Dissection of the Role of VIMP in Endoplasmic Reticulum-Associated Degradation of CFTRΔF508.

Sci Rep. 2018 Mar 19;8(1):4764

Authors: Hou X, Wei H, Rajagopalan C, Jiang H, Wu Q, Zaman K, Xie Y, Sun F

Abstract
Endoplasmic reticulum (ER)-associated protein degradation (ERAD) is an important quality control mechanism that eliminates misfolded proteins from the ER. The Derlin-1/VCP/VIMP protein complex plays an essential role in ERAD. Although the roles of Derlin-1 and VCP are relatively clear, the functional activity of VIMP in ERAD remains to be understood. Here we investigate the role of VIMP in the degradation of CFTRΔF508, a cystic fibrosis transmembrane conductance regulator (CFTR) mutant known to be a substrate of ERAD. Overexpression of VIMP markedly enhances the degradation of CFTRΔF508, whereas knockdown of VIMP increases its half-life. We demonstrate that VIMP is associated with CFTRΔF508 and the RNF5 E3 ubiquitin ligase (also known as RMA1). Thus, VIMP not only forms a complex with Derlin-1 and VCP, but may also participate in recruiting substrates and E3 ubiquitin ligases. We further show that blocking CFTRΔF508 degradation by knockdown of VIMP substantially augments the effect of VX809, a drug that allows a fraction of CFTRΔF508 to fold properly and mobilize from ER to cell surface for normal functioning. This study provides insight into the role of VIMP in ERAD and presents a potential target for the treatment of cystic fibrosis patients carrying the CFTRΔF508 mutation.

PMID: 29555962 [PubMed - in process]

Real-time exhaled breath analysis in patients with cystic fibrosis and controls.

J Breath Res. 2018 Mar 20;:

Authors: Gaisl T, Bregy L, Stebler N, Gaugg MT, Bruderer T, García-Gómez D, Moeller A, Singer F, Schwarz EI, Benden C, Sinues PM, Zenobi R, Kohler M

Abstract
We aimed at defining profiles of volatile organic compounds in exhaled breath from patients with cystic fibrosis (CF) using a novel real-time mass spectrometry technique.
 In this prospective matched case-control study, 30 patients with CF, and 30 healthy control subjects were matched one-to-one according to age, gender, and smoking state. We performed exhaled breath analysis by untargeted secondary electrospray ionization-high resolution mass spectrometry (SESI-HRMS). 
 Patients with CF (mean age 26.0±13.0 years) and controls (mean age 27.9±14.0 years) were analysed using SESI-HRMS. 49 exhaled breath features were found to be altered (p-value < 0.05 / q-value < 0.1) in CF patients, in comparison to healthy controls. The two most discriminating features showed a prediction AUROC of 77.1% (95% CI 62.2% - 87.8%) with a specificity of 80.0% and a sensitivity of 63.3%. Levels of oxidative stress metabolites such as fatty acids were found to differ significantly between patients with CF and healthy controls. Furthermore, in patients with CF, 11 features correlated with the mucus concentration of Stenotrophomonas maltophilia bacteria.
 Exhaled Breath analysis with SESI-HRMS allows to identify CF specific compounds in real-time and may trace bacterial strains in affected patients with CF.

PMID: 29555894 [PubMed - as supplied by publisher]

Identification and Characterization of Novel Receptor Interacting Serine/threonine-Protein Kinase 2 (RIPK2) Inhibitors Using Structural Similarity Analysis.

J Pharmacol Exp Ther. 2018 Mar 19;:

Authors: Salla M, Aguayo-Ortiz R, Gaddafi Ibrahim D, Zare A, Said A, Moore J, Pandya V, Manaloor R, Fong S, Blankstein AR, Gibson S, Garcia LR, Meier P, Bhullar KS, Hubbard BP, Fiteh Y, Vliagoftis H, Goping IS, Brocks D, Hwang P, Martinez Velazquez JCA, Baksh S

Abstract
Receptor interacting protein kinase 2 (RIP2 or RICK herein referred to as RIPK2) is linked to the pathogen pathway that activates NFkB and autophagic activation. Using molecular modeling (docking) and chemoinformatics analyses we utilized the RIPK2/ponatinib crystal structure and searched in chemical databases for small molecules exerting binding interactions similar to those exerted by ponatinib. The identified RIPK2 inhibitors potently inhibited the proliferation of cancer cells by > 70% as well as inhibition of NFkB activity. More importantly, in vivo inhibition of intestinal and lung inflammation rodent models suggest effectiveness to resolve inflammation with low toxicity to the animals. Thus, our identified RIPK2 inhibitor may offer a possible therapeutic control of inflammation in diseases such as inflammatory bowel disease, asthma, cystic fibrosis, primary sclerosing cholangitis and pancreatitis.

PMID: 29555876 [PubMed - as supplied by publisher]

Design of a broad-range bacteriophage cocktail that reduces Pseudomonas aeruginosa biofilms and treats acute infections in two animal models.

Antimicrob Agents Chemother. 2018 Mar 19;:

Authors: Forti F, Roach DR, Cafora M, Pasini ME, Horner DS, Fiscarelli EV, Rossitto M, Cariani L, Briani F, Debarbieux L, Ghisotti D

Abstract
The alarming diffusion of multidrug resistant (MDR) bacterial strains requires investigations on non-antibiotic therapies. Amongst them, the use of bacteriophages (phages) as antimicrobial agents, namely phage therapy, is a promising treatment strategy with support by recent successful compassionate treatments in Europe and the U.S.A. In this work, we combined host range and genomic information to design a 6-phage cocktail killing several clinical strains of P. aeruginosa, including those collected from Italian cystic fibrosis (CF) patients, and analyzed the cocktail performance. We demonstrated that the cocktail composed of four novel (PYO2, DEV, E215 and E217) and two previously characterized (PAK_P1 and PAK_P4) phages was able to lyse P. aeruginosa both in planktonic liquid cultures and in biofilm. In addition, we showed that the phage cocktail could cure acute respiratory infection in mouse and treat bacteremia in the wax moth Galleria mellonella larvae. Furthermore, administration of the cocktail to larvae prior to bacterial infection provided prophylaxis. In this regard, efficiency of the phage cocktail was found to be unaffected by the MDR or mucoid phenotype of the pseudomonal strain. The cocktail was found to be superior to individual phages in destroying biofilms and providing a faster treatment in mice. We also found the Galleria larvae model to be cost-effective for testing clinical strains susceptibility to phages, suggesting that it could be implemented in the frame of developing personalized phage therapies.

PMID: 29555626 [PubMed - as supplied by publisher]

Cystic fibrosis patient registries: A valuable source for clinical research.

J Cyst Fibros. 2018 Mar 16;:

Authors: Dasenbrook EC, Sawicki GS

Abstract
Cystic Fibrosis (CF) patient registries are valuable data sources for researchers studying the natural history, treatment paradigms, and long-term health outcomes of individuals with CF. In this review, we discuss the role of CF patient registries in facilitating comparative effectiveness research, particularly evaluating therapies and variation in health care delivery. We also discuss the limitations of registry-based research, particularly indication bias, as well as statistical methods that can be used to address these issues.

PMID: 29555479 [PubMed - as supplied by publisher]

Fertility and infertility: Definition and epidemiology.

Clin Biochem. 2018 Mar 16;:

Authors: Mélodie VB, Christine W

Abstract
Infertility is a disease characterized by the failure to establish a clinical pregnancy after 12 months of regular and unprotected sexual intercourse. It is estimated to affect between 8 and 12% of reproductive-aged couples worldwide. Males are found to be solely responsible for 20-30% of infertility cases but contribute to 50% of cases overall. Secondary infertility is the most common form of female infertility around the globe, often due to reproductive tract infections. The three major factors influencing the spontaneous probability of conception are the time of unwanted non-conception, the age of the female partner and the disease-related infertility. The chance of becoming spontaneously pregnant declines with the duration before conception. The fertility decline in female already starts around 25-30 years of age and the median age at last birth is 40-41 years in most studied populations experiencing natural fertility. The disease-related infertility may affect both genders or be specific to one gender. The factors affecting both genders' fertility are hypogonadotrophic hypogonadism, hyperprolactinemia, disorders of ciliary function, cystic fibrosis, infections, systemic diseases and lifestyle related factors/diseases. Premature ovarian insufficiency, polycystic ovary syndrome, endometriosis, uterine fibroids and endometrial polyps may play a role in female infertility. Male infertility may be due to testicular and post-testicular deficiencies. Semen decline that has been observed over the years, endocrine disrupting chemicals and consanguinity are other factors that may be involved.

PMID: 29555319 [PubMed - as supplied by publisher]

Non-Tuberculous Mycobacteria multispecies biofilms in cystic fibrosis: development of an in vitro Mycobacterium abscessus and Pseudomonas aeruginosa dual species biofilm model.

Int J Med Microbiol. 2018 Mar 06;:

Authors: Rodríguez-Sevilla G, García-Coca M, Romera-García D, Aguilera-Correa JJ, Mahíllo-Fernández I, Esteban J, Pérez-Jorge C

Abstract
Lung disease in cystic fibrosis (CF) is characterized by the progressive colonization of the respiratory tract by different bacteria, which develop polymicrobial biofilms. In the past decades, there has been an increase in the number of CF patients infected with Non-Tuberculous Mycobacteria (NTM). Although Mycobacterium abscessus is the main NTM isolated globally, little is known about M. abscessus multispecies biofilm formation. In the present study we developed an in vitro model to study the phenotypic characteristics of biofilms formed by M. abscessus and Pseudomonas aeruginosa, a major pathogen in CF. For that purpose, dual species biofilms were grown on polycarbonate membranes with a fixed concentration of P. aeruginosa and different inoculums of M. abscessus. The biofilms were sampled at 24, 48, and 72 h and bacteria were quantified in specific media. The results revealed that the increasing initial concentration of M. abscessus in dual species biofilms had an effect on its population only at 24 and 48 h, whereas P. aeruginosa was not affected by the different concentrations used of M. abscessus. Time elapsed increased biofilm formation of both species, specially between 24 and 48 h. According to the results, the conditions to produce a mature dual species biofilm in which the relative species distribution remained stable were 72 h growth of the mixed microbial culture at a 1:1 ratio. A significant decrease in mycobacterial population in dual compared to single species biofilms was found, suggesting that P. aeruginosa has a negative influence on M. abscessus. Finally, in a proof of concept experiment, young and mature dual species biofilms were exposed to clarithromycin.

PMID: 29555180 [PubMed - as supplied by publisher]

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Polymorphism genotyping based on loop-mediated isothermal amplification and smartphone detection.

Biosens Bioelectron. 2018 Mar 08;109:177-183

Authors: Yamanaka ES, Tortajada-Genaro LA, Pastor N, Maquieira Á

Abstract
The genotyping of a single-nucleotide polymorphism (SNP) is addressed through methods based on loop-mediated isothermal amplification (LAMP) combined with user-friendly optical read-outs to cover the current demand for point-of-care DNA biomarker detection. The modification of primer design and reaction composition improved the assay selectivity yielding allele-specific results and reducing false-positive frequency. Furthermore, the reduced cost, ease of use and effectiveness of colorimetric detection (solution and hybridisation chip formats) were availed for the image capture by a smartphone, reching high sensitivity. In order to evaluate their discriminating capacities, LAMP-based methods were applied to human samples to genotype a SNP biomarker (rs1954787) located in the GRIK4 gene and related to the treatment response to anti-depressants drugs. Sensitive (limit of detection: 100 genomic DNA copies), reproducible (< 15% error), fast (around 70 min) and low-cost assays were accomplished. Patient subgroups were correctly discriminated, agreeing with reference sequencing techniques. The achieved analytical performances using the developed amplification-detection principles confirmed the approach potential for point-of-care optical DNA testing.

PMID: 29558731 [PubMed - as supplied by publisher]

When the Safe Alternative Is Not That Safe: Tramadol Prescribing in Children.

Front Pharmacol. 2018;9:148

Authors: Rodieux F, Vutskits L, Posfay-Barbe KM, Habre W, Piguet V, Desmeules JA, Samer CF

Abstract
Children represent a vulnerable population in which management of nociceptive pain is complex. Drug responses in children differ from adults due to age-related differences. Moreover, therapeutic choices are limited by the lack of indication for a number of analgesic drugs due to the challenge of conducting clinical trials in children. Furthermore the assessment of efficacy as well as tolerance may be complicated by children's inability to communicate properly. According to the World Health Organization, weak opioids such as tramadol and codeine, may be used in addition to paracetamol and ibuprofen for moderate nociceptive pain in both children and adults. However, codeine prescription has been restricted for the last 5 years in children because of the risk of fatal overdoses linked to the variable activity of cytochrome P450 (CYP) 2D6 which bioactivates codeine. Even though tramadol has been considered a safe alternative to codeine, it is well established that tramadol pharmacodynamic opioid effects, efficacy and safety, are also largely influenced by CYP2D6 activity. For this reason, the US Food and Drug Administration recently released a boxed warning regarding the use of tramadol in children. To provide safe and effective tramadol prescription in children, a personalized approach, with dose adaptation according to CYP2D6 activity, would certainly be the safest method. We therefore recommend this approach in children requiring chronic or recurrent nociceptive pain treatment with tramadol. In case of acute inpatients nociceptive pain management, prescribing tramadol at the minimal effective dose, in a child appropriate dosage form and after clear instructions are given to the parents, remains reasonable based on current data. In all other situations, morphine should be preferred for moderate to severe nociceptive pain conditions.

PMID: 29556194 [PubMed]

Pharmacokinetic Study of 7 Compounds Following Oral Administration of Fructus Aurantii to Depressive Rats.

Front Pharmacol. 2018;9:131

Authors: Zhang X, Han L, Liu J, Xu Q, Guo Y, Zheng W, Wang J, Huang X, Ren P

Abstract
In the present study, the pharmacokinetics of multi-components (naringenin, nobiletin, meranzin hydrate, narirutin, naringin, hesperidin, and neohesperidin) were investigated in acute depressive rats following oral administration of Fructus Aurantii (Zhi-Qiao, ZQ) extract (20 g/kg). A rapid and reliable liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was established to quantitatively or qualitatively analyze the 7 absorbed ingredients in the plasma, hippocampus and cortex of acute depressive rats. Biological samples were separated on a 300SB-C18 column, and the 7 compounds were detected with sequential positive and negative ionization modes. Our results confirmed that ZQ has antidepressant effects by decreasing the immobility time. In addition, this validated method showed good linearity (r ≥ 0.9987), and the lower limits of quantification were 2.73-16.38 ng/mL for the 7 analytes. This method successfully determined the pharmacokinetics of the 7 compounds and separated two pairs of isomers in plasma of acute depressive rats following oral administration of ZQ extracts. The 7 active ingredients were also identified as marked compounds in target tissues and should be further examined in pharmacokinetic studies with acute depressive rats. So, pharmacokinetic compounds were precisely linked with the antidepressant effect of ZQ in our study. This relationship is well-understood and contributes to the application of Traditional Chinese Medicine (TCM).

PMID: 29556193 [PubMed]

Array Comparative Genomic Hybridization as the First-line Investigation for Neonates with Congenital Heart Disease: Experience in a Single Tertiary Center.

Korean Circ J. 2018 Mar;48(3):209-216

Authors: Choi BG, Hwang SK, Kwon JE, Kim YH

Abstract
BACKGROUND AND OBJECTIVES: The purpose of the present study was to investigate the advantages and disadvantages of verifying genetic abnormalities using array comparative genomic hybridization (a-CGH) immediately after diagnosis of congenital heart disease (CHD).
METHODS: Among neonates under the age of 28 days who underwent echocardiography from January 1, 2014 to April 30, 2016, neonates whose chromosomal and genomic abnormalities were tested using a-CGH in cases of an abnormal finding on echocardiography were enrolled.
RESULTS: Of the 166 patients diagnosed with CHD, 81 underwent a-CGH and 11 patients (11/81, 13.5%) had abnormal findings on a-CGH. 22q11.2 deletion syndrome was the most common (4/11, 36.4%). On the first a-CGH, 4 patients were negative (4/81, 5%). Three of them were finally diagnosed with Williams syndrome using fluorescent in situ hybridization (FISH), 1 patient was diagnosed with Noonan syndrome through exome sequencing. All of them exhibited diffuse pulmonary artery branch hypoplasia, as well as increased velocity of blood flow, on repeated echocardiography. Five patients started rehabilitation therapy at mean 6 months old age in outpatient clinics and epilepsy was diagnosed in 2 patients. Parents of 2 patients (22q11.2 deletion syndrome and Patau syndrome) refused treatment due to the anticipated prognosis.
CONCLUSIONS: Screening tests for genetic abnormalities using a-CGH in neonates with CHD has the advantage of early diagnosis of genetic abnormality during the neonatal period in which there is no obvious symptom of genetic abnormality. However, there are disadvantages that some genetic abnormalities cannot be identified on a-CGH.

PMID: 29557107 [PubMed]

Congenital glaucoma and CYP1B1: an old story revisited.

Hum Genet. 2018 Mar 19;:

Authors: Alsaif HS, Khan AO, Patel N, Alkuraya H, Hashem M, Abdulwahab F, Ibrahim N, Aldahmesh MA, Alkuraya FS

Abstract
Primary congenital glaucoma is a trabecular meshwork dysgenesis with resultant increased intraocular pressure and ocular damage. CYP1B1 mutations remain the most common identifiable genetic cause. However, important questions about the penetrance of CYP1B1-related congenital glaucoma remain unanswered. Furthermore, mutations in other genes have been described although their exact contribution and potential genetic interaction, if any, with CYP1B1 mutations are not fully explored. In this study, we employed modern genomic approaches to re-examine CYP1B1-related congenital glaucoma. A cohort of 193 patients (136 families) diagnosed with congenital glaucoma. We identified biallelic CYP1B1 mutations in 80.8% (87.5 and 66.1% in familial and sporadic cases, respectively, p < 0.0086). The large family size of the study population allowed us to systematically examine penetrance of all identified alleles. With the exception of c.1103G>A (p.R368H), previously reported pathogenic mutations were highly penetrant (91.2%). We conclude from the very low penetrance and genetic epidemiological analyses that c.1103G>A (p.R368H) is unlikely to be a disease-causing recessive mutation in congenital glaucoma as previously reported. All cases that lacked biallelic CYP1B1 mutations underwent whole exome sequencing. No mutations in LTBP2, MYOC or TEK were encountered. On the other hand, mutations were identified in genes linked to other ophthalmic phenotypes, some inclusive of glaucoma, highlighting conditions that might phenotypically overlap with primary congenital glaucoma (SLC4A4, SLC4A11, CPAMD8, and KERA). We also encountered candidate causal variants in genes not previously linked to human diseases: BCO2, TULP2, and DGKQ. Our results both expand and refine the genetic spectrum of congenital glaucoma with important clinical implications.

PMID: 29556725 [PubMed - as supplied by publisher]

De novo apparent loss-of-function mutations in PRR12 in three patients with intellectual disability and iris abnormalities.

Hum Genet. 2018 Mar 19;:

Authors: Leduc MS, Mcguire M, Madan-Khetarpal S, Ortiz D, Hayflick S, Keller K, Eng CM, Yang Y, Bi W

Abstract
PRR12 encodes a proline-rich protein nuclear factor suspected to be involved in neural development. Its nuclear expression in fetal brains and in the vision system supports its role in brain and eye development more specifically. However, its function and potential role in human disease has not been determined. Recently, a de novo t(10;19) (q22.3;q13.33) translocation disrupting the PRR12 gene was detected in a girl with intellectual disability and neuropsychiatric alterations. Here we report on three unrelated patients with heterozygous de novo apparent loss-of-function mutations in PRR12 detected by clinical whole exome sequencing: c.1918G>T (p.Glu640*), c.4502_4505delTGCC (p.Leu1501Argfs*146) and c.903_909dup (p.Pro304Thrfs*46). All three patients had global developmental delay, intellectual disability, eye and vision abnormalities, dysmorphic features, and neuropsychiatric problems. Eye abnormalities were consistent among the three patients and consisted of stellate iris pattern and iris coloboma. Additional variable clinical features included hypotonia, skeletal abnormalities, sleeping problems, and behavioral issues such as autism and anxiety. In summary, we propose that haploinsufficiency of PRR12 is associated with this novel multisystem neurodevelopmental disorder.

PMID: 29556724 [PubMed - as supplied by publisher]

Exome Sequencing Diagnoses X-Linked Moesin-Associated Immunodeficiency in a Primary Immunodeficiency Case.

Front Immunol. 2018;9:420

Authors: Bradshaw G, Lualhati RR, Albury CL, Maksemous N, Roos-Araujo D, Smith RA, Benton MC, Eccles DA, Lea RA, Sutherland HG, Haupt LM, Griffiths LR

Abstract
Background: We investigated the molecular etiology of a young male proband with confirmed immunodeficiency of unknown cause, presenting with recurrent bacterial and Varicella zoster viral infections in childhood and persistent lymphopenia into early adulthood.
Aim: To identify causative functional genetic variants related to an undiagnosed primary immunodeficiency.
Method: Whole genome microarray copy number variant (CNV) analysis was performed on the proband followed by whole exome sequencing (WES) and trio analysis of the proband and family members. A >4 kbp deletion identified by repeated CNV analysis of exome sequencing data along with three damaging missense single nucleotide variants were validated by Sanger sequencing in all family members. Confirmation of the causative role of the candidate gene was performed by qPCR and Western Blot analyses on the proband, family members and a healthy control.
Results: CNV identified our previously reported interleukin 25 amplification in the proband; however, the variant was not validated to be a candidate gene for immunodeficiency. WES trio analysis, data filtering and in silico prediction identified a novel, damaging (SIFT: 0; Polyphen 1; Grantham score: 101) and disease-causing (MutationTaster) single base mutation in the X chromosome (c.511C > T p.Arg171Trp) MSN gene not identified in the UCSC Genome Browser database. The mutation was validated by Sanger sequencing, confirming the proband was hemizygous X-linked recessive (-/T) at this locus and inherited the affected T allele from his non-symptomatic carrier mother (C/T), with other family members (father, sister) confirmed to be wild type (C/C). Western Blot analysis demonstrated an absence of moesin protein in lymphocytes derived from the proband, compared with normal expression in lymphocytes derived from the healthy control, father and mother. qPCR identified significantly lower MSN mRNA transcript expression in the proband compared to an age- and sex-matched healthy control subject in whole blood (p = 0.02), and lymphocytes (p = 0.01). These results confirmed moesin deficiency in the proband, directly causative of his immunodeficient phenotype.
Conclusion: These findings confirm X-linked moesin-associated immunodeficiency in a proband previously undiagnosed up to 24 years of age. This study also highlights the utility of WES for the diagnosis of rare or novel forms of primary immunodeficiency disease.

PMID: 29556235 [PubMed]

High-throughput sequencing of nodal marginal zone lymphomas identifies recurrent BRAF mutations.

Leukemia. 2018 Feb 28;:

Authors: Pillonel V, Juskevicius D, Ng CKY, Bodmer A, Zettl A, Jucker D, Dirnhofer S, Tzankov A

Abstract
Nodal marginal zone lymphoma (NMZL) is a rare small B-cell lymphoma lacking disease-defining phenotype and precise diagnostic markers. To better understand the mutational landscape of NMZL, particularly in comparison to other nodal small B-cell lymphomas, we performed whole-exome sequencing, targeted high-throughput sequencing, and array-comparative genomic hybridization on a retrospective series. Our study identified for the first time recurrent, diagnostically useful, and potentially therapeutically relevant BRAF mutations in NMZL. Sets of somatic mutations that could help to discriminate NMZL from other closely related small B-cell lymphomas were uncovered and tested on unclassifiable small B-cell lymphoma cases, in which clinical, morphological, and phenotypical features were equivocal. Application of targeted gene panel sequencing gave at many occasions valuable clues for more specific classification.

PMID: 29556019 [PubMed - as supplied by publisher]

Beyond Gene Panels: Whole Exome Sequencing for Diagnosis of Congenital Heart Disease.

Circ Genom Precis Med. 2018 Mar;11(3):e002097

Authors: Paige SL, Saha P, Priest JR

PMID: 29555674 [PubMed - in process]

A Screening Approach to Identify Clinically Actionable Variants Causing Congenital Heart Disease in Exome Data.

Circ Genom Precis Med. 2018 Mar;11(3):e001978

Authors: Szot JO, Cuny H, Blue GM, Humphreys DT, Ip E, Harrison K, Sholler GF, Giannoulatou E, Leo P, Duncan EL, Sparrow DB, Ho JWK, Graham RM, Pachter N, Chapman G, Winlaw DS, Dunwoodie SL

Abstract
BACKGROUND: Congenital heart disease (CHD)-structural abnormalities of the heart that arise during embryonic development-is the most common inborn malformation, affecting ≤1% of the population. However, currently, only a minority of cases can be explained by genetic abnormalities. The goal of this study was to identify disease-causal genetic variants in 30 families affected by CHD.
METHODS: Whole-exome sequencing was performed with the DNA of multiple family members. We utilized a 2-tiered whole-exome variant screening and interpretation procedure. First, we manually curated a high-confidence list of 90 genes known to cause CHD in humans, identified predicted damaging variants in genes on this list, and rated their pathogenicity using American College of Medical Genetics and Genomics-Association for Molecular Pathology guidelines.
RESULTS: In 3 families (10%), we found pathogenic variants in known CHD genes TBX5, TFAP2B, and PTPN11, explaining the cardiac lesions. Second, exomes were comprehensively analyzed to identify additional predicted damaging variants that segregate with disease in CHD candidate genes. In 10 additional families (33%), likely disease-causal variants were uncovered in PBX1, CNOT1, ZFP36L2, TEK, USP34, UPF2, KDM5A, KMT2C, TIE1, TEAD2, and FLT4.
CONCLUSIONS: The pathogenesis of CHD could be explained using our high-confidence CHD gene list for variant filtering in a subset of cases. Furthermore, our unbiased screening procedure of family exomes implicates additional genes and variants in the pathogenesis of CHD, which suggest themselves for functional validation. This 2-tiered approach provides a means of (1) identifying clinically actionable variants and (2) identifying additional disease-causal genes, both of which are essential for improving the molecular diagnosis of CHD.

PMID: 29555671 [PubMed - in process]

Whole-exome sequencing identified mutational profiles of squamous cell carcinomas of anus.

Hum Pathol. 2018 Mar 16;:

Authors: Shin S, Park HC, Kim MS, Han MR, Lee SH, Jung SH, Lee SH, Chung YJ

Abstract
Anal squamous cell carcinoma (ASCC), either with human papillomavirus (HPV) (+) or (-), is a neoplastic disease with frequent recurrence and metastasis. To characterize ASCC genomes, we attempted to disclose novel alterations of ASCC genomes as well as other genetic features including mutation signatures. We performed whole-exome sequencing and copy number alteration (CNA) profiling for 8 ASCC samples from 6 patients (2 cases with primary and recurrent/metastatic tumors). We found known ASCC mutations (TP53, CDKN2A and PIK3CA) and CNAs (gains on 3q and 19q and losses on 11q and 13q). In addition, we discovered novel mutations in HRAS and ARID1A and CNAs (gain on 8q and losses 5q, 9p, 10q and 19p) that had not been reported in ASCCs. We identified 4 signature patterns of the mutations (signatures 1 and 2 with deamination of 5-methyl-cytosin, signature 3 with APOBEC and signature 4 with mismatch repair) in the ASCCs. While the signatures 1-3 have been detected in other SCCs, the signature 4 was first identified in ASCCs. In addition, we first found that ASCCs harbored chromothripsis, copy-neutral losses of heterozygosity and focal amplification of KLF5 super-enhancer. Analyses of primary and recurrent/metastatic pair genomes revealed that driver events in development and progression of ASCC might not be uniform. Our data indicate that ASCCs may have similar mutation and CNA profiles to other SCCs, but that there are unique genomic features of ASCCs as well. Our data may provide useful information for ASCC pathogenesis as well as for developing clinical strategies for ASCC.

PMID: 29555573 [PubMed - as supplied by publisher]

Family History in the Primary Open-Angle African American Glaucoma Genetics Study Cohort.

Am J Ophthalmol. 2018 Mar 16;:

Authors: O'Brien JM, Salowe RJ, Fertig R, Salinas J, Pistilli M, Sankar PS, Miller-Ellis E, Lehman A, Murphy W, Homsher M, Gordon K, Ying GS

Abstract
PURPOSE: To determine the relationship between positive family history (FH) and primary open-angle glaucoma (POAG) diagnosis and clinical presentation in the Primary Open-Angle African American Glaucoma Genetics (POAAGG) cohort.
METHODS: FH of POAG in first-degree relatives was assessed in 2365 subjects in the POAAGG cohort. A standardized interview was used to assess FH of glaucoma, demographic characteristics, lifestyle choices, and medical and ocular comorbidities.
RESULTS: Positive FH was associated with increased risk of POAG (age-adjusted odds ratio and 95% confidence interval 3.4[2.8, 4.1]). In age-adjusted analysis among POAG cases, positive FH was associated with younger age (P<0.001), female gender (P<.001), hypertension (P=.006), use of hypertension medication (P=.03), and prior glaucoma surgery (P=.02). Cases with positive FH also had thicker retinal nerve fiber layers (P=.03).
CONCLUSIONS: The risk conferred by positive FH suggests strong genetic underpinnings for some patients with this disease, which will be investigated by genome-wide association studies and whole exome sequencing.

PMID: 29555482 [PubMed - as supplied by publisher]