therefore, in patients with CVI chromosomal investigations should be routinely performed to warrant a good clinical diagnosis and counseling. [ABSTRACT FROM AUTHOR]

Abstract: Copy number variations (CNVs) have been recently recognized as another important genetic variability complementary to single nucleotide polymorphisms (SNPs). Compelling evidence has indicated that CNVs are responsible for phenotypic traits by changing the copy numbers of functional genes. Myosin heavy chain 3 (MYH3) gene is a critical regulatory factor in skeletal muscle development, and has been detected in the CNVs region by comparative genomic hybridization (CGH) array. This study was conducted to validate and detect the distribution of MYH3 copy numbers (relative to Angus cattle) in four Chinese cattle breeds (NY, QC, LX, and CY), and further to investigate the associations of the copy number changes with its transcriptional expression and cattle growth traits. Substantial genetic differences of MYH3 copy numbers were identified between NY and the other three breeds (P <0.01). The copy numbers of MYH3 gene presented the positive correlations with the transcript level of MYH3 gene in both fetal and adult skeletal muscles (P <0.05). Statistical analysis revealed that CNVs of MYH3 gene were significantly associated with growth traits of NY cattle, and the individuals with copy number gain showed better phenotypes than the loss and/or median groups (P <0.05). This study firstly attempted to establish the correlations between CNVs of candidate genes and growth traits, and our results suggested that the CNVs of MYH3 gene may be utilized as the potential markers for economic traits in selection breeding programs of Chinese cattle. [Copyright &y& Elsevier]

• We identify 7 different protein sequences of PR39, a pig cathelicidin. • PR39 copies ranges from 2 to 10 copies in the commercial pig population. • PR39 expression correlates with the copy number in the genome. • Increased PR39 gene dosage could enhance protection against infectious diseases. Copy number polymorphisms (CNPs) of antimicrobial peptides (AMPs) in livestock can influence the innate immune response of individuals. We conducted a high-resolution analysis of the genomic variations of porcine cathelicidin PR39 using cloned PR39 amplicons corresponding to the 5′ untranslated region (UTR) to 3′ UTR from four individuals of three different pig breeds. We identified 15 different sequences corresponding to 9 different coding domain sequences (CDSs), encoding 7 different protein sequences consisting of 3 functional and 4 non-functional forms. Subsequently, we developed a PR39 CNP typing method using real-time polymerase chain reaction (PCR) and analyzed the PR39 copy numbers from 44 pigs of six breeds. Significant variations in PR39 copies ranging from 2 to 10 copies, with a mean copy number of 5, were observed among all commercial breeds, except the wild boar. Among the different breeds, the PR39 copy number was highest (10) in Korean native pigs. Gene expression analysis showed that PR39 expression was correlated with the copy number. Moreover, the comparative analysis of the cathelicidin cluster-containing region among eight mammalian species showed the complete evolutionary conservation of the region, except for differences in the degree of cathelicidin expansion in each species. Therefore, characterization of CNPs in AMP genes could aid in improving the genetic potential of innate immune responses in livestock animals. [ABSTRACT FROM AUTHOR]

Objective: To delineate the diagnostic efficacy of medical exome, whole exome, and whole genome sequencing according to primary symptoms, the contribution of small copy number variations, and the impact of molecular diagnosis on clinical management.Study Design: This was a prospective study of 17 tertiary care centers in Japan, conducted between April 2019 and March 2021. Critically ill neonates and infants less than 6 months of age were recruited in neonatal intensive care units and in outpatient clinics. The patients underwent medical exome, whole exome, or whole genome sequencing as the first tier of testing. Patients with negative results after medical exome or whole exome sequencing subsequently underwent whole genome sequencing. The impact of molecular diagnosis on clinical management was evaluated through contacting primary care physicians.Results: Of the 85 patients, 41 (48%) had positive results. Based on the primary symptoms, patients with metabolic phenotypes had the highest diagnostic yield (67%, 4/6 patients), followed by renal (60%, 3/5 patients), and neurologic phenotypes (58%, 14/24 patients). Among them, 4 patients had pathogenic small copy number variations identified using whole genome sequencing. In the 41 patients with a molecular diagnosis, 20 (49%) had changes in clinical management.Conclusions: Genome analysis for critically ill neonates and infants had a high diagnostic yield for metabolic, renal, and neurologic phenotypes. Small copy number variations detected using whole genome sequencing contributed to the overall molecular diagnosis in 5% of all the patients. The resulting molecular diagnoses had a significant impact on clinical management. [ABSTRACT FROM AUTHOR]

Objective: To identify copy number variations (CNVs) as a hint toward genes relevant for spermatogenesis and related to male factor infertility. Design: Analysis of genomic DNA with high resolution Illumina SNP arrays (HumanOmni 1-Quad Bead Chip). Sanger sequencing of the CLCA4 gene in all patients of the study. Analysis of CLCA4 expression in various human tissue samples. Setting: University department. Patient(s): A total of 39 infertile men with idiopathic infertility ranging from oligoasthenoteratozoospermia to azoospermia. Intervention(s): None. Main Outcome Measure(s): Copy number variations more than 10 kb. Result(s): We detected a heterozygous deletion including exons 4-9 of the CLCA4 gene in one man with cryptozoospermia, as well as a total of 149 CNVs not yet reported in various databases and carrying 200 protein coding genes in the 39 men. Conclusion(s): According to our results CLCA4 is apparently expressed in postmeiotic germ cells and somatic cells. We therefore conclude that CLCA4 might be functional during human spermatogenesis after meiosis, most likely as a modifier of CFTR gene expression. CLCA4 can thus be considered as a novel dominant germ line gene potentially causing male factor infertility if functionally disrupted. Our study demonstrates the power of DNA arrays to identify novel CNVs carrying candidate genes causing male factor infertility. [ABSTRACT FROM AUTHOR]

Background: General cognitive ability is usually lower in individuals with schizophrenia, partly due to genetic influences. However, the specific genetic features related to general cognitive ability are poorly understood. Individual variation in a specific type of mutation, uncommon genetic deletions, has recently been linked with both general cognitive ability and risk for schizophrenia. Methods: We derived measures of the aggregate number of “uncommon” deletions (i.e., those occurring in 3% or less of our combined samples) and the total number of base pairs affected by these deletions in individuals with schizophrenia (n = 79) and healthy control subjects (n = 110) and related each measure to the first principal component of a large battery of cognitive tests, a common technique for characterizing general cognitive ability. These two measures of mutation load were also evaluated for relationships with total brain gray matter, white matter, and lateral ventricle volume. Results: The groups did not differ on genetic variables. Multivariate general linear models revealed a group (control subjects vs. patients)×uncommon deletion number interaction, such that the latter variable was associated with lower general cognitive ability and larger ventricles in patients but not control subjects. Conclusions: These data suggest that aggregate uncommon deletion burden moderates central features of the schizophrenia phenotype. [ABSTRACT FROM AUTHOR]

Abstract: Obesity is one of the most complex human diseases that are widely concerned and studied. More recently, copy number variations (CNVs) emerge as another important genetic marker to influence various human diseases. To elucidate the relationship between obesity and CNVs, this current study selected obesity-related candidate CNVs and analyzed their association with body mass index (BMI). Results showed that a CNV locus, 8q24.3, was significantly different (P=0.0070) in CNV frequency between the obese and healthy controls in a young eastern Chinese cohort, while no statistical significance was observed in other seven candidate loci including well reported 10q11.22 and 16p11.2 loci. The association of 8q24.3 CNVs with BMI of the subjects only showed marginal significance, while the copy number (CN) of 5p15.33 had a significant correlation with the BMI of the subject. These results suggested that 8q24.3 CN gains was associated with obesity, and 5p15.33 might also contribute to obesity pathogenesis, highlighting the importance of these CNVs for obesity risks, as well as providing new evidence for CNVs in the pathology of common diseases. [Copyright &y& Elsevier]

Highlights: [•] Copy number variations (CNVs) are quantitative genome divergences like duplications and deletions. [•] Rare cancer CNVs affect genes associated with hereditary cancer syndromes. [•] CNV de novo mutations appear orders of magnitude more frequently than point mutations. [•] Somatic copy number aberrations (CNAs) reflect genomic instabilities acquired during tumorigenesis. [•] CNAs are generated by error-prone DNA double-strand break repair activities, which represent a potential breast cancer risk marker. [Copyright &y& Elsevier]

Background: Clinical studies have identified several regions of the genome with copy number variations (CNVs) associated with diverse neurodevelopmental behavioral disorders. Methods: We analyzed 1 million (M) single nucleotide polymorphism genotype arrays for evidence of previously reported recurrent CNVs and enriched genome-wide CNV burden in DNA from 600 brains, including 441 individuals with various psychiatric diagnoses. We explored gene expression in the dorsolateral prefrontal cortex in selected cases with CNVs and in other subjects with Illumina BeadArrays (568 subjects in total) and additionally in 66–92 subjects with quantitative real-time polymerase chain reaction. Results: The CNVs in previously reported genomic regions were identified in 4 of 193 patients with the diagnosis of schizophrenia (1q21.1, 11q25, 15q11.2, 22q11), 4 of 238 patients with mood disorders (11q25, 15q11.2, 22q11), and 1 of 10 patients with autism (2p16.3). No evidence of increased genome-wide CNV burden was observed in cases with schizophrenia or mood disorders, although the study is underpowered to observe rare events. Messenger RNA expression patterns suggested incomplete molecular penetrance of observed CNVs. Conclusions: Our data confirm in brain DNA the presence of certain recurrent CNVs in a small percentage of patients with psychiatric diagnoses. [Copyright &y& Elsevier]

Abstract: Copy number variations (CNVs) have been shown to be associated with several diseases. They can cause deviation of genotypes from Hardy–Weinberg Equilibrium (HWE). Genetic case–control association studies in Thais revealed that genotype distribution of CAPN10 Indel19 was deviated from HWE after correction of genotyping error. Therefore, we aim to identify CNVs within CAPN10 Indel19 region. The semi-quantitative denaturating high performance liquid chromatography (DHPLC) method was used to detect CNVs in the region of CAPN10 Indel19 marker in cohort of 305 patients with type 2 diabetes and 250 control subjects without diabetes. CNVs in the region of CAPN10 Indel19 was successfully detected by DHPLC. After correction of genotype calling based on the status of identified CNVs, CAPN10 Indel19 genotypes were well-fitted for HWE (p >0.05). However, we did not find association between CNV genotypes and risk of type 2 diabetes in our population. CNVs in CAPN10 have been identified in Thais. These CNVs lead to deviation from HWE of CAPN10 Indel19 genotypes. After excluding identified CNVs from the analysis, CAPN10 Indel19 was associated with type 2 diabetes. The information obtained from our study would be helpful for genotyping accuracies of SNPs residing in the CNVs region. [Copyright &y& Elsevier]

Abstract: This study investigates the relationship between genetic copy number variations and brain volume differences in an alcohol use disorder (AUD) population. We hypothesized that copy number variations may influence subject''s risk for alcohol use disorders through variations in regional gray and white matter brain volumes. Since genetic influences upon behavior are the result of many complicated interactions we focus on differences in brain volume as a putative intermediate phenotype between genetic variation and behavior. Copy number variation, alcohol use assessments and brain structural magnetic resonance images from 283 subjects, 199 male and 84 females who were enrolled in two AUD studies were obtained and analyzed using a combination of the Freesurfer image analysis suite and independent component analysis. Because brain volume varies by age we compared participant''s volume variation with that derived from a control cohort of 75 subjects. In addition we also regressed out the possible brain volume changes induced by long term alcohol consumption. Small cerebral cortex, cerebellar and caudate along with large cerebral white matter and 5th ventricle volumes are shown to be significantly associated with increased AUD severity. When these volume variations are compared with control subject volumes; the variations seen in subjects with AUD are markedly different from normal aging effects. CNVs at 11 q14.2 are marginally (p < 0.05 uncorrected) correlated with such brain volume variations and the correlation holds true after controlling for long-term alcohol consumption; deletion carriers have smaller cerebral cortex, cerebellar, caudate and larger cerebral white matter and 5th ventricle volumes than insertion carriers or subjects with no variation in this region. Similarly, deletion carriers also demonstrate higher AUD severity scores than insertion carriers or subjects with no variation. The results presented here suggest that copy number variation and in particular the variation at chromosome 11 q14.2 may have an impact in brain volume variation, potentially influencing AUD behavior. [Copyright &y& Elsevier]

Background: Although variations in neurometabolite concentrations occur in diverse neuropsychiatric and neurodegenerative disorders, little is known about the nature of underlying genetic influences. The current study investigated the importance of a specific type of genetic mutation, copy number variation (CNV), for neurometabolite concentrations in a bilateral anterior cingulate voxel. Methods: These neurometabolic signals were quantified using proton magnetic resonance spectroscopy (1H-MRS): N-acetylaspartate (NAA), creatine-phosphocreatine (Cre), glutamate/glutamine (Glx), myoinositol (mI), and phosphorylcholine-glycerol phosphorylcholine (Cho). Genetic data were collected using the Illumina 1MDuoBeadChip Array from a sample adults with alcohol use disorders (n = 146). Results: The number of base pairs lost through rare copy number deletions (occurring in less than 5% of our sample) predicted lower NAA, Cre, mI, and Glx. More total rare deletions also predicted lower NAA, Cre, and Glx. Principal components analyses of the five neurometabolites identified two correlated components, the first comprised of NAA, Glx, and Cre, and the second comprised of Cho, mI, and to a lesser extent, Cre. The number and length of rare deletions were correlated with the first component, capturing approximately 10% of phenotypic variance, but not the second component. Conclusions: These results suggest that mutation load affects neurometabolite concentrations, potentially increasing risk for neuropsychiatric disorders. The greater effect of CVNs on NAA, Glx, and Cre may reflect a greater sensitivity to the effects of mutations (i.e., reduced canalization) for neurometabolites related to metabolic activity and cellular energetics, due to extensive recent selection pressure on these phenotypes in the human lineage. [ABSTRACT FROM AUTHOR]

Abstract: Neuroacanthocytosis syndromes are mainly comprised of two diseases: chorea-acanthocytosis (ChAc) and McLeod syndrome (MLS). There is a high incidence of psychiatric disorders such as mood disorder and schizophrenia among neuroacanthocytosis patients. We hypothesized that neuroacanthocytosis-related-genes might be associated with susceptibility to these psychiatric disorders. We performed a comprehensive mutation screen of VPS13A and XK, the gene responsible for ChAc and MLS, respectively, in 85 mood disorder subjects and XK in 86 schizophrenia subjects and compared the variants to 100 or more control alleles. We also performed copy number variation (CNV) analysis in 72 mood disorder subjects and 86 schizophrenia subjects. We identified three non-synonymous, two synonymous and six intron variants in mood disorder subjects and a novel GAT triplet repeat polymorphism in VPS13A. By CNV analysis, we identified a heterozygous exon 60–61 deletion in VPS13A in one mood disorder subject. We identified one non-synonymous and one intron variant in mood disorder and schizophrenia subjects, respectively, in XK. The presence of a pathogenic mutation or a potentially functional variant in mood disorder or schizophrenia subjects suggests that neuroacanthocytosis-related-genes might be involved in the pathogenesis of these psychiatric disorders. [Copyright &y& Elsevier]

• The CNV of DYNC1I2 gene had significant effect on Height at hip cross of XN cattle, body Length of PN cattle, Chest width and Hucklebone width of QC cattle and Chest depth of YL cattle. Previous, studies have shown that the dynein transporter compound has a role in diseases such as intellectual disability and cerebral malformations. However, the study of CNV in DYNC1I2 gene has not been reported. Q-PCR and data association analysis were used for DYNC1I2 gene copy in this study. In this study, blood samples were collected from five breeds of Chinese cattle (Qingchuan cattle, Xianan cattle, Yunling cattle, Pinan cattle and Guyuan cattle) for DYNC1I2 gene CNV type detection. SPSS 20.0 software and method of ANOVA were used to analyzed the association between types of CNV and growth traits. Results reveal that the distribution of different copy number types in different cattle breeds is different. Association analysis indicate that CNV of DYNC1I2 gene showed a positive effect in cattle growth: in XN cattle, individuals with deletion types showed better performance on height at hip cross (P < 0.05); individuals with duplication types have better performance on body length (P < 0.05) in PN cattle; individuals with deletion types was significantly correlated with chest width and Hucklebone width (P < 0.05) in QC cattle; individuals with duplication types in Yunling cattle were better than the normal types, and there was a significant correlation between copy number variant and chest depth (P < 0.05). The results showed that CNV markers closely related to cattle production traits were detected at DNA level, which could be used as an important candidate molecular marker for marker-assisted selection of growth traits in Chinese cattle, and provided a new research basis for genetics and breeding of Chinese beef cattle. [ABSTRACT FROM AUTHOR]

• Each cancer is characterized by unique rearrangement endpoint distribution. • DNA damage repair pathway choice may drive rearrangements. • Selection of certain rearrangements that promote cancer progression occurs. Copy number variations (CNVs) which include deletions, duplications, inversions, translocations, and other forms of chromosomal re-arrangements are common to human cancers. In this report we investigated the pattern of these variations with the goal of understanding whether there exist specific cancer signatures. We used re-arrangement endpoint data deposited on the Catalogue of Somatic Mutations in Cancers (COSMIC) for our analysis. Indeed, we find that human cancers are characterized by specific patterns of chromosome rearrangements endpoints which in turn result in cancer specific CNVs. A review of the literature reveals tissue specific mutations which either drive these CNVs or appear as a consequence of CNVs because they confer an advantage to the cancer cell. We also identify several rearrangement endpoints hotspots that were not previously reported. Our analysis suggests that in addition to local chromosomal architecture, CNVs are driven by the internal cellular or nuclear physiology of each cancer tissue. [ABSTRACT FROM AUTHOR]

Abstract: The rapid advancement of high-resolution DNA copy number assessment methods revealed the significant contribution of submicroscopic genetic imbalances to abnormal phenotypes, including mental retardation. In order to detect submicroscopic genetic imbalances, we have screened 20 families with X-linked mental retardation (XLMR) using a chromosome X-specific array-MAPH platform with median resolution of 238kb. Among the 20 families, 18 were experimental, as they were not previously screened with any microarray method, and two were blind controls with known aberrations, as they were previously screened by array-CGH. This study presents the first clinical application of chromosome X-specific array-MAPH methodology. The screening of 20 affected males from 20 unrelated XLMR families resulted in the detection of an unknown deletion, spanning a region of 7–23kb. Family studies and population screening demonstrated that the detected deletion is an unknown rare copy number variant. One of the control samples, carrying approximately 6-Mb duplication was correctly identified, moreover it was found to be interrupted by a previously unknown 19kb region of normal copy number. The second control 50kb deletion was not identified, as this particular region was not covered by array-MAPH probes. This study demonstrates that the chromosome X-specific array-MAPH platform is a valuable tool for screening patients with XLMR, or other X-linked disorders, and emerges the need for introducing new high-resolution screening methods for the detection of genetic imbalances. [Copyright &y& Elsevier]

• The study investigated genomic imbalances in 28 SCOS patients. • Baseline investigation showed higher FSH and lower Inhibin-B in patient group. • FISH identified four cases of sex chromosomal abnormality. • Multiplex STS-PCR identified four cases of Yq microdeletion. • Microarray identified CNVs and LOH that involve many genes related to spermatogenesis. • Intra-individual genomic variations were identified between testis and blood in two patients. Sertoli cell only syndrome (SCOS) is characterized by complete absence of germ cells in seminiferous tubules of testis. SCOS is multifactorial but genetic factors play a major role in pathogenesis of the disorder with idiopathic origin. Genetic factors majorly include sex chromosomal aneuploidy and Yq Microdeletion. But a large number of cases are still idiopathic. The study aimed to evaluate the genomic imbalances (CNVs and LOH) in idiopathic SCOS patients. The study is based on 28 apparent idiopathic SCOS cases and 10 controls. Molecular cytogenetic techniques viz., FISH, STS-Multiplex PCR and Affymetrix cytoscan microarray (750 K) were used. The microarray screened whole genomic imbalances in DNA from peripheral blood of 25 cases (excluded Klinefelter syndrome patients) and testicular FNAC sample of 2 cases. High FSH and low Inhibin B were observed in cases as compared to control controls groups. Four cases of sex chromosomal abnormality (i.e., three non-mosaic 47, XXY males and one non-mosaic 46, XX male) as well as four cases of Yq microdeletion (i.e., three cases with AZFc deletion and one case with complete AZFa, b and c deletion) were identified. Microarray detected unbalanced translocation of two segments of Y-chromosome i.e., Yp11.31-p11.2 (~4.o mb region, involving SRY) and Yp11.2 (~2.5 mb region) on X-chromosome in XX male. Also, loss of segment on same X-chromosome involving PAR1 region was identified. We have identified both autosomal and sex chromosomal CNVs (recurrent as well as private) involving candidate genes like SYCE1, ZFPM2, SRPK1, DAZ1, BPY2, HSFY1, VCY1 etc. All these CNVs are possibly associated with SCOS pathogenesis. CNVs identified in cases were already reported as pathogenic variant in clinical database DECIPHER. Microarray also detected many LOH (all autosomal, >3.0 mb size) that covered genes with spermatogenesis related function. The mechanism of action of LOH in pathogenesis of SCOS still remains unravelled. CNVs and LOH related to spermatogenesis identified from two different sample types (blood vs. testicular tissue) were discordant. This study should be extended for larger cohort of patients. [ABSTRACT FROM AUTHOR]

Background: Alveolar capillary dysplasia with misalignment of pulmonary veins (ACDMPV) is a rare and fatal disorder that occurs in the developing fetal lungs; at birth, infants exhibit an oxygenation disorder accompanied by severe pulmonary hypertension (PH) and have a very short life span. ACDMPV is definitively diagnosed by pathological findings, and infants born with unexplained severe PH may not be properly diagnosed without a biopsy or autopsy.Methods: Japanese infants with unexplained severe PH were enrolled in this study. Genetic analyses were performed on DNA extracted from peripheral blood leukocytes. Sanger sequencing or next-generation sequencing was performed by coding exons and introns for FOXF1 in all samples. For individuals without pathogenic exonic variants, multiplex ligation-dependent probe amplification was performed to identify copy number variations (CNVs) in exons, introns, and in the upstream region of FOXF1.Results: This study included 30 infants who were diagnosed over the course of nine years. Four individuals had the pathogenic variations on the exon 1 of FOXF1, including two frameshift and two missense variations. Pathogenic CNVs were found in another five individuals.Conclusion: In the pathologically proven ACDMPV patients, the ratios of cases with exonic variations, CNVs, and no genetic findings were reported as 45%, 45% and 10%, respectively. We estimate that about 30% (10 (9 + 1) out of 30) of individuals with unexplained severe PH had ACDMPV. [ABSTRACT FROM AUTHOR]

The short arm of chromosome 16 (16p) is enriched for segmental duplications, making it susceptible to recurrent, reciprocal rearrangements implicated in the etiology of several phenotypes, including intellectual disability, speech disorders, developmental coordination disorder, autism spectrum disorders, attention deficit hyperactivity disorders, obesity and congenital skeletal disorders. In our clinical study 73 patients were analyzed by chromosomal microarray, and results were confirmed by fluorescence in situ hybridization or polymerase chain reaction. All patients underwent detailed clinical evaluation, with special emphasis on behavioral symptoms. 16p rearrangements were identified in 10 individuals. We found six pathogenic deletions and duplications of the recurrent regions within 16p11.2: one patient had a deletion of the distal 16p11.2 region associated with obesity, while four individuals had duplications, and one patient a deletion of the proximal 16p11.2 region. The other four patients carried 16p variations as second-site genomic alterations, acting as possible modifying genetic factors. We present the phenotypic and genotypic results of our patients and discuss our findings in relation to the available literature. [ABSTRACT FROM AUTHOR]

• KMT2D CNVs may have effects on sheep growth traits. • The median type of KMT2D CNV is a beneficial genotype to sheep breeds. • The KMT2D CNV could be used as a molecular marker for sheep breeding. Copy number variations (CNVs) are an important source of genetic variation, which can affect a wide range of economic traits by diverse mechanisms. KMT2D (Lysine methyltransferase 2D) is an important positional candidate for growth traits. Quantitative trait loci (QTLs) with large effects on economically important traits cover the KMT2D gene. The KMT2D gene overlays a CNV within its exons, hence it was chosen as a crucial candidate gene to study the association between CNV and growth traits. Further, KMT2D, a major mammalian histone H3K4 mono-methyltransferase, plays a critical role in regulating development, differentiation, metabolism, and tumor suppression. Therefore, we proposed the hypothesis that KMT2D CNV may have phenotypic effects on sheep growth traits. In our study, KMT2D CNVs in three Chinese sheep breeds were detected by quantitative polymerase chain reaction (qPCR), and the loss copy was found to be the dominant genotype. Association analysis between growth traits and KMT2D CNV was also performed, which revealed that individuals with the median copy showed better performance than those with the loss copy in all three breeds. This research suggested that KMT2D CNV can be used as a promising marker for sheep molecular breeding. [ABSTRACT FROM AUTHOR]

• ASD children exhibit co-occurring sensory processing problems, and hyper- or hyporeactivity to sensory input. • Chromosomal rearrangements, copy number variations and coding sequence variants, involving more than 100 genes, have been found in patients with ASD. Studying SHANK 3 gene CNVs and its associated phenotype in ASD patients might provide guidance for future treatment and intervention of ASD. • The studied ASD children displayed sensory processing problems. SHANK3 copy number gains were found in three cases and it signifies the gene dosage effect of SHANK3 in ASD pathogenesis. • To the best of our knowledge, this is the sixth report of 22q13 duplication including SHANK3. Current estimates indicate that >80 % of children with autism spectrum disorder (ASD) exhibit concomitant sensory processing problems and hyper- or hypo-reactivity to sensory input. These are now included as diagnostic criteria for ASD in the Diagnostic and Statistical Manual of Mental Disorders—Fifth Edition. Chromosomal rearrangements, copy number variations (CNVs), and coding sequence variants involving >100 genes have been identified in patients with ASD. Studying the CNVs of one such gene, SHANK3, and the associated phenotype in patients with ASD could provide insights that will guide future ASD treatments and interventions. To assess SHANK3 CNVs in children with ASD and investigate their sensory processing patterns using the Short Sensory Profile (SSP). Forty children with ASD were assessed using the Autism Diagnostic Interview-Revised. SSP was used to evaluate atypical sensory behavior, e.g., hyper- or hypo-reactivity to sensory input or unusual sensory interests. SHANK3 CNVs were assessed in these children using Multiplex Ligation-dependent Probe Amplification. Of the 40 cases, 77.5 % showed sensory reactivity symptoms. The greatest difference from normality was observed in the under-responsive/seeks sensation domain, followed by the tactile sensitivity domain, whereas hypo-activity (low-energy/weak domain) was closest to normal. The sensory reactivity symptoms were significantly correlated with the severity of ASD. However, only three of the 40 cases had de novo duplications at 22q13.33. The duplications included SHANK3 in two of the cases and only the distal flanking region of SHANK3 in the third case. All three duplication cases also showed symptoms associated with the low-energy/weak domain. We found that children with ASD exhibited sensory processing problems. The SHANK3 copy number gains found demonstrate the gene dosage effect of SHANK3 in ASD pathogenesis. This study adds to the growing understanding of 22q13 duplications that include SHANK3. [ABSTRACT FROM AUTHOR]

Copy number variations (CNVs) of the CNTN6 gene - a member of the contactin gene superfamily - have been previously proposed to have an association with neurodevelopmental and autism spectrum disorders. However, no functional evidence has been provided to date and phenotypically normal and mildly affected carriers complicate the interpretation of this aberration. In view of conflicting reports on the pathogenicity of CNVs involving CNTN6 and association with different phenotypes, we, independently, evaluated clinical features of nineteen patients with detected CNV of CNTN6 as part of their clinical microarray analysis at Children's Mercy and Nationwide Children's Hospitals for the period of 2008–2015. The clinical presentations of these patients were variable making it difficult to establish genotype-phenotype correlations. CNVs were inherited in six patients. For thirteen patients, inheritance pattern was not established due to unavailability of parental samples for testing. In three cases CNV was inherited from a healthy parent and in three cases from a parent with neurodevelopmental symptoms. Of the nineteen patients, four had a separate genetic abberation in addition to CNV of the CNTN6 that could independently explain their respective phenotypes. Separately, CNTN6 sequencing was performed on an autism spectrum disorder (ASD) research cohort of 94 children from 80 unrelated families. We found no difference in frequency of rare coding variants between the cohort of patients and controls. We conclude that CNVs involving CNTN6 alone seem to be most likely a neutral variant or a possible modifier rather than a disease-causing variant. Patients with CNVs encompassing CNTN6 could benefit from additional genetic testing since a clinical diagnosis due to a CNV of CNTN6 alone is still questionable. [ABSTRACT FROM AUTHOR]

Introduction/Background Microarray-based comparative genomic hybridization (array CGH) has been widely adopted as a valuable clinical diagnostic test for children with delayed development. Bradley P. Coe et al. suggested copy number variants (CNVs) are associated with many neurocognitive disorders. Hence, overall development was measured between two groups divided by array CGH results. Material and method A retrospective chart review was done in 42 children who underwent array CGH after visiting PM&R Department outpatient clinic with delayed development as chief complaints. Children were evaluated for Denver Developmental Screening Test (DDST), Sequenced Language Scale for Infants (SELSI)/Preschool Receptive-Expressive Language Scale (PRES). A Mann-Whitney U test was conducted to determine statistical differences of Developmental Quotient (DQ), Receptive Language Quotient (RLQ) and Expressive Language Quotient (ELQ) between two groups: 14 children with CNVs and 28 children without CNVs. Results DDST showed that personal social and language DQ were higher and fine motor and gross motor were lower in CNV (+) group than in CNV (−) group, but the difference was not statistically significant. All 22 children who underwent SELSI or PRES showed delayed language in all domains and RLQ and ELQ were higher in CNV (+) group than in CNV (−) group and the difference was statistically significant for ELQ ( P < 0.05). In the CNV (+) group, ELQ was assessed higher than RLQ; In the CNV (−) group, ELQ was assessed lower than RLQ, but statistical significance was not observed in both inter-group. Conclusion DQ in all domains was not significantly lower in children with CNV compared to children without CNV. However, tendency of milder delay of ELQ was observed in children with CNV. Active detection of genomic imbalance could play some vital role in assessing development aspect in children with delayed development. [ABSTRACT FROM AUTHOR]