Efficacy measures for clinical trials: A review series.

J Cyst Fibros. 2016 07;15(4):415

Authors: Flume PA, VanDevanter DR

PMID: 27316664 [PubMed - indexed for MEDLINE]

Beyond the lungs: The new GI frontier.

J Cyst Fibros. 2016 07;15(4):409-10

Authors: Freedman SD, Schwarzenberg SJ

PMID: 27264963 [PubMed - indexed for MEDLINE]

Aminoglycosides: old friend…new foe?

J Cyst Fibros. 2016 07;15(4):411-2

Authors: Simmonds NJ, Thomson AH

PMID: 27264962 [PubMed - indexed for MEDLINE]

Bilateral vision loss due to Leber's hereditary optic neuropathy after long-term alcohol, nicotine and drug abuse.

Doc Ophthalmol. 2018 04;136(2):145-153

Authors: Maass J, Matthé E

Abstract
PURPOSE: Leber's hereditary optic neuropathy is relatively rare, and no clinical pathognomonic signs exist. We present a rare case of bilateral vision loss of a patient with multiple drug abuse in the history.
OBSERVATION: A 31-year-old man presented with a history of progressive, decreased vision in both eyes for 6 month. On examination, his visual acuity was hand motion in both eyes. Funduscopy demonstrated a temporal pallor of the optic disc. Goldmann visual field perimetry showed a crescent visual field in the right eye and a circular decrease to less than 50 ° in the left eye. Electroretinogram showed a scotopic b-wave amplitude reduction. Optical coherence tomographies, Heidelberg Retina tomography, visual evoked potentials, and magnetic resonance imaging with contrast as well as blood tests were normal. The patient reported to consume various kinds of drugs as well as recreational drug use and alcohol consumption since he was 16 years old. We started a hemodilution therapy, believing the patient suffered from a bilateral, toxic optic neuropathy due to his lifestyle. Laboratory results later on showed Leber's hereditary optic neuropathy.
CONCLUSION AND IMPORTANCE: Leber's hereditary optic neuropathy is a rare disease without a typical, pathognomonic presentation. Even though the patient gave good reasons for a toxic optic neuropathy, one should never stop to test for other diseases.

PMID: 29372350 [PubMed - indexed for MEDLINE]

Matchmaker Exchange.

Curr Protoc Hum Genet. 2017 Oct 18;95:9.31.1-9.31.15

Authors: Sobreira NLM, Arachchi H, Buske OJ, Chong JX, Hutton B, Foreman J, Schiettecatte F, Groza T, Jacobsen JOB, Haendel MA, Boycott KM, Hamosh A, Rehm HL, Matchmaker Exchange Consortium

Abstract
In well over half of the individuals with rare disease who undergo clinical or research next-generation sequencing, the responsible gene cannot be determined. Some reasons for this relatively low yield include unappreciated phenotypic heterogeneity; locus heterogeneity; somatic and germline mosaicism; variants of uncertain functional significance; technically inaccessible areas of the genome; incorrect mode of inheritance investigated; and inadequate communication between clinicians and basic scientists with knowledge of particular genes, proteins, or biological systems. To facilitate such communication and improve the search for patients or model organisms with similar phenotypes and variants in specific candidate genes, we have developed the Matchmaker Exchange (MME). MME was created to establish a federated network connecting databases of genomic and phenotypic data using a common application programming interface (API). To date, seven databases can exchange data using the API (GeneMatcher, PhenomeCentral, DECIPHER, MyGene2, matchbox, Australian Genomics Health Alliance Patient Archive, and Monarch Initiative; the latter included for model organism matching). This article guides usage of the MME for rare disease gene discovery. © 2017 by John Wiley & Sons, Inc.

PMID: 29044468 [PubMed - indexed for MEDLINE]

The Rare Bone Disease Working Group: report from the 2016 American Society for Bone and Mineral Research Annual Meeting.

Bone. 2017 Sep;102:80-84

Authors: Drake MT, Collins MT, Hsiao EC

Abstract
A working group on rare bone diseases was held in Atlanta, Georgia as part of the 2016 annual meeting of the American Society for Bone and Mineral Research. The meeting was organized by Matthew Drake. Given recent advances in our understanding of fibrodysplasia ossificans progressiva (FOP), the initial portion of the program was devoted to basic, translational, and clinical aspects of FOP. The remainder of the program was divided into updates on an array of rare bone diseases as detailed below. In total, there were more than 120 scientists from academia and industry in attendance.

PMID: 28115283 [PubMed - indexed for MEDLINE]

Genomic approaches to diagnose rare bone disorders.

Bone. 2017 Sep;102:5-14

Authors: Falardeau F, Camurri MV, Campeau PM

Abstract
Skeletal dysplasias are Mendelian disorders with a prevalence of approximatively 1 in every 5000 individuals and can usually be diagnosed based on clinical and radiological findings. However, given that some diseases can be caused by several different genes, and that some genes can cause a variety of different phenotypes, achieving a molecular diagnosis can be challenging. We review here different approaches, from single gene sequencing to genomic approaches using next-generation sequencing, to reach a molecular diagnosis for skeletal dysplasias. We will further describe the overall advantages and limitations of first, second and third-generation sequencing, including single gene sequencing, whole-exome and genome sequencing (WES and WGS), multiple gene panel sequencing and single molecule sequencing. We also provide a brief overview of potential future applications of emerging technologies.

PMID: 27474525 [PubMed - indexed for MEDLINE]

On the plausibility of socioeconomic mortality estimates derived from linked data: a demographic approach.

Popul Health Metr. 2017 Jul 14;15(1):26

Authors: Lerch M, Spoerri A, Jasilionis D, Viciana Fernandèz F

Abstract
BACKGROUND: Reliable estimates of mortality according to socioeconomic status play a crucial role in informing the policy debate about social inequality, social cohesion, and exclusion as well as about the reform of pension systems. Linked mortality data have become a gold standard for monitoring socioeconomic differentials in survival. Several approaches have been proposed to assess the quality of the linkage, in order to avoid the misclassification of deaths according to socioeconomic status. However, the plausibility of mortality estimates has never been scrutinized from a demographic perspective, and the potential problems with the quality of the data on the at-risk populations have been overlooked.
METHODS: Using indirect demographic estimation (i.e., the synthetic extinct generation method), we analyze the plausibility of old-age mortality estimates according to educational attainment in four European data contexts with different quality issues: deterministic and probabilistic linkage of deaths, as well as differences in the methodology of the collection of educational data. We evaluate whether the at-risk population according to educational attainment is misclassified and/or misestimated, correct these biases, and estimate the education-specific linkage rates of deaths.
RESULTS: The results confirm a good linkage of death records within different educational strata, even when probabilistic matching is used. The main biases in mortality estimates concern the classification and estimation of the person-years of exposure according to educational attainment. Changes in the census questions about educational attainment led to inconsistent information over time, which misclassified the at-risk population. Sample censuses also misestimated the at-risk populations according to educational attainment.
CONCLUSION: The synthetic extinct generation method can be recommended for quality assessments of linked data because it is capable not only of quantifying linkage precision, but also of tracking problems in the population data. Rather than focusing only on the quality of the linkage, more attention should be directed towards the quality of the self-reported socioeconomic status at censuses, as well as towards the accurate estimation of the at-risk populations.

PMID: 28705165 [PubMed - indexed for MEDLINE]

Pharmacogenetics of anticancer drug sensitivity and toxicity in colorectal cancer.

Curr Pharm Des. 2018 Jul 27;:

Authors: Moradi-Marjaneh R, Khazaei M, Seifi S, Hassanian SM, Ferns GA, Avan A

Abstract
Inter-individual differences in drug response are an important cause of failure in anticancer treatment and adverse drug events in cancer patients. Gene polymorphisms related to these outcomes have been investigated in an effort to find new genetic biomarkers to predict toxicity and response to anticancer drugs. Evaluating the value single nucleotide polymorphisms (SNPs) in the genes involved in transportation, activation and metabolism of anticancer drugs provides a promising approach to select the appropriate therapeutic regimes with at least adverse reactions. This review summarizes the current knowledge about the relationship between of SNPs involved in the transportation, activation and metabolism of anticancer drugs and treatment outcomes in colorectal cancer (CRC) patients.

PMID: 30051785 [PubMed - as supplied by publisher]

Impact of incorporating ABCB1 and CYP4F2 polymorphisms in a pharmacogenetics-guided warfarin dosing algorithm for the Brazilian population.

Eur J Clin Pharmacol. 2018 Jul 26;:

Authors: Tavares LC, Duarte NE, Marcatto LR, Soares RAG, Krieger JE, Pereira AC, Santos PCJL

Abstract
PURPOSE: Interpatient variation of warfarin dose requirements may be explained by genetic variations and general and clinical factors. In this scenario, diverse population-calibrated dosing algorithms, which incorporate the main warfarin dosing influencers, have been widely proposed for predicting supposed warfarin maintenance dose, in order to prevent and reduce adverse events. The aim of the present study was to evaluate the impact of the inclusion of ABCB1 c.3435C>T and CYP4F2 c.1297G>A polymorphisms as additional covariates in a previously developed pharmacogenetic-based warfarin dosing algorithm calibrated for the Brazilian population.
METHODS: Two independent cohorts of patients treated with warfarin (n = 832 and n = 133) were included for derivation and replication of the algorithm, respectively. Genotyping of ABCB1 c.3435C>T and CYP4F2 c.1297G>A polymorphisms was performed by polymerase chain reaction followed by melting curve analysis and TaqMan® assay, respectively. A multiple linear regression was performed for the warfarin stable doses as a dependent variable, considering clinical, general, and genetic data as covariates.
RESULTS: The inclusion of ABCB1 and CYP4F2 polymorphisms was able to improve the algorithm's coefficient of determination (R2) by 2.6%. In addition, the partial determination coefficients of these variants revealed that they explained 3.6% of the warfarin dose variability. We also observed a marginal improvement of the linear correlation between observed and predicted doses (from 59.7 to 61.4%).
CONCLUSION: Although our study indicates that the contribution of the combined ABCB1 and CYP4F2 genotypes in explaining the overall variability in warfarin dose is not very large, we demonstrated that these pharmacogenomic data are statistically significant. However, the clinical relevance and cost-effective impact of incorporating additional variants in warfarin dosing algorithms should be carefully evaluated.

PMID: 30051215 [PubMed - as supplied by publisher]

The CYP1A2 -163C>A polymorphism does not alter the effects of caffeine on basketball performance.

PLoS One. 2018;13(4):e0195943

Authors: Puente C, Abián-Vicén J, Del Coso J, Lara B, Salinero JJ

Abstract
PURPOSE: The aim of this investigation was to analyze the influence of the genetic variations of the -163C>A polymorphism of the CYP1A2 gene on the ergogenic effects of caffeine in elite basketball players.
METHODS: Nineteen elite basketball players (10 men and 9 women) ingested 3 mg⋅kg-1 of caffeine or a placebo 60 min before performing 10 repetitions of the following series: the Abalakov jump test followed by the Change-of-Direction and Acceleration Test (CODAT). The players then competed in a 20-min simulated basketball game. Self-perceived performance and side effects were recorded by questionnaires after the trials. The effects of caffeine on basketball performance were established according to players' CYP1A2 genotype (rs762551): AA homozygotes (n = 10) and C-allele carriers (n = 9).
RESULTS: In the 10 repetitions, caffeine increased Abalakov jump height by a mean of 2.9±3.6% in AA homozygotes (p = 0.03) while this effect did not reach statistical significance for C-allele carriers (2.3 ± 6.8%; p = 0.33). Caffeine did not affect sprint time in the CODAT test in either genotype group but it increased the number of impacts performed during the simulated game in both AA homozygotes (4.1 ± 5.3%; p = 0.02) and C-allele carriers (3.3 ± 3.2%; p = 0.01). During the 24 h following the test, AA homozygotes tended to experience increased insomnia with caffeine while C-allele carriers did not present this effect. The remaining variables were unaffected by the genotype.
CONCLUSION: The CYP1A2 -163C>A polymorphism minimally altered the ergogenicity derived from the consumption of a moderate dose of caffeine in elite basketball players.

PMID: 29668752 [PubMed - indexed for MEDLINE]

Individualizing Treatment Approaches for Epileptic Patients with Glucose Transporter Type1 (GLUT-1) Deficiency.

Int J Mol Sci. 2018 Jan 05;19(1):

Authors: Daci A, Bozalija A, Jashari F, Krasniqi S

Abstract
Monogenic and polygenic mutations are important contributors in patients suffering from epilepsy, including metabolic epilepsies which are inborn errors of metabolism with a good respond to specific dietetic treatments. Heterozygous variation in solute carrier family 2, facilitated glucose transporter member 1 (SLC2A1) and mutations of the GLUT1/SLC2A2 gene results in the failure of glucose transport, which is related with a glucose type-1 transporter (GLUT1) deficiency syndrome (GLUT1DS). GLUT1 deficiency syndrome is a treatable disorder of glucose transport into the brain caused by a variety of mutations in the SLC2A1 gene which are the cause of different neurological disorders also with different types of epilepsy and related clinical phenotypes. Since patients continue to experience seizures due to a pharmacoresistance, an early clinical diagnosis associated with specific genetic testing in SLC2A1 pathogenic variants in clinical phenotypes could predict pure drug response and might improve safety and efficacy of treatment with the initiation of an alternative energy source including ketogenic or analog diets in such patients providing individualized strategy approaches.

PMID: 29303961 [PubMed - indexed for MEDLINE]

Characterization of the B-cell receptor repertoires in peanut allergic subjects undergoing oral immunotherapy.

J Hum Genet. 2018 Feb;63(2):239-248

Authors: Kiyotani K, Mai TH, Yamaguchi R, Yew PY, Kulis M, Orgel K, Imoto S, Miyano S, Burks AW, Nakamura Y

Abstract
B-cell receptors (BCRs) play a critical role in adaptive immunity as they generate highly diverse immunoglobulin repertoires to recognize a wide variety of antigens. To better understand immune responses, it is critically important to establish a quantitative and rapid method to analyze BCR repertoire comprehensively. Here, we developed "Bcrip", a novel approach to characterize BCR repertoire by sequencing millions of BCR cDNA using next-generation sequencer. Using this method and quantitative real-time PCR, we analyzed expression levels and repertoires of BCRs in a total of 17 peanut allergic subjects' peripheral blood samples before and after receiving oral immunotherapy (OIT) or placebo. By our methods, we successfully identified all of variable (V), joining (J), and constant (C) regions, in an average of 79.1% of total reads and 99.6% of these VJC-mapped reads contained the C region corresponding to the isotypes that we aimed to analyze. In the 17 peanut allergic subjects' peripheral blood samples, we observed an oligoclonal enrichment of certain immunoglobulin heavy chain alpha (IGHA) and IGH gamma (IGHG) clones (P = 0.034 and P = 0.027, respectively) in peanut allergic subjects after OIT. This newly developed BCR sequencing and analysis method can be applied to investigate B-cell repertoires in various research areas, including food allergies as well as autoimmune and infectious diseases.

PMID: 29192240 [PubMed - indexed for MEDLINE]

Application of Coiled Coil Peptides in Liposomal Anticancer Drug Delivery Using a Zebrafish Xenograft Model.

ACS Nano. 2016 08 23;10(8):7428-35

Authors: Yang J, Shimada Y, Olsthoorn RC, Snaar-Jagalska BE, Spaink HP, Kros A

Abstract
The complementary coiled coil forming peptides E4 [(EIAALEK)4] and K4 [(KIAALKE)4] are known to trigger liposomal membrane fusion when tethered to lipid vesicles in the form of lipopeptides. In this study, we examined whether these coiled coil forming peptides can be used for drug delivery applications. First, we prepared E4 peptide modified liposomes containing the far-red fluorescent dye TO-PRO-3 iodide (E4-Lipo-TP3) and confirmed that E4-liposomes could deliver TP3 into HeLa cells expressing K4 peptide on the membrane (HeLa-K) under cell culture conditions in a selective manner. Next, we prepared doxorubicin-containing E4-liposomes (E4-Lipo-DOX) and confirmed that E4-liposomes could also deliver DOX into HeLa-K cells. Moreover, E4-Lipo-DOX showed enhanced cytotoxicity toward HeLa-K cells compared to free doxorubicin. To prove the suitability of E4/K4 coiled coil formation for in vivo drug delivery, we injected E4-Lipo-TP3 or E4-Lipo-DOX into zebrafish xenografts of HeLa-K. As a result, E4-liposomes delivered TP3 to the implanted HeLa-K cells, and E4-Lipo-DOX could suppress cancer proliferation in the xenograft when compared to nontargeted conditions (i.e., zebrafish xenograft with free DOX injection). These data demonstrate that coiled coil formation enables drug selectivity and efficacy in vivo. It is envisaged that these findings are a step forward toward biorthogonal targeting systems as a tool for clinical drug delivery.

PMID: 27504667 [PubMed - indexed for MEDLINE]

A novel CYCS mutation in the α-helix of the CYCS C-terminal domain causes non-syndromic thrombocytopenia.

Clin Genet. 2018 Jul 26;:

Authors: Uchiyama Y, Yanagisawa K, Kunishima S, Shiina M, Ogawa Y, Nakashima M, Hirato J, Imagawa E, Fujita A, Hamanaka K, Miyatake S, Mitsuhashi S, Takata A, Miyake N, Ogata K, Handa H, Matsumoto N, Mizuguchi T

Abstract
We report a patient with thrombocytopenia from a Japanese family with hemophilia A spanning four generations. Various etiologies of thrombocytopenia, including genetic, immunological, and hematopoietic abnormalities, determine the prognosis for this disease. In this study, we identified a novel heterozygous mutation in a gene encoding cytochrome c, somatic (CYCS, MIM123970) using whole exome sequencing. This variant (c.301_303del:p.Lys101del) is located in the α-helix of the cytochrome c (CYCS) C-terminal domain. In silico structural analysis suggested that this mutation results in protein folding instability. CYCS is one of the key factors regulating the intrinsic apoptotic pathway and the mitochondrial respiratory chain. Using the yeast model system, we clearly demonstrated that this one amino acid deletion (in-frame) resulted in significantly reduced cytochrome c protein expression and functional defects in the mitochondrial respiratory chain, indicating that the loss of function of cytochrome c underlies thrombocytopenia. The clinical features of known CYCS variants have been reported to be confined to mild or asymptomatic thrombocytopenia, as was observed for the patient in our study. This study clearly demonstrates that thrombocytopenia can result from CYCS loss-of-function variants. This article is protected by copyright. All rights reserved.

PMID: 30051457 [PubMed - as supplied by publisher]

Genetic analysis of LRRK2 in Parkinson's disease in Han Chinese population.

Neurobiol Aging. 2018 Jul 04;:

Authors: Zhang JR, Jin H, Li K, Mao CJ, Yang YP, Wang F, Gu CC, Zhang HJ, Chen J, Liu CF

Abstract
Mutations in Leucine-rich repeat kinase 2 (LRRK2) are recognized as the most frequent genetic factors contributing to Parkinson's disease (PD). The aim of our study was to explore LRRK2 variants in PD patients within the mainland Han Chinese population. The whole coding regions of LRRK2 from 296 PD patients were sequenced by targeted regions sequencing and exome sequencing. Eighteen rare variants were identified in 27 PD patients, and 13 of them (M100T, L153W, A459S, S722N, R792K, C925Y, R981K, S1007T, V1447M, R1677S, N2308D, N2313S, and S2350I) were firstly reported in PD. We also tried to explore the genotype-phenotype associations of LRRK2 variants in our data and found that PD with common and rare LRRK2 variants was more likely to have motor fluctuation and nonmotor symptoms. The identification of novel variants in LRRK2 suggests that this gene plays an important role in the pathogenesis and phenotype of PD in Han Chinese population, and our data also rang the alarm bell-more attention should be paid to the whole coding regions of LRRK2.

PMID: 30049590 [PubMed - as supplied by publisher]

Phenotypic expansion and progression of SPATA7-associated retinitis pigmentosa.

Doc Ophthalmol. 2018 04;136(2):125-133

Authors: Sengillo JD, Lee W, Bilancia CG, Jobanputra V, Tsang SH

Abstract
PURPOSE: To report an unusual phenotype of retinitis pigmentosa (RP) caused by compound heterozygous mutations in SPATA7, and describe the progression over a two year follow-up period.
METHODS: Retrospective case study.
RESULTS: A 63-year-old man with a long history of nyctalopia, progressive visual field constriction, and a recent subacute decrease in visual acuity of the left eye presented for evaluation of a suspected retinal degeneration. Multimodal retinal imaging and functional assessment with full-field electroretinogram suggested a severe rod-cone dysfunction masquerading as a choroideremia-like phenotype. A vitreous opacity was found to explain recent changes in the left eye and a 25-guage vitrectomy and membrane peel was performed, yielding no change in visual acuity. Whole-exome sequencing revealed compound heterozygous variants in SPATA7 that were predicted to be pathogenic.
CONCLUSIONS: Compound heterozygous c.1100A > G, p.(Y367C) and c.1102_1103delCT, p.(L368Efs*4) variants in SPATA7 manifest as an unusual RP phenotype in this case, showing extensive choroidal sclerosis and retinal pigment epithelium (RPE) atrophy with evidence of progression over two years on multimodal imaging.

PMID: 29411205 [PubMed - indexed for MEDLINE]

Analysis and Annotation of Whole-Genome or Whole-Exome Sequencing Derived Variants for Clinical Diagnosis.

Curr Protoc Hum Genet. 2017 Oct 18;95:9.24.1-9.24.28

Authors: Worthey EA

Abstract
Over the last 10 years, next-generation sequencing (NGS) has transformed genomic research through substantial advances in technology and reduction in the cost of sequencing, and also in the systems required for analysis of these large volumes of data. This technology is now being used as a standard molecular diagnostic test in some clinical settings. The advances in sequencing have come so rapidly that the major bottleneck in identification of causal variants is no longer the sequencing or analysis (given access to appropriate tools), but rather clinical interpretation. Interpretation of genetic findings in a complex and ever changing clinical setting is scarcely a new challenge, but the task is increasingly complex in clinical genome-wide sequencing given the dramatic increase in dataset size and complexity. This increase requires application of appropriate interpretation tools, as well as development and application of appropriate methodologies and standard procedures. This unit provides an overview of these items. Specific challenges related to implementation of genome-wide sequencing in a clinical setting are discussed. © 2017 by John Wiley & Sons, Inc.

PMID: 29044471 [PubMed - indexed for MEDLINE]

The clinical implications of molecular monitoring and analyses of inherited retinal diseases.

Expert Rev Mol Diagn. 2017 Nov;17(11):1009-1021

Authors: Chacón-Camacho OF, García-Montaño LA, Zenteno JC

Abstract
INTRODUCTION: Retinal dystrophies (RDs) are the most common cause of inherited blindness and one of the most genetically heterogeneous human diseases. RDs arise from mutations in genes involved in development and function of photoreceptors or other retinal cells. Identification of the genetic defect causing RD allows accurate diagnosis, prognosis, and counseling in affected patients. Molecular diagnosis is a tremendous challenge in RDs due to their locus and phenotypic heterogeneity. As conventional DNA sequencing approaches are impractical in such situation, Next Generation Sequencing (NGS)-based protocols are needed to identify RD-causing mutations. This is being accomplished by sequencing RD gene panels or by whole exome or whole genome sequencing approaches. Areas covered: This review discusses the current strategies for molecular diagnosis in RDs including their advantages and limitations, as well as their utility in diagnosis of non-syndromic versus syndromic RDs. Results of ongoing gene therapy protocols in RDs are also presented. Expert commentary: Molecular diagnosis in RD improves the medical management of patients. Importantly, demand for molecular screening for RDs is greatly expanding not only as a result of increasing development and availability of NGS technologies, but also of the growing number of gene-based clinical trials offering a potential treatment to patients.

PMID: 28945154 [PubMed - indexed for MEDLINE]

Whole-Exome Sequencing Reveals Increased Burden of Rare Functional and Disruptive Variants in Candidate Risk Genes in Individuals With Persistent Attention-Deficit/Hyperactivity Disorder.

J Am Acad Child Adolesc Psychiatry. 2016 06;55(6):521-3

Authors: Demontis D, Lescai F, Børglum A, Glerup S, Østergaard SD, Mors O, Li Q, Liang J, Jiang H, Li Y, Wang J, Lesch KP, Reif A, Buitelaar JK, Franke B

PMID: 27238071 [PubMed - indexed for MEDLINE]