Mycobacterium Lentiflavum in Cystic Fibrosis Subjects. A Colonizer or a True Pathogen?

Arch Bronconeumol. 2018 May 31;:

Authors: Moreno Ortega M, Quintana Gallego ME, Carrasco Hernández L, Pérez Borrego E, Delgado Pecellín I

PMID: 29861072 [PubMed - as supplied by publisher]

Functional screening for G protein-coupled receptor targets of 14,15-epoxyeicosatrienoic acid.

Prostaglandins Other Lipid Mediat. 2017 Sep;132:31-40

Authors: Liu X, Qian ZY, Xie F, Fan W, Nelson JW, Xiao X, Kaul S, Barnes AP, Alkayed NJ

Abstract
Epoxyeicosatrienoic acids (EETs) are potent vasodilators that play important roles in cardiovascular physiology and disease, yet the molecular mechanisms underlying the biological actions of EETs are not fully understood. Multiple lines of evidence suggest that the actions of EETs are in part mediated via G protein-coupled receptor (GPCR) signaling, but the identity of such a receptor has remained elusive. We sought to identify 14,15-EET-responsive GPCRs. A set of 105 clones were expressed in Xenopus oocyte and screened for their ability to activate cAMP-dependent chloride current. Several receptors responded to micromolar concentrations of 14,15-EET, with the top five being prostaglandin receptor subtypes (PTGER2, PTGER4, PTGFR, PTGDR, PTGER3IV). Overall, our results indicate that multiple low-affinity 14,15-EET GPCRs are capable of increasing cAMP levels following 14,15-EET stimulation, highlighting the potential for cross-talk between prostanoid and other ecosanoid GPCRs. Our data also indicate that none of the 105 GPCRs screened met our criteria for a high-affinity receptor for 14,15-EET.

PMID: 27649858 [PubMed - indexed for MEDLINE]

De Novo and Inherited Loss-of-Function Variants in TLK2: Clinical and Genotype-Phenotype Evaluation of a Distinct Neurodevelopmental Disorder.

Am J Hum Genet. 2018 May 22;:

Authors: Reijnders MRF, Miller KA, Alvi M, Goos JAC, Lees MM, de Burca A, Henderson A, Kraus A, Mikat B, de Vries BBA, Isidor B, Kerr B, Marcelis C, Schluth-Bolard C, Deshpande C, Ruivenkamp CAL, Wieczorek D, Deciphering Developmental Disorders Study, Baralle D, Blair EM, Engels H, Lüdecke HJ, Eason J, Santen GWE, Clayton-Smith J, Chandler K, Tatton-Brown K, Payne K, Helbig K, Radtke K, Nugent KM, Cremer K, Strom TM, Bird LM, Sinnema M, Bitner-Glindzicz M, van Dooren MF, Alders M, Koopmans M, Brick L, Kozenko M, Harline ML, Klaassens M, Steinraths M, Cooper NS, Edery P, Yap P, Terhal PA, van der Spek PJ, Lakeman P, Taylor RL, Littlejohn RO, Pfundt R, Mercimek-Andrews S, Stegmann APA, Kant SG, McLean S, Joss S, Swagemakers SMA, Douzgou S, Wall SA, Küry S, Calpena E, Koelling N, McGowan SJ, Twigg SRF, Mathijssen IMJ, Nellaker C, Brunner HG, Wilkie AOM

Abstract
Next-generation sequencing is a powerful tool for the discovery of genes related to neurodevelopmental disorders (NDDs). Here, we report the identification of a distinct syndrome due to de novo or inherited heterozygous mutations in Tousled-like kinase 2 (TLK2) in 38 unrelated individuals and two affected mothers, using whole-exome and whole-genome sequencing technologies, matchmaker databases, and international collaborations. Affected individuals had a consistent phenotype, characterized by mild-borderline neurodevelopmental delay (86%), behavioral disorders (68%), severe gastro-intestinal problems (63%), and facial dysmorphism including blepharophimosis (82%), telecanthus (74%), prominent nasal bridge (68%), broad nasal tip (66%), thin vermilion of the upper lip (62%), and upslanting palpebral fissures (55%). Analysis of cell lines from three affected individuals showed that mutations act through a loss-of-function mechanism in at least two case subjects. Genotype-phenotype analysis and comparison of computationally modeled faces showed that phenotypes of these and other individuals with loss-of-function variants significantly overlapped with phenotypes of individuals with other variant types (missense and C-terminal truncating). This suggests that haploinsufficiency of TLK2 is the most likely underlying disease mechanism, leading to a consistent neurodevelopmental phenotype. This work illustrates the power of international data sharing, by the identification of 40 individuals from 26 different centers in 7 different countries, allowing the identification, clinical delineation, and genotype-phenotype evaluation of a distinct NDD caused by mutations in TLK2.

PMID: 29861108 [PubMed - as supplied by publisher]

TRPV6 Variants Interfere with Maternal-Fetal Calcium Transport through the Placenta and Cause Transient Neonatal Hyperparathyroidism.

Am J Hum Genet. 2018 May 23;:

Authors: Suzuki Y, Chitayat D, Sawada H, Deardorff MA, McLaughlin HM, Begtrup A, Millar K, Harrington J, Chong K, Roifman M, Grand K, Tominaga M, Takada F, Shuster S, Obara M, Mutoh H, Kushima R, Nishimura G

Abstract
Transient neonatal hyperparathyroidism (TNHP) is etiologically a heterogeneous condition. One of the etiologies is an insufficient maternal-fetal calcium transport through the placenta. We report six subjects with homozygous and/or compound-heterozygous mutations in the gene encoding the transient receptor potential cation channel, subfamily V, member 6 (TRPV6), an epithelial Ca2+-selective channel associated with this condition. Exome sequencing on two neonates with skeletal findings consistent with neonatal hyperparathyroidism identified homozygous frameshift mutations before the first transmembrane domain in a subject born to first-cousins parents of Pakistani descent as well as compound-heterozygous mutations (a combination of a frameshift mutation and an intronic mutation that alters mRNA splicing) in an individual born to a non-consanguineous couple of African descent. Subsequently, targeted mutation analysis of TRPV6 performed on four other individuals (born to non-consanguineous Japanese parents) with similar X-rays findings identified compound-heterozygous mutations. The skeletal findings improved or resolved in most subjects during the first few months of life. We identified three missense variants (at the outer edges of the second and third transmembrane domains) that alter the localization of the TRPV6: one recurrent variant at the S2-S3 loop and two recurrent variants (in the fourth ankyrin repeat domain) that impair TRPV6 stability. Compound heterozygous loss-of-function mutations for the pathogenic frameshift allele and the allele with an intronic c.607+5G>A mutation resulted in the most severe phenotype. These results suggest that TNHP is an autosomal-recessive disease caused by TRPV6 mutations that affect maternal-fetal calcium transport.

PMID: 29861107 [PubMed - as supplied by publisher]

Genetic Analyses in Small-for-Gestational-Age Newborns.

J Clin Endocrinol Metab. 2018 03 01;103(3):917-925

Authors: Stalman SE, Solanky N, Ishida M, Alemán-Charlet C, Abu-Amero S, Alders M, Alvizi L, Baird W, Demetriou C, Henneman P, James C, Knegt LC, Leon LJ, Mannens MMAM, Mul AN, Nibbering NA, Peskett E, Rezwan FI, Ris-Stalpers C, van der Post JAM, Kamp GA, Plötz FB, Wit JM, Stanier P, Moore GE, Hennekam RC

Abstract
Context: Small for gestational age (SGA) can be the result of fetal growth restriction, which is associated with perinatal morbidity and mortality. Mechanisms that control prenatal growth are poorly understood.
Objective: The aim of the current study was to gain more insight into prenatal growth failure and determine an effective diagnostic approach in SGA newborns. We hypothesized that one or more copy number variations (CNVs) and disturbed methylation and sequence variants may be present in genes associated with fetal growth.
Design: A prospective cohort study of subjects with a low birth weight for gestational age.
Setting: The study was conducted at an academic pediatric research institute.
Patients: A total of 21 SGA newborns with a mean birth weight below the first centile and a control cohort of 24 appropriate-for-gestational-age newborns were studied.
Interventions: Array comparative genomic hybridization, genome-wide methylation studies, and exome sequencing were performed.
Main Outcome Measures: The numbers of CNVs, methylation disturbances, and sequence variants.
Results: The genetic analyses demonstrated three CNVs, one systematically disturbed methylation pattern, and one sequence variant explaining SGA. Additional methylation disturbances and sequence variants were present in 20 patients. In 19 patients, multiple abnormalities were found.
Conclusion: Our results confirm the influence of a large number of mechanisms explaining dysregulation of fetal growth. We concluded that CNVs, methylation disturbances, and sequence variants all contribute to prenatal growth failure. These genetic workups can be an effective diagnostic approach in SGA newborns.

PMID: 29342293 [PubMed - indexed for MEDLINE]

Intellectual Disability & Rare Disorders: A Diagnostic Challenge.

Adv Exp Med Biol. 2017;1031:39-54

Authors: Kvarnung M, Nordgren A

Abstract
Rare disorders constitute a large and heterogeneous group of diagnoses of which many cause chronic disabilities with significant impact on the lives of affected individuals and their families as well as on the health-care system. Each individual disorder is rare, but when considered as a group, rare disorders are common with a total prevalence of approximately 6-8%. The clinical presentation of these disorders includes a broad diversity of symptoms and signs, often involving the nervous system and resulting in symptoms such as intellectual disability, neuropsychiatric disorders, epilepsy and motor dysfunction. The methods for establishing an etiological diagnosis in patients with rare disorders have improved dramatically during recent years. With the introduction of genomic screening methods, it has been shown that the cause is genetic in the majority of the patients and many will receive an etiological diagnosis in a clinical setting. However, there are a lot of challenges in diagnosing these disorders and despite recent years' advances, a large number of patients with rare disorders still go without an etiological diagnosis. In this chapter we will review the etiology of rare disorders with focus on intellectual disability and what has been learned from massive parallel sequencing studies in deciphering the genetic basis. Furthermore, we will discuss challenges in the etiological diagnostics of these disorders including issues that regard interpretation of the numerous genetic variants detected by genomic screening methods and challenges in the translation of massive parallel sequencing technologies into clinical practice.

PMID: 29214565 [PubMed - indexed for MEDLINE]

Clues for Polygenic Inheritance of Pituitary Stalk Interruption Syndrome From Exome Sequencing in 20 Patients.

J Clin Endocrinol Metab. 2018 02 01;103(2):415-428

Authors: Zwaveling-Soonawala N, Alders M, Jongejan A, Kovacic L, Duijkers FA, Maas SM, Fliers E, van Trotsenburg ASP, Hennekam RC

Abstract
Context: Pituitary stalk interruption syndrome (PSIS) consists of a small/absent anterior pituitary lobe, an interrupted/absent pituitary stalk, and an ectopic posterior pituitary lobe. Mendelian forms of PSIS are detected infrequently (<5%), and a polygenic etiology has been suggested. GLI2 variants have been reported at a relatively high frequency in PSIS.
Objective: To provide further evidence for a non-Mendelian, polygenic etiology of PSIS.
Methods: Exome sequencing (trio approach) in 20 patients with isolated PSIS. In addition to searching for (potentially) pathogenic de novo and biallelic variants, a targeted search was performed in a panel of genes associated with midline brain development (223 genes). For GLI2 variants, both (potentially) pathogenic and relatively rare variants (<5% in the general population) were studied. The frequency of GLI2 variants was compared with that of a reference population.
Results: We found four additional candidate genes for isolated PSIS (DCHS1, ROBO2, CCDC88C, and KIF14) and one for syndromic PSIS (KAT6A). Eleven GLI2 variants were present in six patients. A higher frequency of a combination of two GLI2 variants (M1352V + D1520N) was found in the study group compared with a reference population (10% vs 0.68%). (Potentially) pathogenic variants were identified in genes associated with midline brain anomalies, including holoprosencephaly, hypogonadotropic hypogonadism, and absent corpus callosum and in genes involved in ciliopathies.
Conclusion: Combinations of variants in genes associated with midline brain anomalies are frequently present in PSIS and sustain the hypothesis of a polygenic cause of PSIS.

PMID: 29165578 [PubMed - indexed for MEDLINE]

Homozygous mutation in the NPHP3 gene causing foetal nephronophthisis.

Nephrology (Carlton). 2017 Oct;22(10):818-820

Authors: Abdullah U, Farooq M, Fatima A, Tauseef W, Sarwar Y, Nuri M, Tommerup N, Baig SM

Abstract
We present a case of a foetal sonographic finding of hyper-echogenic kidneys, which led to a strategic series of genetic tests and identified a homozygous mutation (c.424C > T, p. R142*) in the NPHP3 gene. Our study provides a rare presentation of NPHP3-related ciliopathy and adds to the mutation spectrum of the gene, being the first one from Pakistani population. With a thorough literature review, it also advocates for molecular assessment of ciliopathies to improve risk estimate for future pregnancies, and identify predisposed asymptomatic carriers.

PMID: 28921755 [PubMed - indexed for MEDLINE]

Sensitized mutagenesis screen in Factor V Leiden mice identifies thrombosis suppressor loci.

Proc Natl Acad Sci U S A. 2017 09 05;114(36):9659-9664

Authors: Westrick RJ, Tomberg K, Siebert AE, Zhu G, Winn ME, Dobies SL, Manning SL, Brake MA, Cleuren AC, Hobbs LM, Mishack LM, Johnston AJ, Kotnik E, Siemieniak DR, Xu J, Li JZ, Saunders TL, Ginsburg D

Abstract
Factor V Leiden (F5L ) is a common genetic risk factor for venous thromboembolism in humans. We conducted a sensitized N-ethyl-N-nitrosourea (ENU) mutagenesis screen for dominant thrombosuppressor genes based on perinatal lethal thrombosis in mice homozygous for F5L (F5L/L ) and haploinsufficient for tissue factor pathway inhibitor (Tfpi+/- ). F8 deficiency enhanced the survival of F5L/LTfpi+/- mice, demonstrating that F5L/LTfpi+/- lethality is genetically suppressible. ENU-mutagenized F5L/L males and F5L/+Tfpi+/- females were crossed to generate 6,729 progeny, with 98 F5L/LTfpi+/- offspring surviving until weaning. Sixteen lines, referred to as "modifier of Factor 5 Leiden (MF5L1-16)," exhibited transmission of a putative thrombosuppressor to subsequent generations. Linkage analysis in MF5L6 identified a chromosome 3 locus containing the tissue factor gene (F3). Although no ENU-induced F3 mutation was identified, haploinsufficiency for F3 (F3+/- ) suppressed F5L/LTfpi+/- lethality. Whole-exome sequencing in MF5L12 identified an Actr2 gene point mutation (p.R258G) as the sole candidate. Inheritance of this variant is associated with suppression of F5L/LTfpi+/- lethality (P = 1.7 × 10-6), suggesting that Actr2p.R258G is thrombosuppressive. CRISPR/Cas9 experiments to generate an independent Actr2 knockin/knockout demonstrated that Actr2 haploinsufficiency is lethal, supporting a hypomorphic or gain-of-function mechanism of action for Actr2p.R258G Our findings identify F8 and the Tfpi/F3 axis as key regulators in determining thrombosis balance in the setting of F5L and also suggest a role for Actr2 in this process.

PMID: 28827327 [PubMed - indexed for MEDLINE]

Exome sequencing-based molecular autopsy of formalin-fixed paraffin-embedded tissue after sudden death.

Genet Med. 2017 Oct;19(10):1127-1133

Authors: Bagnall RD, Ingles J, Yeates L, Berkovic SF, Semsarian C

Abstract
PURPOSE: Sudden death in the young is a devastating complication of inherited heart disorders. Finding the precise cause of death is important, but it is often unresolved after postmortem investigation. The addition of postmortem genetic testing, i.e., the molecular autopsy, can identify additional causes of death. We evaluated DNA extracted from formalin-fixed paraffin-embedded postmortem tissue for exome sequencing-based molecular autopsy after sudden death in the young.
METHODS: We collected clinical and postmortem information from patients with sudden death. Exome sequencing was performed on DNA extracted from fixed postmortem tissue. Variants relevant to the cause of death were sought.
RESULTS: Five patients with genetically unresolved sudden death were recruited. DNA extracted from fixed postmortem tissue was degraded. Exome sequencing achieved 20-fold coverage of at least 82% of coding regions. A threefold excess of singleton variants was found in the exome sequencing data of one patient. We found a de novo SCN1A frameshift variant in a patient with sudden unexpected death in epilepsy and a LMNA nonsense variant in a patient with dilated cardiomyopathy.
CONCLUSION: DNA extracted from fixed postmortem tissue is applicable to exome sequencing-based molecular autopsy. Fixed postmortem tissues are an untapped resource for exome-based studies of rare causes of sudden death.Genet Med advance online publication 23 March 2017.

PMID: 28333919 [PubMed - indexed for MEDLINE]

The genetics of atrial fibrillation.

Curr Opin Cardiol. 2017 Jan;32(1):10-16

Authors: Hayashi K, Tada H, Yamagishi M

Abstract
PURPOSE OF REVIEW: To describe recent findings regarding the role of rare and common genetic variants in atrial fibrillation.
RECENT FINDINGS: Atrial fibrillation is associated with several clinical risk factors and its development is affected by genetic background. To date, rare variants from more than 30 genes have been identified from studies of familial cases or individuals with lone atrial fibrillation. In addition to using the candidate gene approach for the identification of rare variants, next-generation sequencing approaches such as genomic, whole exome and targeted sequencing have been employed. Furthermore, evidence of association between common variants and atrial fibrillation has been discovered through genome-wide association studies. Although the power of any one single-nucleotide polymorphism (SNP) associated with atrial fibrillation is weak, a genetic risk score comprising 12 SNPs may identify individuals at an increased risk for atrial fibrillation. This SNP panel may also delineate genotypes to enable stratification of atrial fibrillation ablation therapy or periinterventional management.
SUMMARY: Although studies have demonstrated that atrial fibrillation is highly heritable, many aspects of atrial fibrillation remain unknown. Rigorous research efforts continue with the expectation that the contribution of variants and candidate genes that contribute to the overall genetic architecture of atrial fibrillation will be identified and characterized in the coming years.

PMID: 27861186 [PubMed - indexed for MEDLINE]

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The National Sleep Research Resource: towards a sleep data commons.

J Am Med Inform Assoc. 2018 May 31;:

Authors: Zhang GQ, Cui L, Mueller R, Tao S, Kim M, Rueschman M, Mariani S, Mobley D, Redline S

Abstract
Objective: The gold standard for diagnosing sleep disorders is polysomnography, which generates extensive data about biophysical changes occurring during sleep. We developed the National Sleep Research Resource (NSRR), a comprehensive system for sharing sleep data. The NSRR embodies elements of a data commons aimed at accelerating research to address critical questions about the impact of sleep disorders on important health outcomes.
Approach: We used a metadata-guided approach, with a set of common sleep-specific terms enforcing uniform semantic interpretation of data elements across three main components: (1) annotated datasets; (2) user interfaces for accessing data; and (3) computational tools for the analysis of polysomnography recordings. We incorporated the process for managing dataset-specific data use agreements, evidence of Institutional Review Board review, and the corresponding access control in the NSRR web portal. The metadata-guided approach facilitates structural and semantic interoperability, ultimately leading to enhanced data reusability and scientific rigor.
Results: The authors curated and deposited retrospective data from 10 large, NIH-funded sleep cohort studies, including several from the Trans-Omics for Precision Medicine (TOPMed) program, into the NSRR. The NSRR currently contains data on 26 808 subjects and 31 166 signal files in European Data Format. Launched in April 2014, over 3000 registered users have downloaded over 130 terabytes of data.
Conclusions: The NSRR offers a use case and an example for creating a full-fledged data commons. It provides a single point of access to analysis-ready physiological signals from polysomnography obtained from multiple sources, and a wide variety of clinical data to facilitate sleep research.

PMID: 29860441 [PubMed - as supplied by publisher]

Expression and function of Anoctamin 1/TMEM16A calcium-activated chloride channels in airways of in vivo mouse models for cystic fibrosis research.

Pflugers Arch. 2018 Jun 02;:

Authors: Hahn A, Salomon JJ, Leitz D, Feigenbutz D, Korsch L, Lisewski I, Schrimpf K, Millar-Büchner P, Mall MA, Frings S, Möhrlen F

Abstract
Physiological processes of vital importance are often safeguarded by compensatory systems that substitute for primary processes in case these are damaged by gene mutation. Ca2+-dependent Cl- secretion in airway epithelial cells may provide such a compensatory mechanism for impaired Cl- secretion via cystic fibrosis transmembrane conductance regulator (CFTR) channels in cystic fibrosis (CF). Anoctamin 1 (ANO1) Ca2+-gated Cl- channels are known to contribute to calcium-dependent Cl- secretion in tracheal and bronchial epithelia. In the present study, two mouse models of CF were examined to assess a potential protective function of Ca2+-dependent Cl- secretion, a CFTR deletion model (cftr-/-), and a CF pathology model that overexpresses the epithelial Na+ channel β-subunit (βENaC), which is encoded by the Scnn1b gene, specifically in airway epithelia (Scnn1b-Tg). The expression levels of ANO1 were examined by mRNA and protein content, and the channel protein distribution between ciliated and non-ciliated epithelial cells was analyzed. Moreover, Ussing chamber experiments were conducted to compare Ca2+-dependent Cl- secretion between wild-type animals and the two mouse models. Our results demonstrate that CFTR and ANO1 channels were co-expressed with ENaC in non-ciliated cells of mouse tracheal and bronchial epithelia. Ciliated cells did not express these proteins. Despite co-localization of CFTR and ANO1 in the same cell type, cells in cftr-/- mice displayed no altered expression of ANO1. Similarly, ANO1 expression was unaffected by βENaC overexpression in the Scnn1b-Tg line. These results suggest that the CF-related environment in the two mouse models did not induce ANO1 overexpression as a compensatory system.

PMID: 29860639 [PubMed - as supplied by publisher]

Designing trials for new cystic fibrosis modulators.

Lancet Respir Med. 2018 May 30;:

Authors: Cunningham S, McColley SA

PMID: 29859920 [PubMed - as supplied by publisher]