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Repurposing the NRF2 Activator Dimethyl Fumarate as Therapy Against Synucleinopathy in Parkinson's Disease.

Antioxid Redox Signal. 2016 Jul 10;25(2):61-77

Authors: Lastres-Becker I, García-Yagüe AJ, Scannevin RH, Casarejos MJ, Kügler S, Rábano A, Cuadrado A

Abstract
AIMS: This preclinical study was aimed at determining whether pharmacological targeting of transcription factor NRF2, a master controller of many homeostatic genes, might provide a disease-modifying therapy in the animal model of Parkinson's disease (PD) that best reproduces the main hallmark of this pathology, that is, α-synucleinopathy, and associated events, including nigral dopaminergic cell death, oxidative stress, and neuroinflammation.
RESULTS: Pharmacological activation of NRF2 was achieved at the basal ganglia by repurposing dimethyl fumarate (DMF), a drug already in use for the treatment of multiple sclerosis. Daily oral gavage of DMF protected nigral dopaminergic neurons against α-SYN toxicity and decreased astrocytosis and microgliosis after 1, 3, and 8 weeks from stereotaxic delivery to the ventral midbrain of recombinant adeno-associated viral vector expressing human α-synuclein. This protective effect was not observed in Nrf2-knockout mice. In vitro studies indicated that this neuroprotective effect was correlated with altered regulation of autophagy markers SQTSM1/p62 and LC3 in MN9D, BV2, and IMA 2.1 and with a shift in microglial dynamics toward a less pro-inflammatory and a more wound-healing phenotype. In postmortem samples of PD patients, the cytoprotective proteins associated with NRF2 expression, NQO1 and p62, were partly sequestered in Lewy bodies, suggesting impaired neuroprotective capacity of the NRF2 signature.
INNOVATION: These experiments provide a compelling rationale for targeting NRF2 with DMF as a therapeutic strategy to reinforce endogenous brain defense mechanisms against PD-associated synucleinopathy.
CONCLUSION: DMF is ready for clinical validation in PD. Antioxid. Redox Signal. 25, 61-77.

PMID: 27009601 [PubMed - indexed for MEDLINE]

Unmet needs in Schizophrenia.

CNS Neurol Disord Drug Targets. 2017 Aug 03;:

Authors: Pompili M, Meltzer HY

Abstract
The objectives of this article are to describe current trends in the treatment of schizophrenia and the most interesting new approaches to optimizing outcome and fostering the development of new schizophrenia treatments.
RESULTS: Increasing utilization of diverse types of atypical antipsychotic drugs (AAPDs), e.g. clozapine-type serotonin (5-HT)2A and weak dopamine (DA) D2 antagonist, amisulpride, a D2/D3/5-HT7 antagonist, and cariprazine, a D3 partial agonist with additional neurotransmitter targets, is occurring as their advantages in efficacy, especially for cognitive impairment and mood symptoms, and side effects is becoming appreciated. Typical APDs, e.g. haloperidol, are diminishing in favor because of their EPS, especially, tardive dyskinesia (T D) and appreciation that reducing D2 receptor stimulation is not the only means to treat psychosis. Some of the mechanisms inherent in various AAPDs, e.g. 5-HT2A inverse agonism, and D3 receptor partial agonism, are now recognized as effective treatments for psychosis. A new focus on treating the cognitive impairment associated with schizophrenia (CIAS) has emerged via mechanisms such as stimulation of acetyldraline receptor with muscarinic and nicotinic receptor agonists, but demonstrating their efficacy in trials is proving elusive. Pharmacogenetic strategies which may lead to personalized treatment of schizophrenia is emerging but has not yet succeeded in being widely reimbursable. Transcranial stimulation and cognitive enhancement therapy are more common but more evidence for their efficacy is needed.
CONCLUSION: The heterogeneity of the pathophysiology of the various domains of schizophrenia require a diversity of treatments that are best met by the expert use of AAPDs at the current time. Pharmacogenetic efforts are consistent with new evidence that multiple genes are involved in the risk for schizophrenia and the effectiveness of AAPDs.

PMID: 28782490 [PubMed - as supplied by publisher]

In this issue of Pharmacogenomics.

Pharmacogenomics. 2017 Aug;18(12):1117

Authors: Jones S

PMID: 28782463 [PubMed - in process]

Severe sunitinib-induced myelosuppression in a patient with a CYP 3A4 polymorphism.

J Oncol Pharm Pract. 2017 Jan 01;:1078155217724863

Authors: Patel ND, Chakrabory K, Messmer G, Krishnan K, Bossaer JB

Abstract
Sunitinib, an oral vascular endothelial growth factor receptor, is a first-line option for metastatic renal cell carcinoma and widely used in clinical practice. Despite the proven benefit of sunitnib in metastatic renal cell carcinoma, patients may suffer from a variety of adverse events including hypertension, fatigue, hypothyroidism, hand-foot skin reactions, rash, depigmentation, and myelosuppression. Myelosuppression is usually mild, transient and resolves during the two weeks at the end of each cycle where no drug is taken. We present a case of severe and early grade 3 neutropenia and thrombocytopenia occurring two weeks into a six-week cycle. Because of the extreme nature of the toxicity, CYP 3A4 polymorphisms were explored. The patient was found to be heterozygous for CYP 3A4*22, at least partially explaining the early-onset and severity of myelosuppression. This pharmacogenetics information resulted in a rechallenge of dose-reduced sunitinib, which was well tolerated by the patient. The current state of pharmacogenomics concerning sunitinb is also presented, and the need for greater research in this area is highlighted.

PMID: 28782406 [PubMed - as supplied by publisher]

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Free 25(OH)D concentrations are associated with atopy and lung function in children with asthma.

Ann Allergy Asthma Immunol. 2017 Jul;119(1):37-41

Authors: Pollard SL, Lima JJ, Mougey E, Romero K, Tarazona-Meza C, Tomaino K, Guzmán GM, Hansel NN, Checkley W, Genetics of Asthma Susceptibility to Pollution (GASP) Study Investigators

Abstract
BACKGROUND: Evidence suggests free mono-hydroxyvitamin D (25[OH]D) concentrations are more strongly linked to certain outcomes than total concentrations; however, no studies have examined the relation between free 25(OH)D and respiratory or allergic disease.
OBJECTIVE: To examine associations between total and free 25(OH)D concentrations and asthma outcomes.
METHODS: We quantified total and free 25(OH)D concentrations in 137 Peruvian children with asthma and 152 children without asthma and examined associations with asthma outcomes.
RESULTS: Mean age ± SD was 13 ± 2.5 years, and 50.2% were boys. Mean total and measured free 25(OH)D concentrations were 29 ± 9.5 ng/mL and 5.0 ± 1.3 pg/mL, respectively. Lower free but not total 25(OH)D concentrations were significantly associated with atopy in all children (total, odds ratio [OR] 1.3 per 10-ng/mL decrease, 95% confidence interval [CI] 0.95-1.7, P = .12; vs free, OR 1.3 per 1-pg/mL decrease, 95% CI 1.0-1.6, P = .02) and children with asthma (total, OR 1.1 per 10-ng/mL decrease, 95% CI 0.75-1.7, P = .57; vs free, OR 1.6 per 1-pg/mL decrease, 95% CI 1.0-2.5, P = .04). Free but not total 25(OH)D levels were significantly associated with pre-bronchodilator forced expiratory volume in 1 second (total, 0.11 L, -0.12 to 0.34, P = .34; vs free, 0.20 L, 0.021-0.39, P = .03) and forced vital capacity (total, 0.13 L, -0.12 to 0.37, P = .31; vs free, 0.22 L, 0.026-0.42, P = .03) Z-scores in children with asthma.
CONCLUSION: Atopy, forced expiratory volume in 1 second, and forced vital capacity were more strongly linked to free than to total 25(OH)D concentrations, suggesting the free form might be more relevant in modulating allergic disease risk and pulmonary function in children with asthma.

PMID: 28533007 [PubMed - indexed for MEDLINE]

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Individualized Medicine in Gastroenterology and Hepatology.

Mayo Clin Proc. 2017 May;92(5):810-825

Authors: Stephens MC, Boardman LA, Lazaridis KN

Abstract
After the completion of the Human Genome Project, there has been an acceleration in methodologies on sequencing nucleic acids (DNA and RNA) at a high precision and with ever-decreasing turnaround time and cost. Collectively, these approaches are termed next-generation sequencing and are already affecting the transformation of medical practice. In this symposium article, we highlight the current knowledge of the genetics of selected gastrointestinal tract and liver diseases, namely, inflammatory bowel disease, hereditary cholestatic liver disease, and familial colon cancer syndromes. In addition, we provide a stepwise approach to use next-generation sequencing methodologies for clinical practice with the goal to improve the diagnosis as well as management of and/or therapy of the chosen digestive diseases. This early experience of applying next-generation sequencing in the practice of gastroenterology and hepatology will delineate future best practices in the field, ultimately for the benefit of our patients.

PMID: 28473040 [PubMed - indexed for MEDLINE]

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Farnesoid X receptor ablation sensitizes mice to hepatitis b virus X protein-induced hepatocarcinogenesis.

Hepatology. 2017 Mar;65(3):893-906

Authors: Niu Y, Xu M, Slagle BL, Huang H, Li S, Guo GL, Shi G, Qin W, Xie W

Abstract
Chronic hepatitis B virus infection is a major risk factor for hepatocellular carcinoma (HCC). Hepatitis B virus X protein (HBx) is a hepatitis B virus protein that has multiple cellular functions, but its role in HCC pathogenesis has been controversial. Farnesoid X receptor (FXR) is a nuclear receptor with activities in anti-inflammation and inhibition of hepatocarcinogenesis. However, whether or how FXR can impact hepatitis B virus/HBx-induced hepatocarcinogenesis remains unclear. In this study, we showed that HBx can interact with FXR and function as a coactivator of FXR. Expression of HBx in vivo enhanced FXR-responsive gene regulation. HBx also increased the transcriptional activity of FXR in a luciferase reporter gene assay. The HBx-FXR interaction was confirmed by coimmunoprecipitation and glutathione S-transferase pull-down assays, and the FXR activation function 1 domain was mapped to bind to the third α helix in the C terminus of HBx. We also found that the C-terminally truncated variants of HBx, which were found in clinical HCC, were not effective at transactivating FXR. Interestingly, recruitment of the full-length HBx, but not the C-terminally truncated HBx, enhanced the binding of FXR to its response element. In vivo, FXR ablation markedly sensitized mice to HBx-induced hepatocarcinogenesis.
CONCLUSIONS: We propose that transactivation of FXR by full-length HBx may represent a protective mechanism to inhibit HCC and that this inhibition may be compromised upon the appearance of C-terminally truncated HBx or when the expression and/or activity of FXR is decreased. (Hepatology 2017;65:893-906).

PMID: 28102638 [PubMed - indexed for MEDLINE]

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Overexpression of RACK1 Promotes Metastasis by Enhancing Epithelial-Mesenchymal Transition and Predicts Poor Prognosis in Human Glioma.

Int J Environ Res Public Health. 2016 Oct 18;13(10):

Authors: Lv QL, Huang YT, Wang GH, Liu YL, Huang J, Qu Q, Sun B, Hu L, Cheng L, Chen SH, Zhou HH

Abstract
Emerging studies show that dysregulation of the receptor of activated protein kinase C1 (RACK1) plays a crucial role in tumorigenesis and progression of various cancers. However, the biological function and underlying mechanism of RACK1 in glioma remains poorly defined. Here, we found that RACK1 was significantly up-regulated in glioma tissues compared with normal brain tissues, being closely related to clinical stage of glioma both in mRNA and protein levels. Moreover, Kaplan-Meier analysis demonstrated that patients with high RACK1 expression had a poor prognosis (p = 0.0062, HR = 1.898, 95% CI: 1.225-3.203). In vitro functional assays indicated that silencing of RACK1 could dramatically promote apoptosis and inhibit cell proliferation, migration, and invasion of glioma cells. More importantly, knockdown of RACK1 led to a vast accumulation of cells in G0/G1 phase and their reduced proportions at the S phase by suppressing the expression of G1/S transition key regulators Cyclin D1 and CDK6. Additionally, this forced down-regulation of RACK1 significantly suppressed migration and invasion via inhibiting the epithelial-mesenchymal transition (EMT) markers, such as MMP2, MMP9, ZEB1, N-Cadherin, and Integrin-β1. Collectively, our study revealed that RACK1 might act as a valuable prognostic biomarker and potential therapeutic target for glioma.

PMID: 27763568 [PubMed - indexed for MEDLINE]

Intra-session and inter-session variability of nitric oxide pulmonary diffusing capacity in adults with cystic fibrosis.

Respir Physiol Neurobiol. 2017 Aug 03;:

Authors: Radtke T, Benden C, Maggi-Beba M, Kriemler S, van der Lee I, Dressel H

Abstract
We evaluated the intra-session and inter-session variability of the diffusing capacity of nitric oxide (DLNO), carbon monoxide (DLCO), membrane diffusing capacity for carbon monoxide (DMCO) and pulmonary capillary blood volume (Vc) in patients with cystic fibrosis (CF). Patients performed single-breath diffusing capacity measurements during all of 3 consecutive study visits. Precision of gas diffusing parameters was quantified by within- subject standard deviation (SDws) and coefficient of variation (CV). Intra-session and inter-session reproducibility was determined by SDws*2.77. 15 clinically stable patients were included. The intra-session precision of gas diffusing parameters improved over the study visits. The inter-session SDws for DLNO, DLCO, DMCO, and Vc was 4.8, 1.3, 2.4, and 4.3, respectively. Reproducibility was 13.3, 3.8, 6.7 and 12.0mL.min(-1).mmHg(-1); CV was 4.4, 4.7, 4.4 and 5.8%, respectively. The intra-session variability of DLNO, DLCO, DMCO and Vc improves with breath-hold maneuver training in test-naïve patients with CF, indicating a learning effect. Inter-session reproducibility data are lower than those previously reported in healthy subjects.

PMID: 28782664 [PubMed - as supplied by publisher]

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What's unique about acute pancreatitis in children: risk factors, diagnosis and management.

Nat Rev Gastroenterol Hepatol. 2017 Jun;14(6):366-372

Authors: Husain SZ, Srinath AI

Abstract
Pancreatitis in children is an appreciable problem that has become increasingly prevalent. This Review covers the principles related to the definitions, epidemiology, risk factors, diagnosis and management of acute pancreatitis in children and identifies features that are unique among children. Additionally, knowledge gaps related to management principles are identified.

PMID: 28293024 [PubMed - indexed for MEDLINE]

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Biomarkers Predictive of Exacerbations in the SPIROMICS and COPDGene Cohorts.

Am J Respir Crit Care Med. 2017 Feb 15;195(4):473-481

Authors: Keene JD, Jacobson S, Kechris K, Kinney GL, Foreman MG, Doerschuk CM, Make BJ, Curtis JL, Rennard SI, Barr RG, Bleecker ER, Kanner RE, Kleerup EC, Hansel NN, Woodruff PG, Han MK, Paine R, Martinez FJ, Bowler RP, O'Neal WK, COPDGene and SPIROMICS Investigators ‡

Abstract
RATIONALE: Chronic obstructive pulmonary disease exacerbations are associated with disease progression, higher healthcare cost, and increased mortality. Published predictors of future exacerbations include previous exacerbation, airflow obstruction, poor overall health, home oxygen use, and gastroesophageal reflux.
OBJECTIVES: To determine the value of adding blood biomarkers to clinical variables to predict exacerbations.
METHODS: Subjects from the SPIROMICS (Subpopulations and Intermediate Outcomes Measures in COPD Study) (n = 1,544) and COPDGene (Genetic Epidemiology of COPD) (n = 602) cohorts had 90 plasma or serum candidate proteins measured on study entry using Myriad-RBM multiplex panels. We defined total exacerbations as subject-reported worsening in respiratory health requiring therapy with corticosteroids and/or antibiotics, and severe exacerbations as those leading to hospitalizations or emergency room visits. We assessed retrospective exacerbations during the 12 months before enrollment and then documented prospective exacerbations in each cohort. Exacerbations were modeled for biomarker associations with negative binomial regression including clinical covariates (age, sex, percent predicted FEV1, self-reported gastroesophageal reflux, St. George's Respiratory Questionnaire score, smoking status). We used the Stouffer-Liptak test to combine P values for metaanalysis.
MEASUREMENTS AND MAIN RESULTS: Between the two cohorts, 3,471 total exacerbations (1,044 severe) were reported. We identified biomarkers within each cohort that were significantly associated with a history of exacerbation and with a future exacerbation, but there was minimal replication between the cohorts. Although established clinical features were predictive of exacerbations, of the blood biomarkers only decorin and α2-macroglobulin increased predictive value for future severe exacerbations.
CONCLUSIONS: Blood biomarkers were significantly associated with the occurrence of exacerbations but were not robust between cohorts and added little to the predictive value of clinical covariates for exacerbations.

PMID: 27579823 [PubMed - indexed for MEDLINE]

Plasma cell deficiency in humans with heterozygous mutations in SEC61A1.

J Allergy Clin Immunol. 2017 Aug 03;:

Authors: Schubert D, Klein MC, Hassdenteufel S, Caballero-Oteyza A, Yang L, Proietti M, Bulashevska A, Kemming J, Kühn J, Winzer S, Rusch S, Fliegauf M, Schäffer AA, Pfeffer S, Geiger R, Cavalié A, Cao H, Yang F, Li Y, Rizzi M, Eibel H, Kobbe R, Marks AL, Peppers BP, Hostoffer RW, Puck JM, Zimmermann R, Grimbacher B

Abstract
BACKGROUND: Primary antibody deficiencies (PAD) are the most frequent primary immunodeficiencies in humans. The genetic causes for PADs are largely unknown. Sec61 translocon alpha 1 subunit (SEC61A1) is the major subunit of the Sec61 complex, which is the main polypeptide-conducting channel in the endoplasmic reticulum (ER) membrane. SEC61A1 is a target gene of XBP1s and strongly induced during plasma cell differentiation.
OBJECTIVE: Characterization of a novel genetic defect and its pathological mechanism in eleven patients from two unrelated families with PAD.
METHODS: Whole exome sequencing (WES) and targeted sequencing were conducted to identify novel genetic mutations. Functional studies were carried out ex vivo in primary cells of patients and in vitro in different cell lines to assess the effect of SEC61A1 mutations on B cell differentiation and survival.
RESULTS: We investigated two families with patients suffering from hypogammaglobulinemia, severe recurrent respiratory tract infections and normal peripheral B- and T cell subpopulations. Upon in vitro stimulation, B cells showed an intrinsic deficiency to develop into plasma cells (PCs). Genetic analysis and targeted sequencing identified novel heterozygous missense (c.254T>A, p.V85D) and nonsense (c.1325G>T, p.E381*) mutations in SEC61A1, segregating with the disease phenotype. SEC61A1-V85D was deficient in co-translational protein translocation and it disturbed the cellular calcium homeostasis in HeLa cells. Moreover, SEC61A1-V85D triggered the terminal unfolded protein response (UPR) in multiple myeloma (MM) cell lines.
CONCLUSION: We describe a monogenic defect leading to a specific plasma cell deficiency in humans, expanding our knowledge about the pathogenesis of antibody deficiencies.

PMID: 28782633 [PubMed - as supplied by publisher]

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De novo GRIN1 mutations: An emerging cause of severe early infantile encephalopathy.

Eur J Med Genet. 2017 Jun;60(6):317-320

Authors: Zehavi Y, Mandel H, Zehavi A, Rashid MA, Straussberg R, Jabur B, Shaag A, Elpeleg O, Spiegel R

Abstract
De novo GRIN1 mutations have recently been shown to cause severe intellectual disability, hypotonia, hyperkinetic and stereotyped movements, and epilepsy. We report two new cases of severe early onset encephalopathy associated with hyperkinetic and oculogyric-like movements, caused by mutations in the GRIN1 gene; both were identified by whole exome sequencing. One of the patients harbored the novel mutation p.Ser688Tyr and the other patient harbored the p.Gly827Arg mutation, which was previously reported in three patients. In silico studies suggested that the p.Se688Tyr mutation results in disruption of NMDA ligand binding and the p.Gly827Arg mutation results in disrupted gating of the ion channel. Our study highlights the importance of GRIN1 mutations in the etiology of isolated cases of early onset encephalopathy, and the valuable role of whole exome sequencing in identifying these mutations.

PMID: 28389307 [PubMed - indexed for MEDLINE]

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Wiedemann-Steiner syndrome: Novel pathogenic variant and review of literature.

Eur J Med Genet. 2017 Jun;60(6):285-288

Authors: Aggarwal A, Rodriguez-Buritica DF, Northrup H

Abstract
Wiedemann-Steiner syndrome (WDSTS) is a very rare genetic disorder characterized by short stature, intellectual disability and distinctive facial appearance. We present a five-year-old boy who was diagnosed with WDSTS based on identification of a novel de novo pathogenic variant in the KMT2A gene (OMIM: 159555) by Whole Exome Sequencing and supported by some characteristic clinical features. Genotype and phenotype of the patient is compared with the earlier reported patients in the literature, in an attempt to broaden our knowledge of this rare syndrome.

PMID: 28359930 [PubMed - indexed for MEDLINE]

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Longitudinal analysis of treatment-induced genomic alterations in gliomas.

Genome Med. 2017 Feb 02;9(1):12

Authors: Erson-Omay EZ, Henegariu O, Omay SB, Harmancı AS, Youngblood MW, Mishra-Gorur K, Li J, Özduman K, Carrión-Grant G, Clark VE, Çağlar C, Bakırcıoğlu M, Pamir MN, Tabar V, Vortmeyer AO, Bilguvar K, Yasuno K, DeAngelis LM, Baehring JM, Moliterno J, Günel M

Abstract
BACKGROUND: Glioblastoma multiforme (GBM) constitutes nearly half of all malignant brain tumors and has a median survival of 15 months. The standard treatment for these lesions includes maximal resection, radiotherapy, and chemotherapy; however, individual tumors display immense variability in their response to these approaches. Genomic techniques such as whole-exome sequencing (WES) provide an opportunity to understand the molecular basis of this variability.
METHODS: Here, we report WES-guided treatment of a patient with a primary GBM and two subsequent recurrences, demonstrating the dynamic nature of treatment-induced molecular changes and their implications for clinical decision-making. We also analyze the Yale-Glioma cohort, composed of 110 whole exome- or whole genome-sequenced tumor-normal pairs, to assess the frequency of genomic events found in the presented case.
RESULTS: Our longitudinal analysis revealed how the genomic profile evolved under the pressure of therapy. Specifically targeted approaches eradicated treatment-sensitive clones while enriching for resistant ones, generated due to chromothripsis, which we show to be a frequent event in GBMs based on our extended analysis of 110 gliomas in the Yale-Glioma cohort. Despite chromothripsis and the later acquired mismatch-repair deficiency, genomics-guided personalized treatment extended survival to over 5 years. Interestingly, the case displayed a favorable response to immune checkpoint inhibition after acquiring mismatch repair deficiency.
CONCLUSIONS: Our study demonstrates the importance of longitudinal genomic profiling to adjust to the dynamic nature of treatment-induced molecular changes to improve the outcomes of precision therapies.

PMID: 28153049 [PubMed - indexed for MEDLINE]

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Integrative Variation Analysis Reveals that a Complex Genotype May Specify Phenotype in Siblings with Syndromic Autism Spectrum Disorder.

PLoS One. 2017;12(1):e0170386

Authors: Reis VN, Kitajima JP, Tahira AC, Feio-Dos-Santos AC, Fock RA, Lisboa BC, Simões SN, Krepischi AC, Rosenberg C, Lourenço NC, Passos-Bueno MR, Brentani H

Abstract
It has been proposed that copy number variations (CNVs) are associated with increased risk of autism spectrum disorder (ASD) and, in conjunction with other genetic changes, contribute to the heterogeneity of ASD phenotypes. Array comparative genomic hybridization (aCGH) and exome sequencing, together with systems genetics and network analyses, are being used as tools for the study of complex disorders of unknown etiology, especially those characterized by significant genetic and phenotypic heterogeneity. Therefore, to characterize the complex genotype-phenotype relationship, we performed aCGH and sequenced the exomes of two affected siblings with ASD symptoms, dysmorphic features, and intellectual disability, searching for de novo CNVs, as well as for de novo and rare inherited point variations-single nucleotide variants (SNVs) or small insertions and deletions (indels)-with probable functional impacts. With aCGH, we identified, in both siblings, a duplication in the 4p16.3 region and a deletion at 8p23.3, inherited by a paternal balanced translocation, t(4, 8) (p16; p23). Exome variant analysis found a total of 316 variants, of which 102 were shared by both siblings, 128 were in the male sibling exome data, and 86 were in the female exome data. Our integrative network analysis showed that the siblings' shared translocation could explain their similar syndromic phenotype, including overgrowth, macrocephaly, and intellectual disability. However, exome data aggregate genes to those already connected from their translocation, which are important to the robustness of the network and contribute to the understanding of the broader spectrum of psychiatric symptoms. This study shows the importance of using an integrative approach to explore genotype-phenotype variability.

PMID: 28118382 [PubMed - indexed for MEDLINE]

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Funding Opportunity PAR-17-450 from the NIH Guide for Grants and Contracts. The Lasker Clinical Research Scholars Program supports research activities during the early stage careers of independent clinical researchers. This FOA offers the opportunity for current Lasker awardees (Si2) to apply for the transition phase (R00) of the program. In the R00 phase, successful Si2 scholars will receive up to 5 years of NIH support for their research at an extramural research facility.