Novel insights into the phenotypic spectrum and pathogenesis of Hardikar syndrome.

PURPOSE: Hardikar syndrome (HS, MIM #301068) is a female-specific multiple congenital anomaly syndrome characterized by retinopathy, orofacial clefting, aortic coarctation, biliary dysgenesis, genitourinary malformations, and intestinal malrotation. We previously showed that heterozygous nonsense and frameshift variants in MED12 cause HS. The phenotypic spectrum of disease and the mechanism by which MED12 variants cause disease is unknown. We aim to expand the phenotypic and molecular landscape of HS and elucidate the mechanism by which MED12 variants cause disease. METHODS: We assembled and clinically and molecularly characterized a cohort of 11 previously-unreported individuals with HS. We additionally studied the effect of MED12 deficiency on ciliary biology and hedgehog and YAP signaling, pathways implicated in diseases with phenotypic overlap with HS. RESULTS: We report novel phenotypes associated with HS, including cardiomyopathy, arrhythmia, and vascular anomalies and expand the molecular landscape of HS to include splice site variants. We additionally demonstrate that MED12 deficiency causes decreased cell ciliation and impairs hedgehog and YAP signaling. CONCLUSION: Our data support updating HS standard-of-care to include regular cardiac imaging, arrhythmia screening, and vascular imaging. We further propose that dysregulation of ciliogenesis and YAP and hedgehog signaling contributes to the pathogenesis of HS.

Pathological Asymmetry-Guided Progressive Learning for Acute Ischemic Stroke Infarct Segmentation.

Quantitative infarct estimation is crucial for diagnosis, treatment and prognosis in acute ischemic stroke (AIS) patients. As the early changes of ischemic tissue are subtle and easily confounded by normal brain tissue, it remains a very challenging task. However, existing methods often ignore or confuse the contribution of different types of anatomical asymmetry caused by intrinsic and pathological changes to segmentation. Further, inefficient domain knowledge utilization leads to mis-segmentation for AIS infarcts. Inspired by this idea, we propose a pathological asymmetry-guided progressive learning (PAPL) method for AIS infarct segmentation. PAPL mimics the step-by-step learning patterns observed in humans, including three progressive stages: knowledge preparation stage, formal learning stage, and examination improvement stage. First, knowledge preparation stage accumulates the preparatory domain knowledge of the infarct segmentation task, helping to learn domain-specific knowledge representations to enhance the discriminative ability for pathological asymmetries by constructed contrastive learning task. Then, formal learning stage efficiently performs end-to-end training guided by learned knowledge representations, in which the designed feature compensation module (FCM) can leverage the anatomy similarity between adjacent slices from the volumetric medical image to help aggregate rich anatomical context information. Finally, examination improvement stage encourages improving the infarct prediction from the previous stage, where the proposed perception refinement strategy (RPRS) further exploits the bilateral difference comparison to correct the mis-segmentation infarct regions by adaptively regional shrink and expansion. Extensive experiments on public and in-house NCCT datasets demonstrated the superiority of the proposed PAPL, which is promising to help better stroke evaluation and treatment.

GWAS reveals Genetic Susceptibility to Air Pollution-Related Asthma Exacerbations in Children of African Ancestry.

Background: The relationship between ambient air pollution (AAP) exposure and asthma exacerbations is well-established. However, mitigation efforts have yielded mixed results, potentially due to genetic variability in the response to AAP. We hypothesize that common single nucleotide polymorphisms (SNPs) are linked to AAP sensitivity and test this through a Genome Wide Association Study (GWAS). Methods: We selected a cohort of pediatric asthma patients frequently exposed to AAP. Patients experiencing exacerbations immediately following AAP spikes were deemed sensitive. A GWAS compared sensitive versus non-sensitive patients. Findings were validated using data from the All of Us program. Results: Our study included 6,023 pediatric asthma patients. Due to the association between AAP exposure and race, GWAS analysis was feasible only in the African ancestry cohort. Seven risk loci reached genome-wide significance, including four non-intergenic variants. Two variants were validated: rs111970601 associated with sensitivity to CO (odds ratio [OR], 6.58; PL=L1.63L×L10-8; 95% CI, 3.42-12.66) and rs9836522 to PM2.5 sensitivity (OR 0.75; PL=L3,87 ×L10-9; 95% CI, 0.62-0.91). Interpretation: While genetic variants have been previously linked to asthma incidence and AAP exposure, this study is the first to link specific SNPs with AAP-related asthma exacerbations. The identified variants implicate genes with a known role in asthma and established links to AAP. Future research should explore how clinical interventions interact with genetic risk to mitigate the effects of AAP, particularly to enhance health equity for vulnerable populations. What is already known on this topic: The relationship between ambient air pollution (AAP) exposure and asthma exacerbations is well-established. However, efforts to mitigate the impact of AAP on children with asthma have yielded mixed results, potentially due to genetic variability in response to AAP. What this study adds: Using publicly available AAP data, we identify which children with asthma experience exacerbations immediately following spikes in AAP. We then conduct a Genome Wide Association Study (GWAS) comparing these patients with those who have no temporal association between AAP spikes and asthma exacerbations, identifying several Single Nucleotide Polymorphisms (SNPs) significantly associated with AAP sensitivity. How this study might affect research practice or policy: While genetic variants have previously been linked to asthma incidence and AAP exposure, this study is the first to link specific SNPs with AAP-related asthma exacerbations. This creates a framework for identifying children especially at risk when exposed to AAP. These children should be targeted with policy interventions to reduce exposure and may require specific treatments to mitigate the effects of ongoing AAP exposure in the interim.

NASP gene contributes to autism by epigenetic dysregulation of neural and immune pathways.

BACKGROUND: Epigenetics makes substantial contribution to the aetiology of autism spectrum disorder (ASD) and may harbour a unique opportunity to prevent the development of ASD. We aimed to identify novel epigenetic genes involved in ASD aetiology. METHODS: Trio-based whole exome sequencing was conducted on ASD families. Genome editing technique was used to knock out the candidate causal gene in a relevant cell line. ATAC-seq, ChIP-seq and RNA-seq were performed to investigate the functional impact of knockout (KO) or mutation in the candidate gene. RESULTS: We identified a novel candidate gene NASP (nuclear autoantigenic sperm protein) for epigenetic dysregulation in ASD in a Chinese nuclear family including one proband with autism and comorbid atopic disease. The de novo likely gene disruptive variant tNASP(Q289X) subjects the expression of tNASP to nonsense-mediated decay. tNASP KO increases chromatin accessibility, promotes the active promoter state of genes enriched in synaptic signalling and leads to upregulated expression of genes in the neural signalling and immune signalling pathways. Compared with wild-type tNASP, tNASP(Q289X) enhances chromatin accessibility of the genes with enriched expression in the brain. RNA-seq revealed that genes involved in neural and immune signalling are affected by the tNASP mutation, consistent with the phenotypic impact and molecular effects of nasp-1 mutations in Caenorhabditis elegans. Two additional patients with ASD were found carrying deletion or deleterious mutation in the NASP gene. CONCLUSION: We identified novel epigenetic mechanisms mediated by tNASP which may contribute to the pathogenesis of ASD and its immune comorbidity.

A Protective Role of Low Polygenic Risk Score in Healthy Individuals Carrying Attention-Deficit/Hyperactivity Disorder-Associated Copy Number Variations.

BACKGROUND: Previous studies have implicated both rare copy number variations (CNVs) and common variants in liability for attention-deficit/hyperactivity disorder (ADHD). However, how common and rare genetic variants jointly contribute to individual liability requires further investigation in larger cohorts. METHODS: This study comprises 9385 participants of European descent and 7810 participants of African American ancestry who were recruited from the greater Philadelphia area by the Children's Hospital of Philadelphia. The polygenic risk score (PRS) of each participant was estimated by linkage disequilibrium pruning and p-value thresholding (P + T) methods using PRSice-2. We investigated whether the risk of ADHD follows a polygenic liability threshold model wherein 1) the risk of ADHD requires less contribution from common variants in the presence of a rare CNV, and 2) control carriers of ADHD-associated CNVs have lower common risk allele burden than noncarriers. RESULTS: CNVs previously reported in ADHD cases were significantly associated with ADHD risk in both the European American cohort and the African American cohort. Healthy control participants carrying those same risk CNVs had lower PRSs than those without risk CNVs in the European American cohort. This result was replicated in the African American cohort. However, PRSs were not significantly different in case participants carrying risk CNVs versus those without risk CNVs. CONCLUSIONS: These findings provide evidence in support of interactive effects of PRS and ADHD-associated CNVs on disease risk and add novel insights into the genetic basis of ADHD by highlighting a protective role of low PRS in ADHD.

High Comorbidity of Pediatric Cancers in Patients with Birth Defects: Insights from Whole Genome Sequencing Analysis of Copy Number Variations.

BACKGROUND: Patients with birth defects (BD) exhibit an elevated risk of cancer. We aimed to investigate the potential link between pediatric cancers and BDs, exploring the hypothesis of shared genetic defects contributing to the coexistence of these conditions. METHODS: This study included 1454 probands with BDs (704 females and 750 males), including 619 (42.3%) with and 845 (57.7%) without co-occurrence of pediatric onset cancers. Whole genome sequencing (WGS) was done at 30X coverage through the Kids First/Gabriella Miller X01 Program. RESULTS: 8211 CNV loci were called from the 1454 unrelated individuals. 191 CNV loci classified as pathogenic/likely pathogenic (P/LP) were identified in 309 (21.3%) patients, with 124 (40.1%) of these patients having pediatric onset cancers. The most common group of CNVs are pathogenic deletions covering the region ChrX:52,863,011-55,652,521, seen in 162 patients including 17 males. Large recurrent P/LP duplications >5MB were detected in 33 patients. CONCLUSIONS: This study revealed that P/LP CNVs were common in a large cohort of BD patients with high rate of pediatric cancers. We present a comprehensive spectrum of P/LP CNVs in patients with BDs and various cancers. Notably, deletions involving E2F target genes and genes implicated in mitotic spindle assembly and G2/M checkpoint were identified, potentially disrupting cell-cycle progression and providing mechanistic insights into the concurrent occurrence of BDs and cancers.

Mitochondrial DNA Haplogroup K Is Protective Against Autism Spectrum Disorder Risk in Populations of European Ancestry.

OBJECTIVE: Accumulative evidence indicates a critical role of mitochondrial function in autism spectrum disorders (ASD), implying that ASD risk may be linked to mitochondrial dysfunction due to DNA (mtDNA) variations. Although a few studies have explored the association between mtDNA variations and ASD, the role of mtDNA in ASD is still unclear. Here, we aimed to investigate whether mitochondrial DNA haplogroups are associated with the risk of ASD. METHOD: Two European cohorts and an Ashkenazi Jewish (AJ) cohort were analyzed, including 2,062 ASD patients in comparison with 4,632 healthy controls. DNA samples were genotyped using Illumina HumanHap550/610 and Illumina 1M arrays, inclusive of mitochondrial markers. Mitochondrial DNA (mtDNA) haplogroups were identified from genotyping data using HaploGrep2. A mitochondrial genome imputation pipeline was established to detect mtDNA variants. We conducted a case-control study to investigate potential associations of mtDNA haplogroups and variants with the susceptibility to ASD. RESULTS: We observed that the ancient adaptive mtDNA haplogroup K was significantly associated with decreased risk of ASD by the investigation of 2 European cohorts including a total of 2,006 cases and 4,435 controls (odds ratio = 0.64, P=1.79 × 10-5), and we replicated this association in an Ashkenazi Jewish (AJ) cohort including 56 cases and 197 controls (odds ratio = 0.35, P = 9.46 × 10-3). Moreover, we demonstrate that the mtDNA variants rs28358571, rs28358584, and rs28358280 are significantly associated with ASD risk. Further expression quantitative trait loci (eQTLs) analysis indicated that the rs28358584 and rs28358280 genotypes are associated with expression levels of nearby genes in brain tissues, suggesting those mtDNA variants may confer risk for ASD via regulation of expression levels of genes encoded by the mitochondrial genome. CONCLUSION: This study helps to shed light on the contribution of mitochondria in ASD and provides new insights into the genetic mechanism underlying ASD, suggesting the potential involvement of mtDNA-encoded proteins in the development of ASD.

Genomic variants exclusively identified in children with birth defects and concurrent malignant tumors predispose to cancer development.

Children with birth defects (BD) express distinct clinical features that often have various medical consequences, one of which is predisposition to the development of cancers. Identification of the underlying genetic mechanisms related to the development of cancer in BD patients would allow for preventive measures. We performed a whole genome sequencing (WGS) study on blood-derived DNA samples from 1566 individuals without chromosomal anomalies, including 454 BD probands with at least one type of malignant tumors, 767 cancer-free BD probands, and 345 healthy individuals. Exclusive recurrent variants were identified in BD-cancer and BD-only patients and mapped to their corresponding genomic regions. We observed statistically significant overlaps for protein-coding/ncRNA with exclusive variants in exons, introns, ncRNAs, and 3'UTR regions. Exclusive exonic variants, especially synonymous variants, tend to occur in prior exons locus in BD-cancer children. Intronic variants close to splicing site (< 500 bp from exon) have little overlaps in BD-cancer and BD-only patients. Exonic variants in non-coding RNA (ncRNA) tend to occur in different ncRNAs exons regardless of the overlaps. Notably, genes with 5' UTR variants are almost mutually exclusive between the two phenotypes. In conclusion, we conducted the first genomic study to explore the impact of recurrent variants exclusive to the two distinguished clinical phenotypes under study, BD with or without cancer, demonstrating enrichment of selective protein-coding/ncRNAs differentially expressed between these two phenotypes, suggesting that selective genetic factors may underlie the molecular processes of pediatric cancer development in BD children.

RNA Sequencing in Hypoxia-Adapted T98G Glioblastoma Cells Provides Supportive Evidence for IRE1 as a Potential Therapeutic Target.

Glioblastoma (GBM) is an aggressive brain cancer with a median survival time of 14.6 months after diagnosis. GBM cells have altered metabolism and exhibit the Warburg effect, preferentially producing lactate under aerobic conditions. After standard-of-care treatment for GBM, there is an almost 100% recurrence rate. Hypoxia-adapted, treatment-resistant GBM stem-like cells are thought to drive this high recurrence rate. We used human T98G GBM cells as a model to identify differential gene expression induced by hypoxia and to search for potential therapeutic targets of hypoxia adapted GBM cells. RNA sequencing (RNAseq) and bioinformatics were used to identify differentially expressed genes (DEGs) and cellular pathways affected by hypoxia. We also examined expression of lactate dehydrogenase (LDH) genes using qRT-PCR and zymography as LDH dysregulation is a feature of many cancers. We found 2630 DEGs significantly altered by hypoxia (p < 0.05), 1241 upregulated in hypoxia and 1389 upregulated in normoxia. Hypoxia DEGs were highest in pathways related to glycolysis, hypoxia response, cell adhesion and notably the endoplasmic reticulum, including the inositol-requiring enzyme 1 (IRE1)-mediated unfolded protein response (UPR). These results, paired with numerous published preclinical data, provide additional evidence that inhibition of the IRE1-mediated UPR may have therapeutic potential in treating GBM. We propose a possible drug repurposing strategy to simultaneously target IRE1 and the spleen tyrosine kinase (SYK) in patients with GBM.

Rare recurrent copy number variations in metabotropic glutamate receptor interacting genes in children with neurodevelopmental disorders.

BACKGROUND: Neurodevelopmental disorders (NDDs), such as attention deficit hyperactivity disorder (ADHD) and autism spectrum disorder (ASD), are examples of complex and partially overlapping phenotypes that often lack definitive corroborating genetic information. ADHD and ASD have complex genetic associations implicated by rare recurrent copy number variations (CNVs). Both of these NDDs have been shown to share similar biological etiologies as well as genetic pleiotropy. METHODS: Platforms aimed at investigating genetic-based associations, such as high-density microarray technologies, have been groundbreaking techniques in the field of complex diseases, aimed at elucidating the underlying disease biology. Previous studies have uncovered CNVs associated with genes within shared candidate genomic networks, including glutamate receptor genes, across multiple different NDDs. To examine shared biological pathways across two of the most common NDDs, we investigated CNVs across 15,689 individuals with ADHD (n = 7920), ASD (n = 4318), or both (n = 3,416), as well as 19,993 controls. Cases and controls were matched by genotype array (i.e., Illumina array versions). Three case-control association studies each calculated and compared the observed vs. expected frequency of CNVs across individual genes, loci, pathways, and gene networks. Quality control measures of confidence in CNV-calling, prior to association analyses, included visual inspection of genotype and hybridization intensity. RESULTS: Here, we report results from CNV analysis in search for individual genes, loci, pathways, and gene networks. To extend our previous observations implicating a key role of the metabotropic glutamate receptor (mGluR) network in both ADHD and autism, we exhaustively queried patients with ASD and/or ADHD for CNVs associated with the 273 genomic regions of interest within the mGluR gene network (genes with one or two degrees protein-protein interaction with mGluR 1-8 genes). Among CNVs in mGluR network genes, we uncovered CNTN4 deletions enriched in NDD cases (P = 3.22E - 26, OR = 2.49). Additionally, we uncovered PRLHR deletions in 40 ADHD cases and 12 controls (P = 5.26E - 13, OR = 8.45) as well as clinically diagnostic relevant 22q11.2 duplications and 16p11.2 duplications in 23 ADHD + ASD cases and 9 controls (P = 4.08E - 13, OR = 15.05) and 22q11.2 duplications in 34 ADHD + ASD cases and 51 controls (P = 9.21E - 9, OR = 3.93); those control samples were not with previous 22qDS diagnosis in their EHR records. CONCLUSION: Together, these results suggest that disruption in neuronal cell-adhesion pathways confers significant risk to NDDs and showcase that rare recurrent CNVs in CNTN4, 22q11.2, and 16p11.2 are overrepresented in NDDs that constitute patients predominantly suffering from ADHD and ASD. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02286817 First Posted: 10 November 14, ClinicalTrials.gov Identifier: NCT02777931 first posted: 19 May 2016, ClinicalTrials.gov Identifier: NCT03006367 first posted: 30 December 2016, ClinicalTrials.gov Identifier: NCT02895906 first posted: 12 September 2016.

Genetic architecture of asthma in African American patients.

BACKGROUND: Asthma is a chronic inflammatory disorder with a strong genetic inheritance. Although more than 100 loci were reported through the genome-wide association study of European populations, the genetic underpinning of asthma in African American individuals remains largely elusive. OBJECTIVE: We aimed to identify genetic loci associated with asthma in African American individuals. METHODS: Three cohorts were genotyped at the Children's Hospital of Philadelphia by using the Illumina single-nucleotide polymorphism array platform. Genotype imputation was performed by using the Trans-Omics for Precision Medicine (TOPMed) reference panel, which includes whole genome sequencing data from more than 100,000 individuals. A meta-analysis of 3 Children's Hospital of Philadelphia cohorts and 10 Consortium on Asthma among African Ancestry Populations in the Americas cohorts, totaling 19,628 subjects, was conducted to identify genetic loci associated with asthma in African American individuals. RESULTS: Our study identified 12 loci surpassing the classical genome-wide significance threshold (5 × 10-8). Of those loci, 8 reached the stricter significance threshold (3 × 10-8). The 9p24.1 locus (rs10975467 [P = 1.63 × 10-8]) has previously been associated with asthma in European individuals. Six loci are associated with enhancer activities, 2 loci are in DNase I-hypersensitive regions, and all of them are associated with regulatory motifs. Moreover, the locus 11q13.4 (rs7480008) is an expression quantitative trait locus of XRRA1 in lung (P = 9.4 × 10-10), and the locus 13q14.3 (rs1543525) is a splicing quantitative trait locus of DHRS12 in lung (P = 1.1 × 10-13). CONCLUSIONS: Our findings provide candidate genetic loci for therapeutic target identification and prioritization for African populations.

ParseCNV2: efficient sequencing tool for copy number variation genome-wide association studies.

Improved copy number variation (CNV) detection remains an area of heavy emphasis for algorithm development; however, both CNV curation and disease association approaches remain in its infancy. The current practice of focusing on candidate CNVs, where researchers study specific CNVs they believe to be pathological while discarding others, refrains from considering the full spectrum of CNVs in a hypothesis-free GWAS. To address this, we present a next-generation approach to CNV association by natively supporting the popular VCF specification for sequencing-derived variants as well as SNP array calls using a PennCNV format. The code is fast and efficient, allowing for the analysis of large (>100,000 sample) cohorts without dividing up the data on a compute cluster. The scripts are condensed into a single tool to promote simplicity and best practices. CNV curation pre and post-association is rigorously supported and emphasized to yield reliable results of highest quality. We benchmarked two large datasets, including the UK Biobank (n > 450,000) and CAG Biobank (n > 350,000) both of which are genotyped at >0.5 M probes, for our input files. ParseCNV has been actively supported and developed since 2008. ParseCNV2 presents a critical addition to formalizing CNV association for inclusion with SNP associations in GWAS Catalog. Clinical CNV prioritization, interactive quality control (QC), and adjustment for covariates are revolutionary new features of ParseCNV2 vs. ParseCNV. The software is freely available at: https://github.com/CAG-CNV/ParseCNV2 .

Association of Inherited Copy Number Variation in ADAM3A and ADAM5 Pseudogenes with Oropharynx Cancer Risk and Outcome.

Inherited copy number variations (CNVs) can provide valuable information for cancer susceptibility and prognosis. However, their association with oropharynx squamous cell carcinoma (OPSCC) is still poorly studied. Using microarrays analysis, we identified three inherited CNVs associated with OPSCC risk, of which one was validated in 152 OPSCC patients and 155 controls and related to pseudogene-microRNA-mRNA interaction. Individuals with three or more copies of ADAM3A and ADAM5 pseudogenes (8p11.22 chromosome region) were under 6.49-fold increased risk of OPSCC. ADAM5 shared a highly homologous sequence with the ADAM9 3'-UTR, predicted to be a binding site for miR-122b-5p. Individuals carrying more than three copies of ADAM3A and ADAM5 presented higher ADAM9 expression levels. Moreover, patients with total deletion or one copy of pseudogenes and with higher expression of miR-122b-5p presented worse prognoses. Our data suggest, for the first time, that ADAM3A and ADAM5 pseudogene-inherited CNV could modulate OPSCC occurrence and prognosis, possibly through the interaction of ADAM5 pseudogene transcript, miR-122b-5p, and ADAM9.

Intestinal preservation in a birdlike dinosaur supports conservatism in digestive canal evolution among theropods.

Dromaeosaurids were bird-like dinosaurs with a predatory ecology known to forage on fish, mammals and other dinosaurs. We describe Daurlong wangi gen. et sp. nov., a dromaeosaurid from the Lower Cretaceous Jehol Biota of Inner Mongolia, China. Exceptional preservation in this specimen includes a large bluish layer in the abdomen which represents one of the few occurrences of intestinal remnants among non-avian dinosaurs. Phylogenetically, Daurlong nests among a lineage of short-armed Jehol Biota species closer to eudromaeosaurs than microraptorines. The topographic correspondence between the exceptionally preserved intestine in the more stem-ward Scipionyx and the remnants in the more birdlike Daurlong provides a phylogenetic framework for inferring intestine tract extent in other theropods lacking fossilized visceral tissues. Gastrointestinal organization results conservative among faunivorous dinosaurs, with the evolution of a bird-like alimentary canal restricted to avialan theropods.

Identification of risk variants related to malignant tumors in children with birth defects by whole genome sequencing.

BACKGROUND: Children with birth defects (BD) are more likely to develop cancer and the increased risk of cancer persists into adulthood. Prior population-based assessments have demonstrated that even non-chromosomal BDs are associated with at least two-fold increase of cancer risk. Identification of variants that are associated with malignant tumor in BD patients without chromosomal anomalies may improve our understanding of the underlying molecular mechanisms and provide clues for early cancer detection in children with BD. METHODS: In this study, whole genome sequencing (WGS) data of blood-derived DNA for 1653 individuals without chromosomal anomalies were acquired from the Kids First Data Resource Center (DRC), including 541 BD probands with at least one type of malignant tumors, 767 BD probands without malignant tumor, and 345 healthy family members who are the parents or siblings of the probands. Recurrent variants exclusively seen in cancer patients were selected and mapped to their corresponding genomic regions. The targeted genes/non-coding RNAs were further reduced using random forest and forward feature selection (ffs) models. RESULTS: The filtered genes/non-coding RNAs, including variants in non-coding areas, showed enrichment in cancer-related pathways. To further support the validity of these variants, blood WGS data of additional 40 independent BD probands, including 25 patients with at least one type of cancers from unrelated projects, were acquired. The counts of variants of interest identified in the Kid First data showed clear deviation in the validation dataset between BD patients with cancer and without cancer. Furthermore, a deep learning model was built to assess the predictive abilities in the 40 patients using variants of interest identified in the Kids First cohort as feature vectors. The accuracies are ~ 75%, with the noteworthy observation that variants mapped to non-coding regions provided the highest accuracy (31 out of 40 patients were labeled correctly). CONCLUSION: We present for the first time a panorama of genetic variants that are associated with cancers in non-chromosomal BD patients, implying that our approach may potentially serve for the early detection of malignant tumors in patients with BD.

Identification of novel loci in obstructive sleep apnea in European American and African American children.

STUDY OBJECTIVES: To identify genetic susceptibility variants in pediatric obstructive sleep apnea in European American and African American children. METHODS: A phenotyping algorithm using electronic medical records was developed to recruit cases with OSA and control subjects from the Center for Applied Genomics at Children's Hospital of Philadelphia (CHOP.) Genome-wide association studies (GWAS) were performed in pediatric OSA cases and control subjects with European American (EA) and African American (AA) ancestry followed by meta-analysis and sex stratification. RESULTS: The algorithm accrued 1,486 subjects (46.3% European American, 53.7% African American). We identified genomic loci at 1p36.22 and 15q26.1 that associated with OSA risk in EA and AA, respectively. We also revealed a shared risk locus at 18p11.32 (rs114124196, P =1.72 ×10 -8) across EA and AA populations. Additionally, association at 1q43 (rs12754698) and 2p25.1 (rs72775219) was identified in the male-only analysis of EA children with OSA, while association at 8q21.11 (rs6472959), 11q24.3 (rs4370952) and 15q21.1 (rs149936782) was detected in the female-only analysis of EA children and association at 18p11.23 (rs9964029) was identified in the female-only analysis of African-American children. Moreover, the 18p11.32 locus was replicated in an EA cohort (rs114124196, P =8.8 ×10 -3). CONCLUSIONS: We report the first GWAS for pediatric OSA in European Americans and African Americans. Our results provide novel insights to the genetic underpins of pediatric OSA.

Mutation burden analysis of six common mental disorders in African Americans by whole genome sequencing.

Mental disorders present a global health concern and have limited treatment options. In today's medical practice, medications such as antidepressants are prescribed not only for depression but also for conditions such as anxiety and attention deficit hyperactivity disorder (ADHD). Therefore, identifying gene targets for specific disorders is important and offers improved precision. In this study, we performed a genetic analysis of six common mental disorders-ADHD, anxiety, depression, delays in mental development, intellectual disabilities (IDs) and speech/language disorder-in the ethnic minority of African Americans (AAs) using whole genome sequencing (WGS). WGS data were generated from blood-derived DNA from 4178 AA individuals, including 1384 patients with the diagnosis of at least one mental disorder. Mutation burden analysis was applied based on rare and deleterious mutations in the AA population between cases and controls, and further analyzed in the context of patients with single mental disorder diagnosis. Certain genes uncovered demonstrated significant P-values in mutation burden analysis. In addition, exclusive recurrences in specific type of disorder were scanned through gene-drug interaction databases to assess for availability of potential medications. We uncovered 15 genes harboring deleterious mutations, including 3-Hydroxy-3-Methylglutaryl-CoA Reductase (HMGCR) and Uronyl 2-Sulfotransferase (UST) for ADHD; Farnesyltransferase, CAAX Box, Beta (FNTB) for anxiety; Xin Actin Binding Repeat Containing 2 (XIRP2), Natriuretic Peptide C (NPPC), Serine/Threonine Kinase 33 (STK33), Pannexin 1 (PANX1) and Neurotensin (NTS) for depression; RUNX Family Transcription Factor 3 (RUNX3), Tachykinin Receptor 1 (TACR1) and NADH:Ubiquinone Oxidoreductase Core Subunit S7 (NDUFS7) for delays in mental development; Hepsin (HPN) for ID and Collagen Type VI Alpha 3 Chain (COL6A3), Damage Specific DNA Binding Protein 1 (DDB1) and NADH:Ubiquinone Oxidoreductase Subunit A11 (NDUFA11) for speech/language disorder. Taken together, we have established critical insights into the development of new precision medicine approaches for mental disorders in AAs.

Saudi Arabian CML patient with a novel four-way translocation at t(9;22;5;2)(q34;q11.2;p13;q44).

BACKGROUND: The vast majority of chronic myeloid leukemia (CML) patients have a single translocation t(9;22)(q34;q11), BCR/ABL1 fusion genes, which is regarded as the hallmark of CML. However, around 5 to 10% of CML patients exhibit the involvement of a third chromosome. In some very rare cases a fourth or even fifth chromosome can be involved with the t(9;22). METHODS: This case report is based on a 40-year-old Saudi Arabian male patient, diagnosed with CML in lymphoid blast crisis, and observed to have a four-way 46 XY, t(9;22;5;2)(q34;q11.2;p13;q44) translocation. The BCR/ABL1 fusion was identified by fluorescent in situ hybridization (FISH). Additionally, the BCR/ABL1 p210 mRNA fusion transcripts were identified by a molecular test. RESULTS: The clinical and prognostic impact of additional partner chromosomes to t(9;22) remains unknown. The CML patient with this novel four-way translocation t(9;22;5;2) progressed to blast crisis and was resistant to Tyrosine Kinase Inhibitor (TKI) therapy. Therefore, this case is more in alignment with the negative impact of additional partner chromosomes to the translocation at t(9;22). CONCLUSION: Here we report for the first time a novel four-way translocation at t(9;22;5;2)(q34;q11.2;p13;q44).

Burden of rare coding variants reveals genetic heterogeneity between obese and non-obese asthma patients in the African American population.

BACKGROUND: Asthma is a complex condition largely attributed to the interactions among genes and environments as a heterogeneous phenotype. Obesity is significantly associated with asthma development, and genetic studies on obese vs. non-obese asthma are warranted. METHODS: To investigate asthma in the minority African American (AA) population with or without obesity, we performed a whole genome sequencing (WGS) study on blood-derived DNA of 4289 AA individuals, included 2226 asthma patients (1364 with obesity and 862 without obesity) and 2006 controls without asthma. The burden analysis of functional rare coding variants was performed by comparing asthma vs. controls and by stratified analysis of obese vs. non-obese asthma, respectively. RESULTS: Among the top 66 genes with P < 0.01 in the asthma vs. control analysis, stratified analysis by obesity showed inverse correlation of natural logarithm (LN) of P value between obese and non-obese asthma (r = - 0.757, P = 1.90E-13). Five genes previously reported in a genome-wide association study (GWAS) on asthma, including TSLP, SLC9A4, PSMB8, IGSF5, and IKZF4 were demonstrated association in the asthma vs. control analysis. The associations of IKZF4 and IGSF5 are only associated with obese asthma; and the association of SLC9A4 is only observed in non-obese asthma. In addition, the association of RSPH3 (the gene is related to primary ciliary dyskinesia) is observed in non-obese asthma. CONCLUSIONS: These findings highlight genetic heterogeneity between obese and non-obese asthma in patients of AA ancestry.