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1.
J Child Neurol ; : 883073819879835, 2019 Oct 17.
Artigo em Inglês | MEDLINE | ID: mdl-31623504

RESUMO

Clinical exome sequencing is currently being used in diagnostics of various genetic disorders, but studies supporting its application in clinical setting are scarce. The aim of this study was to establish diagnostic and clinical utility of clinical exome sequencing in patients with moderate and severe global developmental delay/intellectual disability. Clinical diagnosis was made in 49 of 88 investigated patients, with overall diagnostic yield of 55.7%. Molecular findings are characterized in detail, including the impact of newly made diagnosis on clinical management. Several previously unreported genotype-phenotype correlations and 33 novel variants are described. Genetic and clinical data were shared through publicly available database. In conclusion, clinical exome sequencing allows identification of causative variants in a significant proportion of patients in investigated clinical subgroup. Compared to whole exome sequencing, it shows similar diagnostic and clinical utility with reduced costs, which could be of particular importance for institutions with limited resources.

2.
Sci Rep ; 9(1): 9171, 2019 Jun 24.
Artigo em Inglês | MEDLINE | ID: mdl-31235738

RESUMO

The role of rare genetic variation and the innate immune system in the etiology of multiple sclerosis (MS) is being increasingly recognized. Recently, we described several rare variants in the NLRP1 gene, presumably conveying an increased risk for familial MS. In the present study we aimed to assess rare genetic variation in the inflammasome regulatory network. We performed whole exome sequencing of 319 probands, comprising patients with familial MS, sporadic MS and control subjects. 62 genes involved in the NLRP1/NLRP3 inflammasome regulation were screened for potentially pathogenic rare genetic variation. Aggregate mutational burden was analyzed, considering the variants' predicted pathogenicity and frequency in the general population. We demonstrate an increased (p = 0.00004) variant burden among MS patients which was most pronounced for the exceedingly rare variants with high predicted pathogenicity. These variants were found in inflammasome genes (NLRP1/3, CASP1), genes mediating inflammasome inactivation via auto and mitophagy (RIPK2, MEFV), and genes involved in response to infection with DNA viruses (POLR3A, DHX58, IFIH1) and to type-1 interferons (TYK2, PTPRC). In conclusion, we present new evidence supporting the importance of rare genetic variation in the inflammasome signaling pathway and its regulation via autophagy and interferon-ß to the etiology of MS.

3.
Eur J Med Genet ; 62(12): 103598, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30543990

RESUMO

Primary microcephalies (MCPH) are characterized by microcephaly (HC -2 SD at birth) in the absence of visceral malformations. To date, less than 20 genes have been associated with MCHP, several of which are involved in the formation and function of the centrosome. Here, we report a novel missense variant in the TUBGCP5 gene in a patient with primary microcephaly and mild developmental delay. The TUBCGP5 gene (tubulin gamma complex associated protein 5) is a paralog of TUBGCP4 and TUBGCP6, both of which are known MCPH associated genes, and like its' paralogs, is involved in centrosome formation. Furthermore, the TUBGCP5 gene is located in the 15q11.2 BP1-BP2 microdeletion Burnside-Butler susceptibility locus that is part of the larger Prader-Willi/Angelman region. Common clinical features of the 15q11.2 BP1-BP2 microdeletion include general developmental and neurodevelopmental delay which may occasionally be accompanied by yet unexplained microcephaly. In our patient, the TUBGCP5:c.2180T > G, p.Phe727Cys missense variant was identified in compound heterozygous state with 15q11.2 BP1-BP2 microdeletion using whole exome sequencing, after the initial analyses of known MCPH genes failed to identify a conclusively causative variant. The identified variant is rare and highly conserved, as shown by population allele frequency data from ExAC and GnomAD, as well as comparisons with all other vertebrates. Based on this evidence we suggest that the identified TUBGCP5 variant in our patient may thus represent a novel cause of MCPH with mild developmental delay and may play a role in occurrence of microcephaly in 15q11.2 microdeletion carriers. Further studies are required to further clarify the causality and penetrance of TBGCP5 variants in primary microcephaly.

4.
Am J Hum Genet ; 2018 Nov 19.
Artigo em Inglês | MEDLINE | ID: mdl-30471718

RESUMO

Dysfunction of motile monocilia, altering the leftward flow at the embryonic node essential for determination of left-right body asymmetry, is a major cause of laterality defects. Laterality defects are also often associated with reduced mucociliary clearance caused by defective multiple motile cilia of the airway and are responsible for destructive airway disease. Outer dynein arms (ODAs) are essential for ciliary beat generation, and human respiratory cilia contain different ODA heavy chains (HCs): the panaxonemally distributed γ-HC DNAH5, proximally located ß-HC DNAH11 (defining ODA type 1), and the distally localized ß-HC DNAH9 (defining ODA type 2). Here we report loss-of-function mutations in DNAH9 in five independent families causing situs abnormalities associated with subtle respiratory ciliary dysfunction. Consistent with the observed subtle respiratory phenotype, high-speed video microscopy demonstrates distally impaired ciliary bending in DNAH9 mutant respiratory cilia. DNAH9-deficient cilia also lack other ODA components such as DNAH5, DNAI1, and DNAI2 from the distal axonemal compartment, demonstrating an essential role of DNAH9 for distal axonemal assembly of ODAs type 2. Yeast two-hybrid and co-immunoprecipitation analyses indicate interaction of DNAH9 with the ODA components DNAH5 and DNAI2 as well as the ODA-docking complex component CCDC114. We further show that during ciliogenesis of respiratory cilia, first proximally located DNAH11 and then distally located DNAH9 is assembled in the axoneme. We propose that the ß-HC paralogs DNAH9 and DNAH11 achieved specific functional roles for the distinct axonemal compartments during evolution with human DNAH9 function matching that of ancient ß-HCs such as that of the unicellular Chlamydomonas reinhardtii.

5.
Front Neurol ; 9: 655, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30158895

RESUMO

Epigenetic mechanisms, especially DNA methylation, are suggested to play a role in the age-of-onset in Huntington's disease (HD) based on studies on patient brains, and cellular and animal models. Methylation is tissue-specific and it is not clear how HD specific methylation in the brain correlates with the blood compartment, which represents a much more clinically accessible sample. Therefore, we explored the presence of HD specific DNA methylation patterns in whole blood on a cohort of HDM and healthy controls from Slovenia. We compared CpG site-specific DNA methylation in whole blood of 11 symptomatic and 9 pre-symptomatic HDM (HDM), and 15 healthy controls, by using bisulfite converted DNA on the Infinium® Human Methylation27 BeadChip microarray (Illumina) covering 27,578 CpG sites and 14,495 genes. Of the examined 14,495 genes, 437 were differentially methylated (p < 0.01) in pre-symptomatic HDM compared to controls, with three genes (CLDN16, DDC, NXT2) retaining statistical significance after the correction for multiple testing (false discovery rate, FDR < 0.05). Comparisons between symptomatic HDM and controls, and the comparison of symptomatic and pre-symptomatic HDM further identified 260 and 198 differentially methylated genes (p < 0.01), respectively, whereas the comparison of all HDM (symptomatic and pre-symptomatic) and healthy controls identified 326 differentially methylated genes (p < 0.01), however, none of these changes retained significance (FDR < 0.05) after the correction for multiple testing. The results of our study suggest that methylation signatures in the blood compartment are not robust enough to prove as valuable biomarkers for predicting HD progression, but recognizable changes in methylation deserve further research.

6.
Metab Brain Dis ; 2018 Jul 13.
Artigo em Inglês | MEDLINE | ID: mdl-30006695

RESUMO

Many inborn errors of metabolism may present with epilepsy or seizures, however, current scope of these diseases is unknown. Due to available precision medicine approaches in many inborn errors of metabolism and sophisticated traditional diagnostics, this group of disorders is of special relevance to clinicians. Besides, as current treatment is challenging and unsuccessful in more than 30% of all epilepsy patients, these diseases may provide valuable models for ictogenesis and epileptogenesis studies and potentially pave the ways to identification of novel treatments. The aim of this study was to elucidate genetic architecture of inborn errors of metabolism involving epilepsy or seizures and to evaluate their diagnostic approaches. After extensive search, 880 human genes were identified with a considerable part, 373 genes (42%), associated with inborn errors of metabolism. The most numerous group comprised disorders of energy metabolism (115, 31% of all inborn errors of metabolism). A substantial number of these diseases (26%, 97/373) have established specific treatments, therefore timely diagnosis comes as an obligation. Highly heterogenous, overlapping and non-specific phenotypes in most of inborn errors of metabolism presenting with epilepsy or seizures usually preclude phenotype-driven diagnostics. Besides, as traditional diagnostics involves a range of specialized metabolic tests with low diagnostic yields and is generally inefficient and lengthy, next-generation sequencing-based methods were proposed as a cost-efficient one-step way to shorten "diagnostic odyssey". Extensive list of 373 epilepsy- or seizures-associated inborn errors of metabolism genes may be of value in development of gene panels and as a tool for variants' filtration.

7.
Psychiatr Danub ; 30(2): 216-219, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29930232

RESUMO

BACKGROUND: Dementias are clinically and genetically heterogeneous group of neurodegenerative disorders. Often, dementias with genetic etiology are clinically indistinguishable from non-genetic ones. The aim of this retrospective study was to evaluate the yield of clinical exome sequencing in dementias, potentially associated with monogenic genetic predisposition. SUBJECTS AND METHODS: For this purpose 20 consecutive patients younger than 65 years were studied in the period from January 2014 to December 2017; 14 with the diagnosis of Frontotemporal dementia (FTD), 3 with early-onset Alzheimer disease (EOAD) and 3 with unspecified dementia. In addition to clinical exome sequencing including 57 genes associated with dementia, C9orf72 hexanucleotide expansion as tested in all patients. RESULTS: We found genetic etiology in 6 patients: 2 mutations in the PSEN1 gene (p.Pro264Ser and p.Phe105Cys) in the EOAD patients, C9orf72 expansion and MAPT (c.1920+16C>T), mutation in the FTD group of patients as well as MAPT (c.1920+16C>T) mutation and likely pathogenic mutation in the TYROBP mutation (p.Asp32Asn) in patients with unspecified diagnosis. CONCLUSIONS: Our preliminary results imply significant diagnostic yield in identifying rare genetic causes of dementia, combining comprehensive clinical exome sequencing and targeted C9orf72 expansion testing.


Assuntos
Doença de Alzheimer/genética , Demência/genética , Demência Frontotemporal/genética , Sequenciamento Completo do Exoma , Adulto , Proteína C9orf72/genética , Análise Mutacional de DNA , Feminino , Predisposição Genética para Doença/genética , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos
8.
OMICS ; 22(5): 322-331, 2018 May.
Artigo em Inglês | MEDLINE | ID: mdl-29688803

RESUMO

Sarcoidosis is a multifactorial systemic disease characterized by granulomatous inflammation and greatly impacting on global public health. The etiology and mechanisms of sarcoidosis are not fully understood. Recent high-throughput biological research has generated vast amounts of multi-omics big data on sarcoidosis, but their significance remains to be determined. We sought to identify novel candidate regions, and genes consistently altered in heterogeneous omics studies so as to reveal the underlying molecular mechanisms. We conducted a comprehensive integrative literature analysis on global data on sarcoidosis, including genomic, transcriptomic, proteomic, and phenomic studies. We performed positional integration analysis of 38 eligible datasets originating from 17 different biological layers. Using the integration interval length of 50 kb, we identified 54 regions reaching significance value p ≤ 0.0001 and 15 regions with significance value p ≤ 0.00001, when applying more stringent criteria. Secondary literature analysis of the top 20 regions, with the most significant accumulation of signals, revealed several novel candidate genes for which associations with sarcoidosis have not yet been established, but have considerable support for their involvement based on omic data. These new plausible candidate genes include NELFE, CFB, EGFL7, AGPAT2, FKBPL, NRC3, and NEU1. Furthermore, annotated data were prepared to enable custom visualization and browsing of these sarcoidosis related omics evidence in the University of California Santa Cruz (UCSC) Genome Browser. Further multi-omics approaches are called for sarcoidosis biomarkers and diagnostic and therapeutic innovation. Our approach for harnessing multi-omics data and the findings presented herein reflect important steps toward understanding the etiology and underlying pathological mechanisms of sarcoidosis.

9.
OMICS ; 22(4): 283-294, 2018 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-29652574

RESUMO

Huntington's disease (HD) is a severe neurodegenerative disorder manifesting as progressive impairment of motor function, cognitive decline, psychiatric symptoms, and immunological and endocrine dysfunction. We explored the consistency of blood transcriptomic biomarkers in HD based on a novel Slovene patient cohort and expert review of previous studies. HumanHT-12 v4 BeadChip microarrays were performed on the whole blood samples of a cohort of 23 HD mutation carriers and 23 controls to identify differentially expressed (DE) transcripts. In addition, we performed an expert review of DE transcripts identified in comparable HD studies from whole blood, to identify any consistent signature of HD. In the Slovene cohort, we identified 740 DE transcripts (p < 0.01 and a false discovery rate (FDR) of <0.1) of which 414 were downregulated and 326 were upregulated. Pathway analyses of DE transcripts showed enrichment for pathways involved in systemic, rather than neural processes in HD. With an expert review of comparable studies, we have further identified 15 DE transcripts shared by 3 studies. We suggest transcriptomic changes in blood reflect systemic changes in HD pathogenesis, rather than being a direct result of the neuropathological processes in the central nervous system during HD progression, and thus, have limited value as disease biomarkers.

10.
Ann Neurol ; 83(4): 703-717, 2018 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-29466837

RESUMO

OBJECTIVE: Voltage-gated sodium (Na+ ) channels underlie action potential generation and propagation and hence are central to the regulation of excitability in the nervous system. Mutations in the genes SCN1A, SCN2A, and SCN8A, encoding the Na+ channel pore-forming (α) subunits Nav1.1, 1.2, and 1.6, respectively, and SCN1B, encoding the accessory subunit ß1 , are established causes of genetic epilepsies. SCN3A, encoding Nav1.3, is known to be highly expressed in brain, but has not previously been linked to early infantile epileptic encephalopathy. Here, we describe a cohort of 4 patients with epileptic encephalopathy and heterozygous de novo missense variants in SCN3A (p.Ile875Thr in 2 cases, p.Pro1333Leu, and p.Val1769Ala). METHODS: All patients presented with treatment-resistant epilepsy in the first year of life, severe to profound intellectual disability, and in 2 cases (both with the variant p.Ile875Thr), diffuse polymicrogyria. RESULTS: Electrophysiological recordings of mutant channels revealed prominent gain of channel function, with a markedly increased amplitude of the slowly inactivating current component, and for 2 of 3 mutants (p.Ile875Thr and p.Pro1333Leu), a leftward shift in the voltage dependence of activation to more hyperpolarized potentials. Gain of function was not observed for Nav1.3 variants known or presumed to be inherited (p.Arg1642Cys and p.Lys1799Gln). The antiseizure medications phenytoin and lacosamide selectively blocked slowly inactivating over transient current in wild-type and mutant Nav1.3 channels. INTERPRETATION: These findings establish SCN3A as a new gene for infantile epileptic encephalopathy and suggest a potential pharmacologic intervention. These findings also reinforce the role of Nav1.3 as an important regulator of neuronal excitability in the developing brain, while providing additional insight into mechanisms of slow inactivation of Nav1.3. Ann Neurol 2018;83:703-717.

11.
PLoS One ; 13(1): e0188578, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29293505

RESUMO

Hereditary hearing loss (HL) is a common sensory disorder, with an incidence of 1-2 per 1000 newborns, and has a genetic etiology in over 50% of cases. It occurs either as part of a syndrome or in isolation and is genetically very heterogeneous which poses a challenge for clinical and molecular diagnosis. We used exome sequencing to seek a genetic cause in a group of 56 subjects (49 probands) with HL: 32 with non-syndromic non-GJB2 HL and 17 with syndromic HL. Following clinical examination and clinical exome sequencing, an etiological diagnosis was established in 15 probands (15/49; 30%); eight (8/17;47%) from the syndromic group and seven (7/32; 21%) from the non-syndromic non-GJB2 subgroup. Fourteen different (half of them novel) non-GJB2 variants causing HL were found in 10 genes (CHD7, HDAC8, MITF, NEFL, OTOF, SF3B4, SLC26A4, TECTA, TMPRSS3, USH2A) among 13 probands, confirming the genetic heterogeneity of hereditary HL. Different genetic causes for HL were found in a single family while three probands with apparent syndromic HL were found to have HL as a separate clinical feature, distinct from the complex phenotype. Clinical exome sequencing proved to be an effective tool used to comprehensively address the genetic heterogeneity of HL, to detect clinically unrecognized HL syndromes, and to decipher complex phenotypes in which HL is a separate feature and not part of a syndrome.


Assuntos
Perda Auditiva/genética , Sequenciamento Completo do Exoma , Adolescente , Adulto , Criança , Pré-Escolar , Feminino , Genótipo , Perda Auditiva/diagnóstico , Humanos , Masculino , Fenótipo , Síndrome , Adulto Jovem
12.
PLoS One ; 13(1): e0190601, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29324865

RESUMO

Prevalence of multiple sclerosis varies with geographic latitude. We hypothesized that this fact might be partially associated with the influence of latitude on circadian rhythm and consequently that genetic variability of key circadian rhythm regulators, ARNTL and CLOCK genes, might contribute to the risk for multiple sclerosis. Our aim was to analyse selected polymorphisms of ARNTL and CLOCK, and their association with multiple sclerosis. A total of 900 Caucasian patients and 1024 healthy controls were compared for genetic signature at 8 SNPs, 4 for each of both genes. We found a statistically significant difference in genotype (ARNTL rs3789327, P = 7.5·10-5; CLOCK rs6811520 P = 0.02) distributions in patients and controls. The ARNTL rs3789327 CC genotype was associated with higher risk for multiple sclerosis at an OR of 1.67 (95% CI 1.35-2.07, P = 0.0001) and the CLOCK rs6811520 genotype CC at an OR of 1.40 (95% CI 1.13-1.73, P = 0.002). The results of this study suggest that genetic variability in the ARNTL and CLOCK genes might be associated with risk for multiple sclerosis.


Assuntos
Fatores de Transcrição ARNTL/genética , Proteínas CLOCK/genética , Ritmo Circadiano/genética , Esclerose Múltipla/genética , Adulto , Estudos Transversais , Feminino , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos
13.
Genet Med ; 20(3): 303-312, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-28914264

RESUMO

PurposeWe sought to determine the analytical sensitivity of several extended exome variation analysis approaches in terms of their contribution to diagnostic yield and their clinical feasibility.MethodsWe retrospectively analyzed the results of genetic testing in 1,059 distinct cases referred for exome sequencing to our institution. In these, we routinely employed extended exome analysis approaches in addition to basic variant analysis, including (i) copy-number variation (CNV) detection, (ii) nonconsensus splice defect detection, (ii) genomic breakpoint detection, (iv) homozygosity mapping, and (v) mitochondrial variant analysis.ResultsExtended exome analysis approaches assisted in identification of causative genetic variant in 44 cases, which represented a 4.2% increase in diagnostic yield. The greatest contribution was associated with CNV analysis (1.8%) and splice variant prediction (1.2%), and the remaining approaches contributed an additional 1.2%. Analysis of workload has shown that on average nine additional variants per case had to be interpreted in the extended analysis.ConclusionWe show that extended exome analysis approaches improve the diagnostic yield of heterogeneous genetic disorders and result in considerable increase of diagnostic yield of exome sequencing with a minor increase of interpretative workload.


Assuntos
Exoma , Testes Genéticos , Doenças Raras/diagnóstico , Doenças Raras/genética , Processamento Alternativo , Quebra Cromossômica , Variações do Número de Cópias de DNA , Feminino , Estudos de Associação Genética , Predisposição Genética para Doença , Testes Genéticos/métodos , Testes Genéticos/normas , Variação Genética , Genoma Mitocondrial , Humanos , Masculino , Estudos Retrospectivos , Análise de Sequência de DNA , Sequenciamento Completo do Exoma
14.
Am J Hum Genet ; 101(5): 844-855, 2017 Nov 02.
Artigo em Inglês | MEDLINE | ID: mdl-29100094

RESUMO

A series of simplex cases have been reported under various diagnoses sharing early aging, especially evident in congenitally decreased subcutaneous fat tissue and sparse hair, bone dysplasia of the skull and fingers, a distinctive facial gestalt, and prenatal and postnatal growth retardation. For historical reasons, we suggest naming the entity Fontaine syndrome. Exome sequencing of four unrelated affected individuals showed that all carried the de novo missense variant c.649C>T (p.Arg217Cys) or c.650G>A (p.Arg217His) in SLC25A24, a solute carrier 25 family member coding for calcium-binding mitochondrial carrier protein (SCaMC-1, also known as SLC25A24). SLC25A24 allows an electro-neutral and reversible exchange of ATP-Mg and phosphate between the cytosol and mitochondria, which is required for maintaining optimal adenine nucleotide levels in the mitochondrial matrix. Molecular dynamic simulation studies predict that p.Arg217Cys and p.Arg217His narrow the substrate cavity of the protein and disrupt transporter dynamics. SLC25A24-mutant fibroblasts and cells expressing p.Arg217Cys or p.Arg217His variants showed altered mitochondrial morphology, a decreased proliferation rate, increased mitochondrial membrane potential, and decreased ATP-linked mitochondrial oxygen consumption. The results suggest that the SLC25A24 mutations lead to impaired mitochondrial ATP synthesis and cause hyperpolarization and increased proton leak in association with an impaired energy metabolism. Our findings identify SLC25A24 mutations affecting codon 217 as the underlying genetic cause of human progeroid Fontaine syndrome.


Assuntos
Envelhecimento/genética , Antiporters/genética , Doenças do Desenvolvimento Ósseo/genética , Proteínas de Ligação ao Cálcio/genética , Proteínas Mitocondriais/genética , Mutação/genética , Adenina/metabolismo , Trifosfato de Adenosina/metabolismo , Citosol/metabolismo , Feminino , Morte Fetal , Fibroblastos/metabolismo , Humanos , Lactente , Recém-Nascido , Masculino , Potencial da Membrana Mitocondrial/genética , Mitocôndrias/genética , Mitocôndrias/metabolismo , Proteínas Mitocondriais/metabolismo , Simulação de Dinâmica Molecular , Oxigênio/metabolismo , Fosfatos/metabolismo , Síndrome
15.
OMICS ; 21(10): 565-570, 2017 10.
Artigo em Inglês | MEDLINE | ID: mdl-29049012

RESUMO

Human trisomies have recently been investigated using transcriptomics approaches to identify the gene expression (GE) signatures characteristic of each of these specific aneuploidy conditions. We hypothesized that the viability of cells with gross genomic imbalances might be associated with the activation of resilience mechanisms that are common to different trisomies and that are reflected by specific shared GE patterns. We report in this article our microarray GE analyses of amniocytes from fetuses with viable trisomy conditions, trisomy 21 or trisomy 18, to detect such common expression signatures. Comparative analysis of significantly differentially expressed genes in trisomies 18 and 21 revealed six dysregulated genes common to both: OTUD5, ADAMTSL1, TADA2A, PPID, PIAS2, and MAPRE2. These genes are involved in ubiquitination, protein folding, cell proliferation, and apoptosis. Pathway-based enrichment analyses demonstrated that both trisomies showed dysregulation of the PI3K/AKT pathway, cell cycle G2/M DNA damage checkpoint regulation, and cell death and survival, as well as inhibition of the upstream regulator TP53. Our data collectively suggest that trisomies 18 and 21 share common functional GE signatures, implying that common mechanisms of resilience might be activated in aneuploid cells to resist large genomic imbalances. To the best of our knowledge, this is the first study to use global GE profiling data to identify potential common mechanisms in fetal trisomies. Studies of other trisomies using transcriptomics and multiomics approaches might further clarify mechanisms activated in trisomy syndromes.


Assuntos
Síndrome de Down/genética , Feto/fisiologia , Transcrição Genética/genética , Síndrome da Trissomía do Cromossomo 18/genética , Aneuploidia , Células Cultivadas , Perfilação da Expressão Gênica/métodos , Humanos , Transcriptoma/genética
16.
Neurology ; 89(16): 1676-1683, 2017 Oct 17.
Artigo em Inglês | MEDLINE | ID: mdl-28916538

RESUMO

OBJECTIVE: To examine whether gene expression analysis of a large-scale Parkinson disease (PD) patient cohort produces a robust blood-based PD gene signature compared to previous studies that have used relatively small cohorts (≤220 samples). METHODS: Whole-blood gene expression profiles were collected from a total of 523 individuals. After preprocessing, the data contained 486 gene profiles (n = 205 PD, n = 233 controls, n = 48 other neurodegenerative diseases) that were partitioned into training, validation, and independent test cohorts to identify and validate a gene signature. Batch-effect reduction and cross-validation were performed to ensure signature reliability. Finally, functional and pathway enrichment analyses were applied to the signature to identify PD-associated gene networks. RESULTS: A gene signature of 100 probes that mapped to 87 genes, corresponding to 64 upregulated and 23 downregulated genes differentiating between patients with idiopathic PD and controls, was identified with the training cohort and successfully replicated in both an independent validation cohort (area under the curve [AUC] = 0.79, p = 7.13E-6) and a subsequent independent test cohort (AUC = 0.74, p = 4.2E-4). Network analysis of the signature revealed gene enrichment in pathways, including metabolism, oxidation, and ubiquitination/proteasomal activity, and misregulation of mitochondria-localized genes, including downregulation of COX4I1, ATP5A1, and VDAC3. CONCLUSIONS: We present a large-scale study of PD gene expression profiling. This work identifies a reliable blood-based PD signature and highlights the importance of large-scale patient cohorts in developing potential PD biomarkers.


Assuntos
Biomarcadores/sangue , Doença de Parkinson/sangue , Doença de Parkinson/genética , Transcriptoma/genética , Estudos de Coortes , Feminino , Perfilação da Expressão Gênica , Redes Reguladoras de Genes , Humanos , Masculino , Análise em Microsséries , Doenças Neurodegenerativas/sangue , Doenças Neurodegenerativas/genética , RNA Mensageiro/metabolismo , Curva ROC , Reprodutibilidade dos Testes , Transcriptoma/fisiologia
17.
Hum Mutat ; 38(11): 1477-1484, 2017 11.
Artigo em Inglês | MEDLINE | ID: mdl-28726266

RESUMO

Biallelic GLDN mutations have recently been identified among infants with lethal congenital contracture syndrome 11 (LCCS11). GLDN encodes gliomedin, a protein required for the formation of the nodes of Ranvier and development of the human peripheral nervous system. We report six infants and children from four unrelated families with biallelic GLDN mutations, four of whom survived beyond the neonatal period into infancy, childhood, and late adolescence with intensive care and chronic respiratory and nutritional support. Our findings expand the genotypic and phenotypic spectrum of LCCS11 and demonstrate that the condition may not necessarily be lethal in the neonatal period.


Assuntos
Artrogripose/diagnóstico , Artrogripose/genética , Genes Letais , Proteínas de Membrana/genética , Mutação , Proteínas do Tecido Nervoso/genética , Fenótipo , Artrogripose/mortalidade , Biópsia , Análise Mutacional de DNA , Evolução Fatal , Estudos de Associação Genética , Humanos , Lactente , Recém-Nascido , Masculino , Linhagem , Raízes Nervosas Espinhais/ultraestrutura , Sequenciamento Completo do Exoma
18.
Sci Rep ; 7(1): 3715, 2017 06 16.
Artigo em Inglês | MEDLINE | ID: mdl-28623311

RESUMO

The genetic etiology and the contribution of rare genetic variation in multiple sclerosis (MS) has not yet been elucidated. Although familial forms of MS have been described, no convincing rare and penetrant variants have been reported to date. We aimed to characterize the contribution of rare genetic variation in familial and sporadic MS and have identified a family with two sibs affected by concomitant MS and malignant melanoma (MM). We performed whole exome sequencing in this primary family and 38 multiplex MS families and 44 sporadic MS cases and performed transcriptional and immunologic assessment of the identified variants. We identified a potentially causative homozygous missense variant in NLRP1 gene (Gly587Ser) in the primary family. Further possibly pathogenic NLRP1 variants were identified in the expanded cohort of patients. Stimulation of peripheral blood mononuclear cells from MS patients with putatively pathogenic NLRP1 variants showed an increase in IL-1B gene expression and active cytokine IL-1ß production, as well as global activation of NLRP1-driven immunologic pathways. We report a novel familial association of MS and MM, and propose a possible underlying genetic basis in NLRP1 gene. Furthermore, we provide initial evidence of the broader implications of NLRP1-related pathway dysfunction in MS.

19.
Genet Med ; 18(11): 1102-1110, 2016 11.
Artigo em Inglês | MEDLINE | ID: mdl-27031083

RESUMO

PURPOSE: Genome-wide sequencing approaches are increasingly being used in place of disease gene panel sequencing approaches. Despite the well-recognized benefits of these approaches, they also carry with them an increased burden of analyzing overwhelmingly large gene targets and an increased possibility of detecting incidental findings. METHODS: We propose a novel approach for design of individualized phenotype gene panels using the set of signs and symptoms observed and selecting relevant genes on the basis of known phenotype-gene associations. RESULTS: We used results of diagnostic exome sequencing in 405 cases submitted to our institution to show retrospectively that using the phenotype gene panel increases the sensitivity of masked exome analysis (increase from 25.4 to 29.7% in overall diagnostic yield). We also show that such a strategy enables the possibility of masked analysis of genome-wide sequencing data in patients with poorly defined and multifaceted clinical presentations. Ultimately, we show that this approach enables control over the incidental findings rate (0.25% in phenotype gene panels). Finally, we provide a Web tool for customized phenotype panel creation (available at http://www.kimg.eu/generator). CONCLUSION: In conclusion, we present a novel approach to a phenotype-driven diagnostic process of genome scale sequencing data that harnesses the sensitivity of these approaches while restricting the analysis to genes relevant to clinical presentation in patient.Genet Med 18 11, 1102-1110.


Assuntos
Exoma/genética , Marcação de Genes/métodos , Estudos de Associação Genética , Genoma Humano , Feminino , Variação Genética/genética , Sequenciamento de Nucleotídeos em Larga Escala/tendências , Humanos , Achados Incidentais , Masculino , Análise de Sequência de DNA
20.
Croat Med J ; 57(6): 566-571, 2016 Dec 31.
Artigo em Inglês | MEDLINE | ID: mdl-28051281

RESUMO

AIM: To determine whether maternal leptin (LEP) and leptin receptor (LEPR) gene polymorphisms are associated with idiopathic recurrent spontaneous abortion (IRSA). METHODS: This case-control association study conducted from 2010 to 2012 at the Department of Gynecology and Obstetrics, University Hospital Center Osijek and Clinical Institute of Medical Genetics Ljubljana included 178 women with a history of three or more IRSAs before the 22nd week of gestation and 145 women with at least two live births and no history of pathologic pregnancies during reproductive period. Polymorphisms of maternal LEP (rs7799039, rs2122627, rs11761556, rs10244329) and LEPR (rs1137101, rs7516341, rs1186403, rs12062820) were assessed by allele specific real-time polymerase chain reaction. Genotype distribution, allele frequencies, and frequency of haplotypes at LEP and LEPR genetic loci were determined. RESULTS: We observed more frequent genotype for rs7516341 (nominal P=0.034, odds ratio [OR] 0.61, 95% confidence interval [CI] 0.38-0.97) and rs1137101 (nominal P=0.048, OR 1.66, 95% CI 1.00-2.80) in the LEPR gene in patients than in controls, but these results did not remain significant after correction for multiple testing according to Bonferroni (adjusted P value threshold was set at 0.05). We did not observe differential distribution of genotype frequencies in the LEP gene between cases and controls. In patients with IRSA, GTCC haplotype in the LEPR gene locus was significantly less frequent than in controls (PP=0.00865, OR 0.45), contrary to ACTC haplotype (PP=0.0087, OR 1.98). CONCLUSIONS: We showed that genetic variability in the LEPR gene was associated with IRSA, warranting confirmation on a greater number of patients and pathogenesis investigation.


Assuntos
Aborto Habitual/genética , Leptina/genética , Receptores para Leptina/genética , Adulto , Alelos , Estudos de Casos e Controles , Feminino , Frequência do Gene , Variação Genética , Genótipo , Haplótipos , Humanos , Masculino , Pessoa de Meia-Idade , Razão de Chances , Polimorfismo Genético , Polimorfismo de Nucleotídeo Único , Gravidez , Reação em Cadeia da Polimerase em Tempo Real , Fatores de Risco
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