Publications by authors named "Peining Li"

73 Publications

Detection of cytogenomic abnormalities by OncoScan microarray assay for products of conception from formalin-fixed paraffin-embedded and fresh fetal tissues.

Mol Cytogenet 2021 Apr 2;14(1):21. Epub 2021 Apr 2.

Department of Genetics, Yale University School of Medicine, New Haven, CT, USA.

Background: The OncoScan microarray assay (OMA) using highly multiplexed molecular inversion probes for single nucleotide polymorphism (SNP) loci enabled the detection of cytogenomic abnormalities of chromosomal imbalances and pathogenic copy number variants (pCNV). The small size of molecular inversion probes is optimal for SNP genotyping of fragmented DNA from fixed tissues. This retrospective study evaluated the clinical utility of OMA as a uniform platform to detect cytogenomic abnormalities for pregnancy loss from fresh and fixed tissues of products of conception (POC).

Results: Fresh specimens of POC were routinely subjected to cell culture and then analyzed by karyotyping. POC specimens with a normal karyotype (NK) or culture failure (CF) and from formalin-fixed paraffin-embedded (FFPE) tissues were subjected to DNA extraction for OMA. The abnormality detection rate (ADR) by OMA on 94 cases of POC-NK, 38 cases of POC-CF, and 35 cases of POC-FFPE tissues were 2% (2/94), 26% (10/38), and 57% (20/35), respectively. The detected cytogenomic abnormalities of aneuploidies, triploidies and pCNV accounted for 50%, 40% and 10% in POC-CF and 85%, 10% and 5% in POC-FFPE, respectively. False negative result from cultured maternal cells and maternal cell contamination were each detected in one case. OMA on two cases with unbalanced structural chromosome abnormalities further defined genomic imbalances and breakpoints.

Conclusion: OMA on POC-CF and POC-FFPE showed a high diagnostic yield of cytogenomic abnormalities. This approach circumvented the obstacles of CF from fresh specimens and fragmented DNA from fixed tissues and provided a reliable and effective platform for detecting cytogenomic abnormalities and monitoring true fetal result from maternal cell contamination.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s13039-021-00542-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8019165PMC
April 2021

Cytogenomic Abnormalities in 19 Cases of Salivary Gland Tumors of Parotid Gland Origin.

Case Rep Genet 2020 2;2020:8897541. Epub 2020 Dec 2.

Department of Genetics, Yale University School of Medicine, New Haven, CT, USA.

Salivary gland tumors (SGTs) of parotid origin are a group of diverse neoplasms which are difficult to classify due to their rarity and similar morphologic patterns. Chromosome analysis can detect clonal abnormalities, and array comparative genomic hybridization (aCGH) analysis can define copy number alterations (CNAs) from tumor specimens. Of the 19 cases of various types of SGTs submitted for cytogenomic analyses, an abnormal clone was detected in nine cases (47%), and CNAs were detected in 14 cases (74%). Recurrent rearrangements involving the PLAG1 gene at 8q12, recurrent CNAs including deletions of 6q, 9p (CDKN2A), and 17p (TP53), loss of Y chromosome, and gain of chromosome 7 were defined from these cases. Combined karyotyping and aCGH analyses could improve diagnostic yield. Future study for more precisive correlation of SGT classification with cytogenomic abnormalities will facilitate better diagnosis and treatment.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1155/2020/8897541DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7725583PMC
December 2020

Exome sequencing analysis on products of conception: a cohort study to evaluate clinical utility and genetic etiology for pregnancy loss.

Genet Med 2021 Mar 26;23(3):435-442. Epub 2020 Oct 26.

Departments of Genetics, Yale School of Medicine, New Haven, CT, USA.

Purpose: Pregnancy loss ranging from spontaneous abortion (SAB) to stillbirth can result from monogenic causes of Mendelian inheritance. This study evaluated the clinical application of exome sequencing (ES) in identifying the genetic etiology for pregnancy loss.

Methods: A cohort of 102 specimens from products of conception (POC) with normal karyotype and absence of pathogenic copy-number variants were selected for ES. Abnormality detection rate (ADR) and variants of diagnostic value correlated with SAB and stillbirth were evaluated.

Results: ES detected 6 pathogenic variants, 16 likely pathogenic variants, and 17 variants of uncertain significance favor pathogenic (VUSfp) from this cohort. The ADR for pathogenic and likely pathogenic variants was 22% and reached 35% with the inclusion of VUSfp. The ADRs of SAB and stillbirth were 36% and 33%, respectively. Affected genes included those associated with multisystem abnormalities, neurodevelopmental disorders, cardiac anomalies, skeletal dysplasia, metabolic disorders, and renal diseases.

Conclusion: These results supported the clinical utility of ES for detecting monogenic etiology of pregnancy loss. The identification of disease-associated variants provided information for follow-up genetic counseling of recurrence risk and management of subsequent pregnancies. Discovery of novel variants could provide insight for underlying molecular mechanisms causing fetal death.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41436-020-01008-6DOI Listing
March 2021

Ring chromosome formation by intra-strand repairing of subtelomeric double stand breaks and clinico-cytogenomic correlations for ring chromosome 9.

Am J Med Genet A 2020 12 26;182(12):3023-3028. Epub 2020 Sep 26.

Department of Genetics, Yale University School of Medicine, New Haven, Connecticut, USA.

Constitutional ring chromosome 9, r(9), is a rare chromosomal disorder. Cytogenomic analyses by karyotyping, array comparative genomic hybridization (aCGH) and whole genome sequencing (WGS) were performed in a patient of r(9). Karyotyping detected a mosaic pattern of r(9) and monosomy 9 in 83% and 17% of cells, respectively. aCGH detected subtelomeric deletions of 407 kb at 9p24.3 and 884 kb at 9q34.3 and an interstitial duplication of 5.879 Mb at 9q33.2q34.11. WGS revealed double strand breaks (DSBs) at ends of 9p24.3 and 9q34.3, inverted repeats at ends of subtelomeric and 9q33.2q34.11 regions, and microhomology sequences at the junctions of this r(9). This is the first report of r(9) analyzed by WGS to delineate the mechanism of ring chromosome formation from repairing of subtelomeric DSBs. The loss of telomeres by subtelomeric DSBs triggered inverted repeats induced intra-strand foldback and then microhomology mediated synthesis and ligation, which resulted in the formation of this r(9) with distal deletions and an interstitial duplication. Review of literature found seven patients of r(9) with clinical and cytogenomic findings. These patients and the present patient were registered into the Human Ring Chromosome Registry and a map correlating critical regions and candidate genes with relevant phenotypes was constructed. Variable phenotypes of r(9) patients could be explained by critical regions and genes of DOCK8, DMRT, SMARCA2, CD274, IL33, PTPRD, CER1, FREM1 for 9p deletions, and the EHMT1 gene for 9q34 deletion syndrome. This interactive registry of r(9) could provide information for cytogenomic diagnosis, genetics counseling and clinical management.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/ajmg.a.61890DOI Listing
December 2020

Collective near-field coupling and nonlocal phenomena in infrared-phononic metasurfaces for nano-light canalization.

Nat Commun 2020 Jul 21;11(1):3663. Epub 2020 Jul 21.

IKERBASQUE, Basque Foundation for Science, 48013, Bilbao, Spain.

Polaritons - coupled excitations of photons and dipolar matter excitations - can propagate along anisotropic metasurfaces with either hyperbolic or elliptical dispersion. At the transition from hyperbolic to elliptical dispersion (corresponding to a topological transition), various intriguing phenomena are found, such as an enhancement of the photonic density of states, polariton canalization and hyperlensing. Here, we investigate theoretically and experimentally the topological transition, the polaritonic coupling and the strong nonlocal response in a uniaxial infrared-phononic metasurface, a grating of hexagonal boron nitride (hBN) nanoribbons. By hyperspectral infrared nanoimaging, we observe a synthetic transverse optical phonon resonance (strong collective near-field coupling of the nanoribbons) in the middle of the hBN Reststrahlen band, yielding a topological transition from hyperbolic to elliptical dispersion. We further visualize and characterize the spatial evolution of a deeply subwavelength canalization mode near the transition frequency, which is a collimated polariton that is the basis for hyperlensing and diffraction-less propagation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41467-020-17425-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7374561PMC
July 2020

The impact of novel coronavirus SARS-CoV-2 among healthcare workers in hospitals: An aerial overview.

Am J Infect Control 2020 08 26;48(8):915-917. Epub 2020 May 26.

Department of Gastrointestinal Surgery, Wuhan Peritoneal Cancer Clinical Medical Research Center, Zhongnan Hospital of Wuhan University, Hubei Key Laboratory of Tumor Biological Behaviors and Hubei Cancer Clinical Study Center, Wuhan, Hubei, China. Electronic address:

The ongoing outbreak of COVID-19, caused by the novel coronavirus SARS-CoV-2, places healthcare workers at an increased risk of infection as they are in close contact with patients. In this article, we report an overview of cases of infected healthcare workers in China and Italy during the early periods of the COVID-19 epidemic. China's coronavirus response highlights the importance of implementing effective public health strategies. The authorities worldwide therefore, need to be extremely cautious when they implement stringent protective measures that safeguard healthcare workers in hospitals and counteract the threats created by the pandemic.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ajic.2020.05.020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7247977PMC
August 2020

Diagnostic cytogenetic testing following positive noninvasive prenatal screening results of sex chromosome abnormalities: Report of five cases and systematic review of evidence.

Mol Genet Genomic Med 2020 07 8;8(7):e1297. Epub 2020 May 8.

Department of Genetics, Yale University School of Medicine, New Haven, CT, USA.

Background: Follow-up cytogenetic analysis has been recommended for cases with positive noninvasive prenatal screening (NIPS) results. This study of five cases with numerical and structural sex chromosomal abnormalities (SCA) and a review of large case series of NIPS provided guidance to improve prenatal diagnosis for SCA.

Methods: Following positive NIPS results for SCA, karyotype analysis, chromosomal microarray analysis (CMA), fluorescence in situ hybridization (FISH), and locus-specific quantitative PCR were performed on cultured amniocytes, chorionic villi cells, and stimulated lymphocytes. Review of large case series was performed to evaluate the NIPS positive rate, follow-up rate of cytogenetic analysis, positive predictive value (PPV) for major types of SCA, and relative frequencies of subtypes of major SCA.

Results: Of the five cases with positive NIPS for SCA, case 1 showed a mosaic pattern of monosomy X and isodicentric Y; case 2 showed a mosaic pattern of monosomy X confined to the placenta; cases 3 and 4 had an isochromosome of Xq, and case 5 showed a derivative chromosome 14 from a Yq/14p translocation of maternal origin. Review of literature showed that mean positive rate of NIPS for SCA was 0.61%, follow-up rate of cytogenetics analysis was 76%, and mean PPV for SCA was 48%. Mosaic patterns and structural rearrangements involving sex chromosomes were estimated in 3%-20% and 3% of SCA cases, respectively.

Conclusion: These five cases further demonstrated the necessity to pursue follow-up cytogenetic analysis to characterize mosaic patterns and structural abnormalities involving sex chromosomes and their value for prenatal genetic counseling. A workflow showing the performance of current NIPS and cytogenetic analysis for SCA was summarized. These results could facilitate an evidence-based approach to guide prenatal diagnosis of SCA.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/mgg3.1297DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7336728PMC
July 2020

Molecular and clinicopathologic characterization of intravenous leiomyomatosis.

Mod Pathol 2020 09 27;33(9):1844-1860. Epub 2020 Apr 27.

Department of Pathology, Yale University School of Medicine, New Haven, CT, USA.

Intravenous leiomyomatosis (IVL) is an unusual uterine smooth muscle proliferation that can be associated with aggressive clinical behavior despite a histologically benign appearance. It has some overlapping molecular characteristics with both uterine leiomyoma and leiomyosarcoma based on limited genetic data. In this study, we assessed the clinical and morphological characteristics of 28 IVL and their correlation with molecular features and protein expression, using array comparative genomic hybridization (aCGH) and Cyclin D1, p16, phosphorylated-Rb, SMARCB1, SOX10, CAIX, SDHB and FH immunohistochemistry. The most common morphologies were cellular (n = 15), usual (n = 11), and vascular (n = 5; including 3 cellular IVL showing both vascular and cellular features). Among the immunohistochemical findings, the most striking was that all IVL showed differential expression of either p16 or Cyclin D1 in comparison to surrounding nonneoplastic tissue. Cytoplasmic phosphorylated-Rb was present in all but one IVL with hyalinization. SMARCB1, FH, and SDHB were retained; S0X10 and CAIX were not expressed. The most common genetic alterations involved 1p (39%), 22q (36%), 2q (29%), 1q (25%), 13q (21%), and 14q (21%). Hierarchical clustering analysis of recurrent aberrations revealed three molecular groups: Groups 1 (29%) and 2 (18%) with associated del(22q), and Group 3 (18%) with del(10q). The remaining IVL had nonspecific or no alterations by aCGH. Genomic index scores were calculated for all cases and showed no significant difference between the 14 IVL associated with aggressive clinical behavior (extrauterine extension or recurrence) and those without (median scores 5.15 vs 3.5). Among the 5 IVL associated with recurrence, 4 had a vascular morphology and 3 had alterations of 8q. Recurrent chromosome alterations detected herein overlap with those observed in the spectrum of uterine smooth muscle tumors and involve genes implicated in mesenchymal tumors at different sites with distinct morphological features.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41379-020-0546-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7483566PMC
September 2020

[Principles guiding the development of clinical practice guidelines for medical genetics and genomics specialty].

Zhonghua Yi Xue Yi Chuan Xue Za Zhi 2020 Mar;37(3):219-225

Department of Genetics, Cincinnati Children's Hospital, University of Cincinnati, OH 45229, USA.

The development of clinical practice guidelines for medical genetics and genomics specialty is a key step in translating basic and clinical genetic research into evidence-based and precision clinical services. This paper briefly expounds the principles of writing high-quality and trustworthy clinical practice guidelines. According to these principles, the management framework, writing process, review and revision procedures, and application monitoring of medical genetic specialty guidelines are described. Systematic review of relevant literature for evidence applicable to the screening, diagnosis, counseling, treatment and prevention of specific genetic diseases is summarized. Specific requirements for writing and reviewing high-quality professional guidelines for medical genetics are introduced. These principles and requirements can ensure that the evidence-based methods and recommendations in the written guidelines conform to current international standards and have specific clinical purposes, scope of practice and time-tracking mechanism. Implementation of such guidelines can promote the translation of basic and clinical genetic research, promote cooperation of medical genetics and other clinical specialties and coordination of interdisciplinary clinical practice guidelines, and provide effective and safe clinical services for patients and their families.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3760/cma.j.issn.1003-9406.2020.03.001DOI Listing
March 2020

ERas Enhances Resistance to Cisplatin-Induced Apoptosis by Suppressing Autophagy in Gastric Cancer Cell.

Front Cell Dev Biol 2019 21;7:375. Epub 2020 Jan 21.

The First Affiliated Hospital, Biomedical Translational Research Institute, Jinan University, Guangzhou, China.

Gastric cancer (GC), a common type of malignant cancer, remains the fifth most frequently diagnosed cancer and the third leading cause of cancer-related deaths worldwide. Despite developments in the treatment of GC, the prognosis remains poor. Embryonic stem cell-expressed Ras (ERas), a novel member of the Ras protein family, has recently been identified as an oncogene involved in the tumorigenic growth of embryonic stem cells. A recent study reported that ERas is expressed in most GC cell lines and GC specimens, and it promotes tumorigenicity in GC through induction of the epithelial mesenchymal transition (EMT) and activation of the PI3K/AKT pathway. Here, we found that ERas blocked autophagy flux in BGC-823 and AGS GC cells, which may occur through activation of the AKT/mTOR signaling pathway. Moreover, ERas overexpression suppressed cisplatin-induced apoptosis, and rapamycin treatment significantly attenuated ERas-mediated cisplatin resistance in GC cells. These data suggest that ERas may be a potential therapeutic target to improve the outcomes of GC patients by regulating the autophagy process.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fcell.2019.00375DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7005724PMC
January 2020

Nanoscale Guiding of Infrared Light with Hyperbolic Volume and Surface Polaritons in van der Waals Material Ribbons.

Adv Mater 2020 Mar 24;32(9):e1906530. Epub 2020 Jan 24.

CIC nanoGUNE BRTA, 20018, Donostia-San Sebastian, Spain.

Van der Waals (vdW) materials host a variety of polaritons, which make them an emerging material platform for manipulating light at the nanoscale. Due to the layered structure of vdW materials, the polaritons can exhibit a hyperbolic dispersion and propagate as nanoscale-confined volume modes in thin flakes. On the other hand, surface-confined modes can be found at the flake edges. Surprisingly, the guiding of these modes in ribbons-representing typical linear waveguide structures-is widely unexplored. Here, a detailed study of hyperbolic phonon polaritons propagating in hexagonal boron nitride ribbons is reported. Employing infrared nanoimaging, a variety of modes are observed. Particularly, the fundamental volume waveguide mode that exhibits a cutoff width is identified, which, interestingly, can be lowered by reducing the waveguide thickness. Further, hybridization of the surface modes and their evolution with varying frequency and waveguide width are observed. Most importantly, it is demonstrated that the symmetrically hybridized surface mode does not exhibit a cutoff width, and thus enables linear waveguiding of the polaritons in arbitrarily narrow ribbons. The experimental data, supported by simulations, establish a solid basis for the understanding of hyperbolic polaritons in linear waveguides, which is of critical importance for their application in future photonic devices.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/adma.201906530DOI Listing
March 2020

A Retrospective Analysis of 10-Year Data Assessed the Diagnostic Accuracy and Efficacy of Cytogenomic Abnormalities in Current Prenatal and Pediatric Settings.

Front Genet 2019 20;10:1162. Epub 2019 Nov 20.

Department of Genetics, Yale University School of Medicine, New Haven, CT, United States.

Array comparative genomic hybridization (aCGH), karyotyping and fluorescence hybridization (FISH) analyses have been used in a clinical cytogenetic laboratory. A systematic analysis on diagnostic findings of cytogenomic abnormalities in current prenatal and pediatric settings provides approaches for future improvement. A retrospective analysis was performed on abnormal findings by aCGH, karyotyping, and FISH from 3,608 prenatal cases and 4,509 pediatric cases during 2008-2017. The diagnostic accuracy was evaluated by comparing the abnormality detection rate (ADR) and the relative frequency (RF) of different types of cytogenomic abnormalities between prenatal and pediatric cases. A linear regression correlation between known prevalence and ADR of genomic disorders was used to extrapolate the prevalence of other genomic disorders. The diagnostic efficacy was estimated as percentage of detected abnormal cases by expected abnormal cases from served population. The composite ADR for numerical chromosome abnormalities, structural chromosome abnormalities, recurrent genomic disorders, and sporadic pathogenic copy number variants (pCNVs) in prenatal cases were 13.03%, 1.77%, 1.69%, and 0.9%, respectively, and were 5.13%, 2.84%, 7.08%, and 2.69% in pediatric cases, respectively. The chromosomal abnormalities detected in prenatal cases (14.80%) were significantly higher than that of pediatric cases (7.97%) (p < 0.05), while the pCNVs detected in prenatal cases (2.59%) were significantly lower than that of pediatric cases (9.77%) (p < 0.05). The prevalence of recurrent genomic disorders and total pCNVs was estimated to be 1/396 and 1/291, respectively. Approximately, 29% and 35% of cytogenomic abnormalities expected from the population served were detected in current prenatal and pediatric diagnostic practice, respectively. For chromosomal abnormalities, effective detection of Down syndrome (DS) and Turner syndrome (TS) and under detection of sex chromosome numerical abnormalities in both prenatal and pediatric cases were noted. For pCNVs, under detection of pCNVs in prenatal cases and effective detection of DiGeorge syndrome (DGS) and variable efficacy in detecting other pCNVs in pediatric cases were noted. Extend aCGH analysis to more prenatal cases with fetal ultrasonographic anomalies, enhanced non-invasive prenatal (NIPT) testing screening for syndromic genomic disorders, and better clinical indications for pCNVs are approaches that could improve diagnostic yield of cytogenomic abnormalities.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fgene.2019.01162DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6902283PMC
November 2019

Toric Spines at a Site of Learning.

eNeuro 2020 Jan/Feb;7(1). Epub 2020 Jan 3.

Center for Neuroscience, University of California, Davis, CA 95618

We discovered a new type of dendritic spine. It is found on space-specific neurons in the barn owl inferior colliculus, a site of experience-dependent plasticity. Connectomic analysis revealed dendritic protrusions of unusual morphology including topological holes, hence termed "toric" spines ( = 76). More significantly, presynaptic terminals converging onto individual toric spines displayed numerous active zones (up to 49) derived from multiple axons (up to 11) with incoming trajectories distributed widely throughout 3D space. This arrangement is suited to integrate input sources. Dense reconstruction of two toric spines revealed that they were unconnected with the majority (∼84%) of intertwined axons, implying a high capacity for information storage. We developed an slice preparation and provide the first published data on space-specific neuron intrinsic properties, including cellular subtypes with and without toric-like spines. We propose that toric spines are a cellular locus of sensory integration and behavioral learning.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1523/ENEURO.0197-19.2019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6944481PMC
January 2020

Inverted duplication, triplication and quintuplication through sequential breakage-fusion-bridge events induced by a terminal deletion at 5p in a case of spontaneous abortion.

Mol Genet Genomic Med 2019 10 2;7(10):e00965. Epub 2019 Sep 2.

Clinical Cytogenetics Laboratory, Department of Genetics, Yale University School of Medicine, New Haven, CT, USA.

Background: Integrated chromosome, fluorescence in situ hybridization (FISH) and array comparative genomic hybridization (aCGH) analyses have been effective in defining unbalanced chromosomal rearrangements. Discordant chromosome and aCGH results are rarely reported.

Methods: Routine cytogenomic analyses and literature review were performed in the study of a case from products of conception (POC).

Results: Chromosome and FISH analysis revealed a mosaic pattern consisting of a primary aberration of an inverted duplication of 5p and derived secondary and tertiary aberrations from sequential triplication and quintuplication of 5p, respectively. The aCGH analysis detected only a 1.521 Mb terminal deletion at 5p15.33 with no other pathogenic copy number variants in the genome. This mosaic karyotypic pattern likely resulted from chromosome instability induced by sequential breakage-fusion-bridge events during in vitro cell culture. A review of literature found heterogeneous distal deletion and inverted duplication of 5p in prenatal and pediatric cases.

Conclusion: This is the first case reported in POC with a unique mosaic pattern and discordant chromosome and aCGH results. Caution should be applied in reporting and interpreting these discordant results and further analysis for underlying mechanism should be considered.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/mgg3.965DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6785443PMC
October 2019

Efficient genome-wide first-generation phenotypic screening system in mice using the transposon.

Proc Natl Acad Sci U S A 2019 09 26;116(37):18507-18516. Epub 2019 Aug 26.

Department of Genetics, Boyer Center for Molecular Medicine, Yale University School of Medicine, New Haven, CT 06536;

Genome-wide phenotypic screens provide an unbiased way to identify genes involved in particular biological traits, and have been widely used in lower model organisms. However, cost and time have limited the utility of such screens to address biological and disease questions in mammals. Here we report a highly efficient () transposon-based first-generation (F1) dominant screening system in mice that enables an individual investigator to conduct a genome-wide phenotypic screen within a year with fewer than 300 cages. The screening system uses visually trackable transposons to induce both gain- and loss-of-function mutations and generates genome-wide distributed new insertions in more than 55% of F1 progeny. Using this system, we successfully conducted a pilot F1 screen and identified 5 growth retardation mutations. One of these mutants, a Six1/4 mutant, revealed a role in milk intake behavior. The mutant animals exhibit abnormalities in nipple recognition and milk ingestion, as well as developmental defects in cranial nerves V, IX, and X. This F1 screening system offers individual laboratories unprecedented opportunities to conduct affordable genome-wide phenotypic screens for deciphering the genetic basis of mammalian biology and disease pathogenesis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1073/pnas.1906354116DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6744845PMC
September 2019

1q21.1 Deletions and Duplications in 2 Siblings with Psychiatric Problems.

Indian J Pediatr 2019 11 4;86(11):1068. Epub 2019 Jul 4.

Department of Clinical Genetics, Yale University, New Haven, CT, USA.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s12098-019-03014-2DOI Listing
November 2019

A Cell-free DNA Barcode-Enabled Single-Molecule Test for Noninvasive Prenatal Diagnosis of Monogenic Disorders: Application to β-Thalassemia.

Adv Sci (Weinh) 2019 Jun 1;6(11):1802332. Epub 2019 Apr 1.

Department of Medical Genetics School of Basic Medical Sciences Southern Medical University Guangzhou Guangdong 510515 China.

Noninvasive prenatal testing of common aneuploidies has become routine over the past decade, but testing of monogenic disorders remains a challenge in clinical implementation. Most recent studies have inherent limitations, such as complicated procedures, a lack of versatility, and the need for prior knowledge of parental genotypes or haplotypes. To overcome these limitations, a robust and versatile next-generation sequencing-based cell-free DNA (cfDNA) allelic molecule counting system termed cfDNA barcode-enabled single-molecule test (cfBEST) is developed for the noninvasive prenatal diagnosis (NIPD) of monogenic disorders. The accuracy of cfBEST is found to be comparable to that of droplet digital polymerase chain reaction (ddPCR) in detecting low-abundance mutations in cfDNA. The analytical validity of cfBEST is evidenced by a β-thalassemia assay, in which a blind validation study of 143 at-risk pregnancies reveals a sensitivity of 99.19% and a specificity of 99.92% on allele detection. Because the validated cfBEST method can be used to detect maternal-fetal genotype combinations in cfDNA precisely and quantitatively, it holds the potential for the NIPD of human monogenic disorders.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/advs.201802332DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6548944PMC
June 2019

Highly Confined and Switchable Mid-Infrared Surface Phonon Polariton Resonances of Planar Circular Cavities with a Phase Change Material.

Nano Lett 2019 04 1;19(4):2549-2554. Epub 2019 Apr 1.

Institute of Physics (IA) , RWTH Aachen University , 52074 Aachen , Germany.

Mid-infrared (MIR) photonics demands highly confined optical fields to obtain efficient interaction between long-wavelength light and nanomaterials. Surface polaritons excited on polar semiconductor and metallic material interfaces exhibit near-fields localized on subwavelength scales. However, realizing a stronger field concentration in a cavity with a high quality ( Q) factor and a small mode volume is still challenging in the MIR region. This study reports MIR field concentration of surface phonon polaritons (SPhPs) using planar circular cavities with a high Q factor of ∼150. The cavities are fabricated on a thin film of the phase change material GeSbTe (GST) deposited on a silicon carbide (SiC) substrate. Scattering-type scanning near-field optical microscopy visualizes the near-field distribution on the samples and confirms directly that the SPhP field is strongly concentrated at the center of the centrosymmetric cavities. The smallest concentrated field size is 220 nm in diameter which corresponds to 1/50 of the wavelength of the incident light that is far below the diffraction limit. The thin GST film enhances the SPhP confinement, and it is used to switch the confinement off by tuning the cavity resonance induced by the phase change from the amorphous to the crystalline phase. This subwavelength and switchable field concentration within a high- Q polariton cavity has the potential to greatly enhance the light-matter interaction for molecular sensing and emission enhancement in MIR systems.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/acs.nanolett.9b00304DOI Listing
April 2019

Analytical validation and chromosomal distribution of regions of homozygosity by oligonucleotide array comparative genomic hybridization from normal prenatal and postnatal case series.

Mol Cytogenet 2019 6;12:12. Epub 2019 Mar 6.

1Department of Genetics, Yale University School of Medicine, New Haven, CT 06520 USA.

Background: Regions of homozygosity (ROH) are continuous homozygous segments commonly seen in the human genome. The integration of single nucleotide polymorphism (SNP) probes into current array comparative genomic hybridization (aCGH) analysis has enabled the detection of the ROH. However, for detecting and reporting biologically relevant ROH in a clinical setting, it is necessary to assess the analytical validity of SNP calling and the chromosomal distribution of ROH in normal populations.

Methods: The analytical validity was evaluated by correlating the consistency of SNP calling with the quality parameters of aCGH and by accessing the accuracy of SNP calling using PCR based restriction enzyme digestion and Sanger sequencing. The distribution of ROH was evaluated by the numbers, sizes, locations, and frequencies of ROH from the collection of data from parental, postnatal, and prenatal case series that had normal aCGH and chromosome results.

Results: The SNP calling failure rate was 20-30% with a derivative Log2 ratio (DLR) below 0.2 and increased significantly to 30-40% with DLR of 0.2-0.4. The accuracy of SNP calling is 93%. Of the 958 cases tested, 34% had no ROH, 64% had one to four ROH, and less than 1% had more than five ROH. Of the 1196 ROH detected, 95% were less than 10 Mb. The distribution of numbers and sizes of ROH showed no differences among the parental, pediatric and prenatal case series and test tissues. The chromosomal distribution of ROH was non-random with ROH seen most frequently in chromosome 8, less frequently in chromosomes 2, 6, 10, 12, 11 and 18, and most rarely seen on chromosomes 15, 19, 21 and 22. Recurrent ROH occurring with a frequency greater than 1% were detected in 17 chromosomal loci which locates either in the pericentric or interstitial regions.

Conclusion: With a quality control parameter of DLR set at below 0.2, the consistency of SNP calling would be 75%, the accuracy of SNP call could be 93%, and the observed chromosomal distribution of ROH could be used as a reference. This aCGH analysis could be a reliable screening tool to document biologically relevant ROH and recommend further molecular analysis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s13039-019-0424-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6404290PMC
March 2019

Boron nitride nanoresonators for phonon-enhanced molecular vibrational spectroscopy at the strong coupling limit.

Light Sci Appl 2018 6;7:17172. Epub 2018 Apr 6.

IKERBASQUE, Basque Foundation for Science, Bilbao 48013, Spain.

Enhanced light-matter interactions are the basis of surface-enhanced infrared absorption (SEIRA) spectroscopy, and conventionally rely on plasmonic materials and their capability to focus light to nanoscale spot sizes. Phonon polariton nanoresonators made of polar crystals could represent an interesting alternative, since they exhibit large quality factors, which go far beyond those of their plasmonic counterparts. The recent emergence of van der Waals crystals enables the fabrication of high-quality nanophotonic resonators based on phonon polaritons, as reported for the prototypical infrared-phononic material hexagonal boron nitride (h-BN). In this work we use, for the first time, phonon-polariton-resonant h-BN ribbons for SEIRA spectroscopy of small amounts of organic molecules in Fourier transform infrared spectroscopy. Strikingly, the interaction between phonon polaritons and molecular vibrations reaches experimentally the onset of the strong coupling regime, while numerical simulations predict that vibrational strong coupling can be fully achieved. Phonon polariton nanoresonators thus could become a viable platform for sensing, local control of chemical reactivity and infrared quantum cavity optics experiments.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/lsa.2017.172DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6060053PMC
April 2018

[A practice-based competencies training, certifying and evaluating system for genetic counseling in the United States].

Zhonghua Yi Xue Yi Chuan Xue Za Zhi 2019 Jan;36(1):37-43

Department of Genetics, Yale University, New Haven, CT 06510, USA. Email:

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3760/cma.j.issn.1003-9406.2019.01.007DOI Listing
January 2019

Integrated FISH, Karyotyping and aCGH Analyses for Effective Prenatal Diagnosis of Common Aneuploidies and Other Cytogenomic Abnormalities.

Med Sci (Basel) 2019 Jan 23;7(2). Epub 2019 Jan 23.

Laboratory of Clinical Cytogenetics, Department of Genetics, Yale School of Medicine, New Haven, CT 06520, USA.

Current prenatal genetic evaluation showed a significantly increase in non-invasive screening and the reduction of invasive diagnostic procedures. To evaluate the diagnostic efficacy on detecting common aneuploidies, structural chromosomal rearrangements, and pathogenic copy number variants (pCNV), we performed a retrospective analysis on a case series initially analyzed by aneuvysion fluorescence in situ hybridization (FISH) and karyotyping then followed by array comparative genomic hybridization (aCGH). Of the 386 cases retrieved from the past decade, common aneuploidies were detected in 137 cases (35.5%), other chromosomal structural rearrangements were detected in four cases (1%), and pCNV were detected in five cases (1.3%). The relative frequencies for common aneuploidies suggested an under detection of sex chromosome aneuploidies. Approximately 9.5% of cases with common aneuploidies showed a mosaic pattern. Inconsistent results between FISH and karyotyping were noted in cases with pseudo-mosaicism introduced by culture artifact or variable cellular proliferation from cells with mosaic karyotypic complements under in vitro cell culture. Based on findings from this case series, cell-based FISH and karyotyping should be performed to detect common aneuploidies, structural chromosomal abnormalities, and mosaic pattern. DNA-based aCGH and reflex FISH should be performed to detect and confirm genomic imbalances and pCNV. Practice points to ensure the diagnostic accuracy and efficacy were summarized.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/medsci7020016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6410168PMC
January 2019

In-plane anisotropic and ultra-low-loss polaritons in a natural van der Waals crystal.

Nature 2018 10 24;562(7728):557-562. Epub 2018 Oct 24.

Institute of Functional Nano and Soft Materials (FUNSOM), Jiangsu Key Laboratory for Carbon-based Functional Materials and Devices, and Collaborative Innovation Center of Suzhou Nano Science and Technology, Soochow University, Suzhou, China.

Polaritons-hybrid light-matter excitations-enable nanoscale control of light. Particularly large polariton field confinement and long lifetimes can be found in graphene and materials consisting of two-dimensional layers bound by weak van der Waals forces (vdW materials). These polaritons can be tuned by electric fields or by material thickness, leading to applications including nanolasers, tunable infrared and terahertz detectors, and molecular sensors. Polaritons with anisotropic propagation along the surface of vdW materials have been predicted, caused by in-plane anisotropic structural and electronic properties. In such materials, elliptic and hyperbolic in-plane polariton dispersion can be expected (for example, plasmon polaritons in black phosphorus), the latter leading to an enhanced density of optical states and ray-like directional propagation along the surface. However, observation of anisotropic polariton propagation in natural materials has so far remained elusive. Here we report anisotropic polariton propagation along the surface of α-MoO, a natural vdW material. By infrared nano-imaging and nano-spectroscopy of semiconducting α-MoO flakes and disks, we visualize and verify phonon polaritons with elliptic and hyperbolic in-plane dispersion, and with wavelengths (up to 60 times smaller than the corresponding photon wavelengths) comparable to those of graphene plasmon polaritons and boron nitride phonon polaritons. From signal oscillations in real-space images we measure polariton amplitude lifetimes of 8 picoseconds, which is more than ten times larger than that of graphene plasmon polaritons at room temperature. They are also a factor of about four larger than the best values so far reported for phonon polaritons in isotopically engineered boron nitride and for graphene plasmon polaritons at low temperatures. In-plane anisotropic and ultra-low-loss polaritons in vdW materials could enable directional and strong light-matter interactions, nanoscale directional energy transfer and integrated flat optics in applications ranging from bio-sensing to quantum nanophotonics.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41586-018-0618-9DOI Listing
October 2018

Human ring chromosome registry for cases in the Chinese population: re-emphasizing Cytogenomic and clinical heterogeneity and reviewing diagnostic and treatment strategies.

Mol Cytogenet 2018 27;11:19. Epub 2018 Feb 27.

2Laboratory of Clinical Cytogenetics and Genomics, Department of Genetics, Yale School of Medicine, New Haven, CT 06520 USA.

Background: Constitutional ring chromosomes are rare orphan chromosomal disorders. Ring chromosome syndrome featuring growth retardation and mild to intermediate intellectual disability is likely caused by the dynamic behavior of ring chromosome through cell cycles. Chromosomal and regional specific phenotypes likely result from segmental losses and gains during the ring formation. Although recent applications of genomic copy number and sequencing analyses revealed various ring chromosome structures from an increasing number of case studies, there was no organized effort for compilating and curating cytogenomic and clinical finding for ring chromosomes.

Methods: A web-based interactive 'Human Ring Chromosome Registry' using Microsoft Access based relational database was developed to present genetic and phenotypic findings of ring chromosome cases. Chinese ring chromosome cases reported in the literature was reviewed and compiled as a testing data set to validate this registry.

Results: A total of 113 cases of ring chromosomes were retrieved in all chromosomes except for chromosomes 16, 17 and 19. The most frequently seen ring chromosomes by a decreasing order of relative frequencies were ring 13 (14%), X (12%), 22 (10%), 15 (9%), 14 (7%), and 18 (7%). Genomic imbalances were detected in 18 out of 19 cases analyzed by microarray or sequencing. Variable clinical manifestations of developmental delay, dysmorphic facial features, intellectual disability, microcephaly, and hypotonia were noted in most autosomal rings. Chromosomal specific syndromic phenotypes included Wolf-Hirschhorn syndrome in a ring chromosome 4, cri-du-chat syndrome in a ring chromosome 5, epilepsy in ring chromosomes 14 and 20, Turner syndrome in ring chromosome X, and infertility in ring chromosomes 13, 21, 22 and Y. Effective growth hormone supplemental treatment for growth retardation in a ring chromosome 18 was noted.

Conclusions: Based on findings from these Chinese ring chromosome cases, guidelines for cytogenomic diagnosis and criteria for case registration were proposed. Further research to define underlying mechanisms of ring chromosome formation and dynamic mosaicism, to delineate the genotype-phenotype correlations, and to develop chromosome therapy for ring chromosomes were discussed.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s13039-018-0367-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5828142PMC
February 2018

Infrared hyperbolic metasurface based on nanostructured van der Waals materials.

Science 2018 02;359(6378):892-896

IKERBASQUE, Basque Foundation for Science, 48013 Bilbao, Spain.

Metasurfaces with strongly anisotropic optical properties can support deep subwavelength-scale confined electromagnetic waves (polaritons), which promise opportunities for controlling light in photonic and optoelectronic applications. We developed a mid-infrared hyperbolic metasurface by nanostructuring a thin layer of hexagonal boron nitride that supports deep subwavelength-scale phonon polaritons that propagate with in-plane hyperbolic dispersion. By applying an infrared nanoimaging technique, we visualize the concave (anomalous) wavefronts of a diverging polariton beam, which represent a landmark feature of hyperbolic polaritons. The results illustrate how near-field microscopy can be applied to reveal the exotic wavefronts of polaritons in anisotropic materials and demonstrate that nanostructured van der Waals materials can form a highly variable and compact platform for hyperbolic infrared metasurface devices and circuits.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1126/science.aaq1704DOI Listing
February 2018

De novo paternal origin duplication of chromosome 11p15.5: report of two Chinese cases with Beckwith-Wiedemann syndrome.

Mol Cytogenet 2017 19;10:46. Epub 2017 Dec 19.

Shenzhen Maternity and Child Healthcare Hospital, 3012 Fuqiang Road, Shenzhen, Guangdong 518028 China.

Background: The molecular etiology of Beckwith-Wiedemann syndrome (BWS) is complex and heterogeneous. Several subtypes of epigenetic-genetic alterations including aberrant methylation patterns, segmental uniparental disomy, single gene mutations, and copy number changes have been described. An integrated molecular approach to analyze the epigenetic-genetic alterations is required for accurate diagnosis of BWS.

Case Presentation: We reported two Chinese cases with BWS detected by genome-wide copy number analysis and locus-specific methylation profiling. Prenatal analysis on cord blood of patient 1 showed a de novo paternal origin duplication spanning 896Kb at 11p15.5. Patient 2 was referred at 2-month old and the genetic analysis showed a de novo 228.8Kb deletion at 11p15.5 telomeric end and a de novo duplication of 2.5 Mb at 11p15.5-15.4. Both the duplications are of paternal origin with gain of methylation at the imprinting center 1 and thus belong to the subgroup of a low tumor risk.

Conclusion: Results from these two cases and other reported cases from literature indicated that paternally derived duplications at 11p15.5 region cause BWS. Combined chromosome microarray analysis and methylation profiling provided reliable diagnosis for this subtype of BWS. Characterization of genetic defects in BWS patients could lead to better understanding the genetic mechanisms of this clinically and genetically heterogeneous disorder.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s13039-017-0347-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5738159PMC
December 2017

Prenatal Diagnosis of Twin Fetuses with a Novel AR Gene Mutation in a Chinese Family of Complete Androgen Insensitivity Syndrome.

Fetal Pediatr Pathol 2017 Dec 5;36(6):432-436. Epub 2017 Dec 5.

a Shenzhen Maternity and Child Healthcare Hospital, Medical Genetics Center , Shenzhen , China.

Introduction And Aims: Androgen insensitivity syndrome (AIS) is an X-linked recessive genetic disorder caused by mutations in the androgen receptor (AR) gene. Only a few cases of AIS with AR gene mutations have been diagnosed prenatally. This study aimed to investigate the gene mutation in a Chinese complete androgen insensitivity syndrome family and perform prenatal diagnosis for twin fetuses.

Case Report: We evaluated the AR gene of the child proband in a Chinese CAIS family, and detected a novel mutation c.3864T>C (p. Phe917Leu). Amniocentesis was performed when the mother presented to our hospital with a subsequent twin pregnancy. Mutation analysis revealed that both fetuses were hemizygous for this mutation. The aborted fetuses had typical female external genitalia and bilateral testes in abdomen.

Conclusion: The c.3864T>C AR novel mutation is responsible for complete androgen insensitivity syndrome, and its identification was subsequently used for a subsequent successful prenatal diagnosis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1080/15513815.2017.1332120DOI Listing
December 2017

Vascular smooth muscle cells derived from inbred swine induced pluripotent stem cells for vascular tissue engineering.

Biomaterials 2017 Dec 19;147:116-132. Epub 2017 Sep 19.

Yale Cardiovascular Research Center, Section of Cardiovascular Medicine, Department of Internal Medicine Yale School of Medicine, New Haven, CT 06511, USA; Yale Stem Cell Center, New Haven, CT 06520, USA; Vascular Biology and Therapeutics Program, Yale University School of Medicine, New Haven, CT 06520, USA; Department of Pathology, Yale School of Medicine, New Haven, CT 06520, USA. Electronic address:

Development of autologous tissue-engineered vascular constructs using vascular smooth muscle cells (VSMCs) derived from human induced pluripotent stem cells (iPSCs) holds great potential in treating patients with vascular disease. However, preclinical, large animal iPSC-based cellular and tissue models are required to evaluate safety and efficacy prior to clinical application. Herein, swine iPSC (siPSC) lines were established by introducing doxycycline-inducible reprogramming factors into fetal fibroblasts from a line of inbred Massachusetts General Hospital miniature swine that accept tissue and organ transplants without immunosuppression within the line. Highly enriched, functional VSMCs were derived from siPSCs based on addition of ascorbic acid and inactivation of reprogramming factor via doxycycline withdrawal. Moreover, siPSC-VSMCs seeded onto biodegradable polyglycolic acid (PGA) scaffolds readily formed vascular tissues, which were implanted subcutaneously into immunodeficient mice and showed further maturation revealed by expression of the mature VSMC marker, smooth muscle myosin heavy chain. Finally, using a robust cellular self-assembly approach, we developed 3D scaffold-free tissue rings from siPSC-VSMCs that showed comparable mechanical properties and contractile function to those developed from swine primary VSMCs. These engineered vascular constructs, prepared from doxycycline-inducible inbred siPSCs, offer new opportunities for preclinical investigation of autologous human iPSC-based vascular tissues for patient treatment.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.biomaterials.2017.09.019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5638652PMC
December 2017

Novel homozygous FANCL mutation and somatic heterozygous SETBP1 mutation in a Chinese girl with Fanconi Anemia.

Eur J Med Genet 2017 Jul 15;60(7):369-373. Epub 2017 Apr 15.

Shenzhen Maternity and Child Healthcare Hospital, Shenzhen, Guangdong, China. Electronic address:

Fanconi Anemia (FA) is a rare genetically heterogeneous disorder with 17 known complement groups caused by mutations in different genes. FA complementation group L (FA-L, OMIM #608111) occurred in 0.2% of all FA and only eight mutant variants in the FANCL gene were documented. Phenotype and genotype correlation in FANCL associated FA is still obscure. Here we describe a Chinese girl with FA-L caused by a novel homozygous mutation c.822_823insCTTTCAGG (p.Asp275LeufsX13) in the FANCL gene. The patient's clinical course was typical for FA with progression to bone marrow failure, and death from acute myelomonocytic leukemia (AML-M4) at 9 years of age. Mutation analysis also detected a likely somatic c.2608G > A (p.Gly870Ser) in the SETBP1 gene. Consistent copy number losses of 7q and 18p and gains of 3q and 21q and accumulated non-clonal single cell chromosomal abnormalities were detected in blood leukocytes as her FA progressed. This is the first Chinese FA-L case caused by a novel FANCL mutation. The somatic gene mutation and copy number aberrations could be used to monitor disease progression and the clinical findings provide further information for genotype-phenotype correlation for FA-L.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ejmg.2017.04.008DOI Listing
July 2017