Genetic addiction risk score (GARS) ™, a predictor of vulnerability to opioid dependence.

Front Biosci (Elite Ed). 2018 01 01;10:175-196

Authors: Blum K, Chen ALC, Thanos PK, Febo M, Demetrovics Z, Dushaj K, Kovoor A, Baron D, Smith DE, Roy AK, Fried L, Chen TJH, Chapman E, Modestino EJ, Steinberg B, Badgaiyan RD

Abstract
The interaction of neurotransmitters and genes that control the release of dopamine is the Brain Reward Cascade (BRC). Variations within the BRC, whether genetic or epigenetic, may predispose individuals to addictive behaviors and altered pain tolerance. This discussion authored by a group of concerned scientists and clinicians examines the Genetic Addiction Risk Score (GARS), the first test to accurately predict vulnerability to pain, addiction, and other compulsive behaviors, defined as Reward Deficiency Syndrome (RDS). Innovative strategies to combat epidemic opioid, iatrogenic prescription drug abuse and death, based on the role of dopaminergic tone in pain pathways, are proposed. Sensitivity to pain may reside in the mesolimbic projection system, where genetic polymorphisms associate with a predisposition to pain vulnerability or tolerance. They provide unique therapeutic targets that could assist in the treatment of pain, and identify risk for subsequent addiction. Pharmacogenomic testing of candidate genes like CB1, mu receptors, and PENK might result in pharmacogenomic, personalized solutions, and improved clinical outcomes. Genetically identifying risk for all RDS behaviors, especially in compromised populations, may be a frontline tool to assist municipalities to provide better resource allocation.

PMID: 28930612 [PubMed - indexed for MEDLINE]

Genome-wide association study of neovascular age-related macular degeneration in the Thai population.

J Hum Genet. 2017 Nov;62(11):957-962

Authors: Ruamviboonsuk P, Tadarati M, Singhanetr P, Wattanapokayakit S, Kunhapan P, Wanitchanon T, Wichukchinda N, Mushiroda T, Akiyama M, Momozawa Y, Kubo M, Mahasirimongkol S

Abstract
We performed a genome-wide association study on 377 cases of neovascular age-related macular degeneration (AMD) and 1074 controls to determine the association of previously reported genetic variants associated with neovascular AMD in the Thai population. All patients were of Thai ancestry. We confirmed the association of age-related maculopathy susceptibility 2 (ARMS2) rs10490924 (P=7.38 × 10-17), HTRA1 rs11200638 (P=5.47 × 10-17) and complement factor H gene (CFH) rs800292 (P=2.53 × 10-8) with neovascular AMD, all loci passing the genome-wide significance level (P<5.22 × 10-8). We also found association of the previously reported CFH rs10737680 (P=1.76 × 10-6) locus in the discovery sample. Two loci not previously reported to be associated with neovascular AMD were selected for replication in 222 cases and 623 controls. The loci included LINCO1317 rs6733379 and rs2384550 on chromosome 12. LINCO1317 rs6733379 (P=3.85 × 10-2) remained significantly associated with neovascular AMD after replication. In conclusion, we confirm that ARMS2, HTRA1 and CFH variants are associated with neovascular AMD in the Thai population. Findings from this study also suggest that variants contributing to the susceptibility of neovascular AMD in the Thai population are mostly similar to other Asians with additional local genetic risks that may specifically be identified in Thai population.

PMID: 28703135 [PubMed - indexed for MEDLINE]

A pharmacogenomic approach validates AG-221 as an effective and on-target therapy in IDH2 mutant AML.

Leukemia. 2017 06;31(6):1466-1470

Authors: Kats LM, Vervoort SJ, Cole R, Rogers AJ, Gregory GP, Vidacs E, Li J, Nagaraja R, Yen KE, Johnstone RW

PMID: 28280273 [PubMed - indexed for MEDLINE]

Spleen Tyrosine Kinase as a Target Therapy for Pseudomonas aeruginosa Infection.

J Innate Immun. 2018 Jun 20;:1-9

Authors: Alhazmi A

Abstract
Spleen tyrosine kinase (SYK) is a nonreceptor tyrosine kinase which associates directly with extracellular receptors, and is critically involved in signal transduction pathways in a variety of cell types for the regulation of cellular responses. SYK is expressed ubiquitously in immune and nonimmune cells, and has a much wider biological role than previously recognized. Several studies have highlighted SYK as a key player in the pathogenesis of a multitude of diseases. Pseudomonas aeruginosa is an opportunistic gram-negative pathogen, which is responsible for systemic infections in immunocompromised individuals, accounting for a major cause of severe chronic lung infection in cystic fibrosis patients and subsequently resulting in a progressive deterioration of lung function. Inhibition of SYK activity has been explored as a therapeutic option in several allergic disorders, autoimmune diseases, and hematological malignancies. This review focuses on SYK as a therapeutic target, and describes the possibility of how current knowledge could be translated for therapeutic purposes to regulate the immune response to the opportunistic pathogen P. aeruginosa.

PMID: 29925062 [PubMed - as supplied by publisher]

A Proteomic Variant Approach (ProVarA) for Personalized Medicine of Inherited and Somatic Disease.

J Mol Biol. 2018 Jun 17;:

Authors: Hutt D, Loguercio S, Campos AR, Balch WE

Abstract
The advent of precision medicine for genetic diseases has been hampered by the large number of variants that cause familial and somatic disease, a complexity that is further confounded by the impact of genetic modifiers. To begin to understand differences in onset, progression and therapeutic response that exist among disease-causing variants, we present the proteomic variant approach (ProVarA), a proteomic method that integrates mass spectrometry with genomic tools to dissect the etiology of disease. To illustrate its value, we examined the impact of variation in cystic fibrosis (CF), where 2025 disease-associated mutations in the CF transmembrane conductance regulator (CFTR) gene have been annotated and where individual genotypes exhibit phenotypic heterogeneity and response to therapeutic intervention. A comparative analysis of variant-specific proteomics allows us to identify a number of protein interactions contributing to the basic defects associated with F508del- and G551D-CFTR, 2 of the most common disease-associated variants in the patient population. We demonstrate that a number of these causal interactions are significantly altered in response to treatment with Vx809 and Vx770, small molecule therapeutics that respectively target the F508del and G551D variants. ProVarA represents the first comparative proteomic analysis among multiple disease-causing mutations, thereby providing a methodological approach that provides a significant advancement to existing proteomic efforts in understanding the impact of variation in CF disease. We posit that the implementation of ProVarA for any familial or somatic mutation will provide a substantial increase in the knowledge base needed to implement a precision medicine-based approach for clinical management of disease.

PMID: 29924966 [PubMed - as supplied by publisher]

A G542X cystic fibrosis mouse model for examining nonsense mutation directed therapies.

PLoS One. 2018;13(6):e0199573

Authors: McHugh DR, Steele MS, Valerio DM, Miron A, Mann RJ, LePage DF, Conlon RA, Cotton CU, Drumm ML, Hodges CA

Abstract
Nonsense mutations are present in 10% of patients with CF, produce a premature termination codon in CFTR mRNA causing early termination of translation, and lead to lack of CFTR function. There are no currently available animal models which contain a nonsense mutation in the endogenous Cftr locus that can be utilized to test nonsense mutation therapies. In this study, we create a CF mouse model carrying the G542X nonsense mutation in Cftr using CRISPR/Cas9 gene editing. The G542X mouse model has reduced Cftr mRNA levels, demonstrates absence of CFTR function, and displays characteristic manifestations of CF mice such as reduced growth and intestinal obstruction. Importantly, CFTR restoration is observed in G542X intestinal organoids treated with G418, an aminoglycoside with translational readthrough capabilities. The G542X mouse model provides an invaluable resource for the identification of potential therapies of CF nonsense mutations as well as the assessment of in vivo effectiveness of these potential therapies targeting nonsense mutations.

PMID: 29924856 [PubMed - in process]

Outer-membrane protein LptD (PA0595) plays a role in the regulation of alginate synthesis in Pseudomonas aeruginosa.

J Med Microbiol. 2018 Jun 20;:

Authors: Pandey S, Delgado C, Kumari H, Florez L, Mathee K

Abstract
PURPOSE: The presence of alginate-overproducing (Alg+) strains of Pseudomonas aeruginosa in cystic fibrosis patients is indicative of chronic infection. The Alg+ phenotype is generally due to a mutation in the mucA gene, encoding an innermembrane protein that sequesters AlgT/U, the alginate-specific sigma factor. AlgT/U release from the anti-sigma factor MucA is orchestrated via a complex cascade called regulated intramembrane proteolysis. The goal of this study is to identify new players involved in the regulation of alginate production.
METHODOLOGY: Previously, a mutant with a second-site suppressor of alginate production (sap), sap27, was isolated from the constitutively Alg+ PDO300 that harbours the mucA22 allele. A cosmid from a P. aeruginosa minimum tiling path library was identified via en masse complementation of sap27. The cosmid was transposon mutagenized to map the contributing gene involved in the alginate production. The identified gene was sequenced in sap27 along with algT/U, mucA, algO and mucP. The role of the novel gene was explored using precise in-frame algO and algW deletion mutants of PAO1 and PDO300.Results/Key findings. The gene responsible for restoring the mucoid phenotype was mapped to lptD encoding an outer-membrane protein. However, the sequencing of sap27 revealed a mutation in algO, but not in lptD. In addition, we demonstrate that lipopolysaccharide transport protein D (LptD)-dependent alginate production requires AlgW in PAO1 and AlgO in PDO300.
CONCLUSION: LptD plays a specific role in alginate production. Our findings suggest that there are two pathways for the production of alginate in P. aeruginosa, one involving AlgW in the wild-type, and one involving AlgO in the mucA22 mutant.

PMID: 29923820 [PubMed - as supplied by publisher]

Lung Transplant - The Western Australian Experience.

Intern Med J. 2018 Jun 19;:

Authors: Dhillon S, McKinnon E, Wrobel J, Lavender M, Lawrence S, Gabbay E, Musk M

Abstract
BACKGROUND: The Western Australian lung transplant program commenced in 2004 to serve the growing demand of patients with end-stage lung disease.
AIM: This report summarises our eleven-year experience in lung transplantation.
METHODS: Data on 115 consecutive patients and their respective donors transplanted between 2004 and 2015 was collected. Kaplan-Meier method was used to estimate survival. Cox regression was used to analyse impact of donor and recipient characteristics on survival.
RESULTS: A total of 88 bilateral, 22 single-lung and 5 heart-lung transplants were performed in Western Australia during the first 11 years of the lung transplant program. The most common indications for transplantation were Interstitial Lung Disease (30.4%), Cystic Fibrosis (27.8%), and Chronic Obstructive Pulmonary Disease (excluding alpha-1 antitrypsin deficiency) (22.6%). Median recipient age was 50 years. Overall survival rates were 96% at 3 months, 93% at 1 year, 84% at 3 years, and 70% at 5 years. Older age, higher BMI, and lower donor to recipient height ratio negatively impacted survival. Chronic Lung Allograft Dysfunction was the leading cause of late mortality.
CONCLUSION: Lung transplantation is a treatment option in end-stage lung disease, with annual transplant rates in Western Australia continuing to rise. Our patients enjoy survival rates that compare favourably against international standards. This article is protected by copyright. All rights reserved.

PMID: 29923278 [PubMed - as supplied by publisher]

Aspergillus fumigatus Inhibits Pseudomonas aeruginosa in Co-culture: Implications of a Mutually Antagonistic Relationship on Virulence and Inflammation in the CF Airway.

Front Microbiol. 2018;9:1205

Authors: Reece E, Doyle S, Greally P, Renwick J, McClean S

Abstract
Many cystic fibrosis (CF) airway infections are considered to be polymicrobial and microbe-microbe interactions may play an important role in disease pathology. Pseudomonas aeruginosa and Aspergillus fumigatus are the most prevalent bacterial and fungal pathogens isolated from the CF airway, respectively. We have previously shown that patients co-colonized with these pathogens had comparable outcomes to those chronically colonized with P. aeruginosa. Our objective was to examine the interactions between A. fumigatus and P. aeruginosa, specifically the effects of co-colonization on biofilm formation, virulence and host pro-inflammatory responses. Our findings suggest that co-infections of A. fumigatus and P. aeruginosa in the Galleria mellonella acute infection model showed that pre-exposure of larvae to sub-lethal inocula of A. fumigatus increased the mortality caused by subsequent P. aeruginosa infection. Co-infection of human bronchial epithelial cells (CFBE41o-) with both pathogens did not enhance IL-6 and IL-8 production beyond the levels observed following single infections. In addition, both pathogens stimulated cytokine secretion via the same two mitogen-activated protein kinases (MAPKs) signaling pathways, ERK and p38. Mixed species biofilms showed overall reduced biofilm development with crystal violet staining. Quantification by species-specific qPCR revealed that both pathogens had mutually antagonistic effects on each other. A. fumigatus supernatants showed strong anti-Pseudomonal activity and gliotoxin was the main active agent. Gliotoxin resulted in varying levels of anti-biofilm activity toward other bacteria commonly found in the CF airways. Gliotoxin produced by A. fumigatus colonizing the CF airways may have a significant impact on the CF airway microbiome composition with potential clinical implications.

PMID: 29922270 [PubMed]

Opposite Expression of Hepatic and Pulmonary Corticosteroid-Binding Globulin in Cystic Fibrosis Patients.

Front Pharmacol. 2018;9:545

Authors: Tchoukaev A, Taytard J, Rousselet N, Rebeyrol C, Debray D, Blouquit-Laye S, Moisan MP, Foury A, Guillot L, Corvol H, Tabary O, Le Rouzic P

Abstract
Cystic fibrosis (CF) is characterized by a chronic pulmonary inflammation. In CF, glucocorticoids (GC) are widely used, but their efficacy and benefit/risk ratio are still debated. In plasma, corticosteroid-binding globulin (CBG) binds 90% of GC and delivers them to the inflammatory site. The main goal of this work was to study CBG expression in CF patients in order to determine whether CBG could be used to optimize GC treatment. The expression of CBG was measured in liver samples from CF cirrhotic and non-CF cirrhotic patients by qPCR and Western blot and in lung samples from non-CF and CF patients by qPCR. CBG binding assays with 3H-cortisol and the measurement of the elastase/α1-antitrypsin complex were performed using the plasmas. CBG expression increased in the liver at the transcript and protein level but not in the plasma of CF patients. This is possibly due to an increase of plasmatic elastase. We demonstrated that pulmonary CBG was expressed in the bronchi and bronchioles and its expression decreased in the CF lungs, at both levels studied. Despite the opposite expression of hepatic and pulmonary CBG in CF patients, the concentration of CBG in the plasma was normal. Thus, CBG might be useful to deliver an optimized synthetic GC displaying high affinity for CBG to the main inflammatory site in the context of CF, e.g., the lung.

PMID: 29922157 [PubMed]

Characteristics and outcomes of oral antibiotic treated pulmonary exacerbations in children with cystic fibrosis.

J Cyst Fibros. 2018 Jun 16;:

Authors: Hoppe JE, Wagner BD, Accurso FJ, Zemanick ET, Sagel SD

Abstract
BACKGROUND: Pulmonary exacerbations (PEx) in children with cystic fibrosis (CF) are frequently treated in the outpatient setting with oral antibiotics. However, little is known about the characteristics of PEx managed on an outpatient basis and the effectiveness of oral antibiotic therapy. We sought to prospectively evaluate clinical and laboratory changes associated with oral antibiotic treatment for PEx.
METHODS: Children with CF between 8 and 18 years of age prescribed two weeks of oral antibiotics for a PEx were eligible to enroll. The study consisted of a visit within 48 h of starting antibiotics and a second visit within one week of antibiotic completion. Twenty-eight participants were evaluated by exacerbation score, quality of life measurements, lung function, sputum microbiology and inflammation.
RESULTS: Oral antibiotic treatment was associated with a significant improvement in exacerbation score and quality of life measured by the CF Questionnaire-Revised (CFQ-R) respiratory domain. Following treatment, forced expiratory volume in 1 s (FEV1) % predicted increased [median (range)] 9% (-8%, 31%), and 22 (81%) subjects returned to 90% or higher of baseline FEV1. Bacterial density of the primary organism identified on sputum culture decreased significantly with a median (range) decrease of 0.8 log10 cfu/mL (-8 log10, 2 log10, p = 0.03). Sputum neutrophil elastase [-37 μg/mL (-464, 272), p = 0.02] and IL-1β [-2.8 × 103μg/mL (-6.9 × 104, 3.3 × 104), p = 0.03] decreased significantly following treatment in this cohort.
CONCLUSIONS: Treatment of PEx with oral antibiotics was associated with measurable improvements in patient reported outcomes, lung function, bacterial density and sputum inflammatory markers.

PMID: 29921503 [PubMed - as supplied by publisher]

Off-Label use of drugs and adverse drug reactions in pediatric units: a prospective, multicenter study.

Curr Drug Saf. 2018 Jun 19;:

Authors: Pratico AD, Longo L, Mansueto S, Gozzo L, Barberi I, Tiralongo V, Salvo V, Falsaperla R, Vitaliti G, La Rosa M, Rotondo A, Avola N, Sgarlata D, Damiano A, Tirantello M, Anzelmo G, Cipolla D, Rizzo A, Russo A, Ruggieri M, Salomone S, Drago F

Abstract
BACKGROUND: Given the growing use of off-label in pediatric practice, there is a growing interest on pharmacovigilance programs monitoring the occurrence of adverse drug reactions related to off-label drug prescription in childhood.
PATIENTS AND METHODS: The results of a one-year program of pharmacovigilance issued in the Sicilian Region, Italy, are herein presented. The study involved 6 pediatric and neonatal centres and prospectively reviewed the prescriptions of 5,060 patients, who were stratified for age (newborn, infant, children, adolescents).
RESULTS: A total of 14,916 prescriptions were issued for 5,060 patients. Among them, 454 patients [8.97%] received at least one off-label drug. Among the off-label treated patients, 255 (56.2%) were newborns. Anti-infectives drugs were the most frequent off-label used drugs, followed by drugs for alimentary tract and metabolism and drugs for blood or blood forming organs. Ninety adverse drug reactions were recorded [1.78% of the total patients]. They occurred after an off-label prescription in 33 out of 90 [36.7%], while those occurring after an on-label prescription were 57 [63.3%]. Patients treated with an off-label drug had a significantly higher risk of adverse drug reactions [7.3% vs 1.2%; p <0.01].
CONCLUSIONS: The present study indicates that children admitted to neonatal intensive care units are likely to receive an off-label medication; children who receive an off-label medication are usually more likely to be treated with more medication than the others; adverse drug reactions occur in patients admitted in neonatal intensive care and pediatrics units are more frequently with off-label than with on-label drugs.

PMID: 29921210 [PubMed - as supplied by publisher]

Pre-anaesthetic evaluation of the patient with end-stage lung disease.

Best Pract Res Clin Anaesthesiol. 2017 Jun;31(2):249-260

Authors: Prabhu M, Valchanov K

Abstract
Lung transplantation is a viable alternative for end-stage lung diseases, which offers good quality of life and survival outcomes for recipients. The aims of pre-assessment for potential lung transplant recipients are to assess fitness for surgery, optimise co-morbidities, commence interventions or investigations, weigh risk-benefit ratio, plan appropriate analgesia and obtain informed consent. The assessment information is gathered from the medical record, patient interview, physical examination and pre-operative tests. A comprehensive workup includes cardiopulmonary evaluation, haematological, biochemical, microbiological and immunological investigations. Most of the evidence regarding lung transplantation is gleaned from retrospective data from single, multi-centre or multinational registries. The lack of good quality evidence means that the guidelines are based on expert consensus.

PMID: 29110797 [PubMed - indexed for MEDLINE]

[Pathogen decay of airborne bacteria in bioaereosols].

Assist Inferm Ric. 2017 Jul-Sep;36(3):168-169

Authors: Cavicchioli A

PMID: 28956874 [PubMed - indexed for MEDLINE]

Kleine-Levin syndrome is associated with LMOD3 variants.

J Sleep Res. 2018 Jun 19;:e12718

Authors: Al Shareef SM, Basit S, Li S, Pfister C, Pradervand S, Lecendreux M, Mayer G, Dauvilliers Y, Salpietro V, Houlden H, BaHammam AS, Tafti M

Abstract
Kleine-Levin syndrome (KLS) is a rare periodic hypersomnia with associated behavioural abnormalities but with often favourable prognosis. There is excess risk of KLS in first-degree relatives, suggesting a strong genetic contribution. So far, no mutation is identified in KLS and comprehensive genetic analysis of affected individuals is lacking. Here we performed whole genome single-nucleotide polymorphism (SNP) genotyping and exome sequencing in a large family with seven affected members. The identified gene with a mutation was resequenced in 38 sporadic KLS patients and the expression of the gene product was mapped in the mouse brain. Linkage analysis mapped the disease locus to chromosome 3 and exome analysis identified a heterozygous missense variant in LMOD3 (p.E142D) in the linkage interval. The variant was found to segregate in all affected and one presumably unaffected member of the family. Resequencing LMOD3 in 38 other KLS patients and their families revealed three other low frequency or rare missense variants in seven cases that were inherited with incomplete penetrance. LMOD3 is expressed in the brain and colocalized with major structures involved in the regulation of vigilance states. LMOD proteins are structural proteins and seem to be developmentally regulated. Our findings suggest that KLS might be a structural/neurodevelopmental brain disease.

PMID: 29923248 [PubMed - as supplied by publisher]

CIRCULATING TUMOR DNA ANALYSIS ENABLES MOLECULAR CHARACTERIZATION OF PEDIATRIC RENAL TUMORS AT DIAGNOSIS.

Int J Cancer. 2018 Jun 19;:

Authors: Jiménez I, Chicard M, Colmet-Daage L, Clément N, Danzon A, Lapouble E, Pierron G, Bohec M, Baulande S, Berrebi D, Fréneaux P, Coulomb A, Galmiche-Rolland L, Sarnacki S, Audry G, Philippe-Chomette P, Brisse HJ, Doz F, Michon J, Delattre O, Schleiermacher G

Abstract
Circulating tumor DNA (ctDNA) is a powerful tool for the molecular characterization of cancer. The most frequent pediatric kidney tumors (KT) are Wilms' tumors (WT), but other diagnoses may occur. According to the SIOP strategy, in most countries pediatric KT have a presumptive diagnosis of WT if they are clinically and radiologically compatible. The histologic confirmation is established after post-chemotherapy nephrectomy. Thus, there is a risk for a small fraction of patients to receive neoadjuvant chemotherapy that is not adapted to the disease. The aim of this work is to perform molecular diagnosis of pediatric KT by tumor genetic characterization based on the analysis of ctDNA. We analyzed ctDNA extracted from plasma samples of 18 pediatric patients with KT by whole-exome sequencing and compared the results to their matched tumor and germline DNA. Copy number alterations (CNAs) and single nucleotide variations (SNVs) were analyzed. We were able to detect tumor cell specific genetic alterations -CNAs, SNVs or both- in ctDNA in all patients except in one (for whom the plasma sample was obtained long after nephrectomy). These results open the door to new applications for the study of ctDNA with regards to the molecular diagnosis of KT, with a possibility of its usefulness for adapting the treatment early after diagnosis, but also for disease monitoring and follow up. This article is protected by copyright. All rights reserved.

PMID: 29923174 [PubMed - as supplied by publisher]

De novo ATP1A3 and compound heterozygous NLRP3 mutations in a child with autism spectrum disorder, episodic fatigue and somnolence, and muckle-wells syndrome.

Mol Genet Metab Rep. 2018 Sep;16:23-29

Authors: Torres A, Brownstein CA, Tembulkar SK, Graber K, Genetti C, Kleiman RJ, Sweadner KJ, Mavros C, Liu KX, Smedemark-Margulies N, Maski K, Yang E, Agrawal PB, Shi J, Beggs AH, D'Angelo E, Lincoln SH, Carroll D, Dedeoglu F, Gahl WA, Biggs CM, Swoboda KJ, Berry GT, Gonzalez-Heydrich J

Abstract
Complex phenotypes may represent novel syndromes that are the composite interaction of several genetic and environmental factors. We describe an 9-year old male with high functioning autism spectrum disorder and Muckle-Wells syndrome who at age 5  years of age manifested perseverations that interfered with his functioning at home and at school. After age 6, he developed intermittent episodes of fatigue and somnolence lasting from hours to weeks that evolved over the course of months to more chronic hypersomnia. Whole exome sequencing showed three mutations in genes potentially involved in his clinical phenotype. The patient has a predicted pathogenic de novo heterozygous p.Ala681Thr mutation in the ATP1A3 gene (chr19:42480621C>T, GRCh37/hg19). Mutations in this gene are known to cause Alternating Hemiplegia of Childhood, Rapid Onset Dystonia Parkinsonism, and CAPOS syndrome, sometimes accompanied by autistic features. The patient also has compound heterozygosity for p.Arg490Lys/p.Val200Met mutations in the NLRP3 gene (chr1:247588214G>A and chr1:247587343G>A, respectively). NLRP3 mutations are associated in an autosomal dominant manner with clinically overlapping auto-inflammatory conditions including Muckle-Wells syndrome. The p.Arg490Lys is a known pathogenic mutation inherited from the patient's father. The p.Val200Met mutation, inherited from his mother, is a variant of unknown significance (VUS). Whether the de novoATP1A3mutation is responsible for or plays a role in the patient's episodes of fatigue and somnolence remains to be determined. The unprecedented combination of two NLRP3 mutations may be responsible for other aspects of his complex phenotype.

PMID: 29922587 [PubMed]

Clinical implications of systematic phenotyping and exome sequencing in patients with primary antibody deficiency.

Genet Med. 2018 Jun 19;:

Authors: Abolhassani H, Aghamohammadi A, Fang M, Rezaei N, Jiang C, Liu X, Pan-Hammarström Q, Hammarström L

Abstract
PURPOSE: The etiology of 80% of patients with primary antibody deficiency (PAD), the second most common type of human immune system disorder after human immunodeficiency virus infection, is yet unknown.
METHODS: Clinical/immunological phenotyping and exome sequencing of a cohort of 126 PAD patients (55.5% male, 95.2% childhood onset) born to predominantly consanguineous parents (82.5%) with unknown genetic defects were performed. The American College of Medical Genetics and Genomics criteria were used for validation of pathogenicity of the variants.
RESULTS: This genetic approach and subsequent immunological investigations identified potential disease-causing variants in 86 patients (68.2%); however, 27 of these patients (31.4%) carried autosomal dominant (24.4%) and X-linked (7%) gene defects. This genetic approach led to the identification of new phenotypes in 19 known genes (38 patients) and the discovery of a new genetic defect (CD70 pathogenic variants in 2 patients). Medical implications of a definite genetic diagnosis were reported in ~50% of the patients.
CONCLUSION: Due to misclassification of the conventional approach for targeted sequencing, employing next-generation sequencing as a preliminary step of molecular diagnostic approach to patients with PAD is crucial for management and treatment of the patients and their family members.

PMID: 29921932 [PubMed - as supplied by publisher]

Unexpected cancer-predisposition gene variants in Cowden syndrome and Bannayan-Riley-Ruvalcaba syndrome patients without underlying germline PTEN mutations.

PLoS Genet. 2018 04;14(4):e1007352

Authors: Yehia L, Ni Y, Sesock K, Niazi F, Fletcher B, Chen HJL, LaFramboise T, Eng C

Abstract
Patients with heritable cancer syndromes characterized by germline PTEN mutations (termed PTEN hamartoma tumor syndrome, PHTS) benefit from PTEN-enabled cancer risk assessment and clinical management. PTEN-wildtype patients (~50%) remain at increased risk of developing certain cancers. Existence of germline mutations in other known cancer susceptibility genes has not been explored in these patients, with implications for different medical management. We conducted a 4-year multicenter prospective study of incident patients with features of Cowden/Cowden-like (CS/CS-like) and Bannayan-Riley-Ruvalcaba syndromes (BRRS) without PTEN mutations. Exome sequencing and targeted analysis were performed including 59 clinically actionable genes from the American College of Medical Genetics and Genomics (ACMG) and 24 additional genes associated with inherited cancer syndromes. Pathogenic or likely pathogenic cancer susceptibility gene alterations were found in 7 of the 87 (8%) CS/CS-like and BRRS patients and included MUTYH, RET, TSC2, BRCA1, BRCA2, ERCC2 and HRAS. We found classic phenotypes associated with the identified genes in 5 of the 7 (71.4%) patients. Variant positive patients were enriched for the presence of second malignant neoplasms compared to patients without identified variants (OR = 6.101, 95% CI 1.143-35.98, p = 0.035). Germline variant spectrum and frequencies were compared to The Cancer Genome Atlas (TCGA), including 6 apparently sporadic cancers associated with PHTS. With comparable overall prevalence of germline variants, the spectrum of mutated genes was different in our patients compared to TCGA. Intriguingly, we also found notable enrichment of variants of uncertain significance (VUS) in our patients (OR = 2.3, 95% CI 1.5-3.5, p = 0.0002). Our data suggest that only a small subset of PTEN-wildtype CS/CS-like and BRRS patients could be accounted for by germline variants in some of the known cancer-related genes. Thus, the existence of alterations in other and more likely non-classic cancer-associated genes is plausible, reflecting the complexity of these heterogeneous hereditary cancer syndromes.

PMID: 29684080 [PubMed - indexed for MEDLINE]

Clinical Manifestations Associated With the N-Terminal-Acetyltransferase NAA10 Gene Mutation in a Girl: Ogden Syndrome.

Pediatr Neurol. 2017 Nov;76:82-85

Authors: Sidhu M, Brady L, Tarnopolsky M, Ronen GM

Abstract
BACKGROUND: Ogden syndrome is a rare X-linked disorder caused by pathogenic variants in the NAA10 gene. This syndrome, reported in just over 20 children, has been associated with dysmorphic features, failure to thrive, developmental impairments, hypotonia, and cardiac arrhythmias.
PATIENT DESCRIPTION: We describe a 14-year-old girl who presented in infancy with hypotonia, global developmental delay, and dysmorphic features. She later developed autism spectrum disorder, epileptic encephalopathy, extrapyramidal signs, early morning lethargy with hypersomnolence, and hypertension with left ventricular hypertrophy. Magnetic resonance imaging showed a thin corpus callosum and progressive white matter loss. Whole exome sequencing identified a de novo pathogenic variant in the NAA10 gene (c.247C>T, p.R83C). Much of her early presentation was in keeping with what has been previously described with Ogden syndrome.
CONCLUSIONS: We have identified additional evolving neurological impairments in this, to date, oldest documented girl with Ogden syndrome. We recommend screening patients with Ogden syndrome for these newly identified features of early life trajectories to guide management.

PMID: 28967461 [PubMed - indexed for MEDLINE]