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2.
PLoS One ; 15(7): e0236962, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32735577

RESUMO

The diffusion of next-generation sequencing technologies has revolutionized research and diagnosis in the field of rare Mendelian disorders, notably via whole-exome sequencing (WES). However, one of the main issues hampering achievement of a diagnosis via WES analyses is the extended list of variants of unknown significance (VUS), mostly composed of missense variants. Hence, improved solutions are needed to address the challenges of identifying potentially deleterious variants and ranking them in a prioritized short list. We present MISTIC (MISsense deleTeriousness predICtor), a new prediction tool based on an original combination of two complementary machine learning algorithms using a soft voting system that integrates 113 missense features, ranging from multi-ethnic minor allele frequencies and evolutionary conservation, to physiochemical and biochemical properties of amino acids. Our approach also uses training sets with a wide spectrum of variant profiles, including both high-confidence positive (deleterious) and negative (benign) variants. Compared to recent state-of-the-art prediction tools in various benchmark tests and independent evaluation scenarios, MISTIC exhibits the best and most consistent performance, notably with the highest AUC value (> 0.95). Importantly, MISTIC maintains its high performance in the specific case of discriminating deleterious variants from benign variants that are rare or population-specific. In a clinical context, MISTIC drastically reduces the list of VUS (<30%) and significantly improves the ranking of "causative" deleterious variants. Pre-computed MISTIC scores for all possible human missense variants are available at http://lbgi.fr/mistic.


Assuntos
Doenças Genéticas Inatas , Mutação de Sentido Incorreto , Software , Sequenciamento Completo do Exoma/métodos , Biologia Computacional , Doenças Genéticas Inatas/diagnóstico , Doenças Genéticas Inatas/genética , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Humanos , Aprendizado de Máquina
3.
Am J Hum Genet ; 107(3): 418-431, 2020 09 03.
Artigo em Inglês | MEDLINE | ID: mdl-32758451

RESUMO

While genome-wide association studies have identified susceptibility variants for numerous traits, their combined utility for predicting broad measures of health, such as mortality, remains poorly understood. We used data from the UK Biobank to combine polygenic risk scores (PRS) for 13 diseases and 12 mortality risk factors into sex-specific composite PRS (cPRS). These cPRS were moderately associated with all-cause mortality in independent data within the UK Biobank: the estimated hazard ratios per standard deviation were 1.10 (95% confidence interval: 1.05, 1.16) and 1.15 (1.10, 1.19) for women and men, respectively. Differences in life expectancy between the top and bottom 5% of the cPRS were estimated to be 4.79 (1.76, 7.81) years and 6.75 (4.16, 9.35) years for women and men, respectively. These associations were substantially attenuated after adjusting for non-genetic mortality risk factors measured at study entry (i.e., middle age for most participants). The cPRS may be useful in counseling younger individuals at higher genetic risk of mortality on modification of non-genetic factors.


Assuntos
Doenças Genéticas Inatas/mortalidade , Predisposição Genética para Doença , Herança Multifatorial/genética , Medição de Risco/estatística & dados numéricos , Bancos de Espécimes Biológicos , Feminino , Doenças Genéticas Inatas/genética , Doenças Genéticas Inatas/patologia , Estudo de Associação Genômica Ampla , Humanos , Masculino , Pessoa de Meia-Idade , Fenótipo , Polimorfismo de Nucleotídeo Único/genética , Modelos de Riscos Proporcionais , Fatores de Risco , Reino Unido
4.
Am J Hum Genet ; 107(2): 352-363, 2020 08 06.
Artigo em Inglês | MEDLINE | ID: mdl-32693025

RESUMO

MORC2 encodes an ATPase that plays a role in chromatin remodeling, DNA repair, and transcriptional regulation. Heterozygous variants in MORC2 have been reported in individuals with autosomal-dominant Charcot-Marie-Tooth disease type 2Z and spinal muscular atrophy, and the onset of symptoms ranges from infancy to the second decade of life. Here, we present a cohort of 20 individuals referred for exome sequencing who harbor pathogenic variants in the ATPase module of MORC2. Individuals presented with a similar phenotype consisting of developmental delay, intellectual disability, growth retardation, microcephaly, and variable craniofacial dysmorphism. Weakness, hyporeflexia, and electrophysiologic abnormalities suggestive of neuropathy were frequently observed but were not the predominant feature. Five of 18 individuals for whom brain imaging was available had lesions reminiscent of those observed in Leigh syndrome, and five of six individuals who had dilated eye exams had retinal pigmentary abnormalities. Functional assays revealed that these MORC2 variants result in hyperactivation of epigenetic silencing by the HUSH complex, supporting their pathogenicity. The described set of morphological, growth, developmental, and neurological findings and medical concerns expands the spectrum of genetic disorders resulting from pathogenic variants in MORC2.


Assuntos
Adenosina Trifosfatases/genética , Anormalidades Craniofaciais/genética , Transtornos do Crescimento/genética , Mutação/genética , Transtornos do Neurodesenvolvimento/genética , Fatores de Transcrição/genética , Adolescente , Adulto , Criança , Pré-Escolar , Feminino , Doenças Genéticas Inatas/genética , Heterozigoto , Humanos , Lactente , Deficiência Intelectual/genética , Masculino , Microcefalia/genética , Pessoa de Meia-Idade , Fenótipo , Adulto Jovem
5.
Mol Cell ; 79(3): 504-520.e9, 2020 08 06.
Artigo em Inglês | MEDLINE | ID: mdl-32707033

RESUMO

Protein kinases are essential for signal transduction and control of most cellular processes, including metabolism, membrane transport, motility, and cell cycle. Despite the critical role of kinases in cells and their strong association with diseases, good coverage of their interactions is available for only a fraction of the 535 human kinases. Here, we present a comprehensive mass-spectrometry-based analysis of a human kinase interaction network covering more than 300 kinases. The interaction dataset is a high-quality resource with more than 5,000 previously unreported interactions. We extensively characterized the obtained network and were able to identify previously described, as well as predict new, kinase functional associations, including those of the less well-studied kinases PIM3 and protein O-mannose kinase (POMK). Importantly, the presented interaction map is a valuable resource for assisting biomedical studies. We uncover dozens of kinase-disease associations spanning from genetic disorders to complex diseases, including cancer.


Assuntos
Redes Reguladoras de Genes , Doenças Genéticas Inatas/genética , Neoplasias/genética , Proteínas Quinases/genética , Proteínas Serina-Treonina Quinases/genética , Proteínas Proto-Oncogênicas/genética , Biologia Computacional/métodos , Conjuntos de Dados como Assunto , Regulação da Expressão Gênica , Ontologia Genética , Doenças Genéticas Inatas/enzimologia , Doenças Genéticas Inatas/patologia , Humanos , Redes e Vias Metabólicas/genética , Anotação de Sequência Molecular , Distrofias Musculares/enzimologia , Distrofias Musculares/genética , Distrofias Musculares/patologia , Neoplasias/enzimologia , Neoplasias/patologia , Doenças Neurodegenerativas/enzimologia , Doenças Neurodegenerativas/genética , Doenças Neurodegenerativas/patologia , Mapeamento de Interação de Proteínas/métodos , Proteínas Quinases/química , Proteínas Quinases/classificação , Proteínas Quinases/metabolismo , Proteínas Serina-Treonina Quinases/química , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Proto-Oncogênicas/química , Proteínas Proto-Oncogênicas/metabolismo , Transdução de Sinais
7.
Nat Biotechnol ; 38(7): 845-855, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32601435

RESUMO

Genome editing has the potential to treat an extensive range of incurable monogenic and complex diseases. In particular, advances in sequence-specific nuclease technologies have dramatically accelerated the development of therapeutic genome editing strategies that are based on either the knockout of disease-causing genes or the repair of endogenous mutated genes. These technologies are progressing into human clinical trials. However, challenges remain before the therapeutic potential of genome editing can be fully realized. Delivery technologies that have serendipitously been developed over the past couple decades in the protein and nucleic acid delivery fields have been crucial to genome editing success to date, including adeno-associated viral and lentiviral vectors for gene therapy and lipid nanoparticle and other non-viral vectors for nucleic acid and protein delivery. However, the efficiency and tissue targeting capabilities of these vehicles must be further improved. In addition, the genome editing enzymes themselves need to be optimized, and challenges regarding their editing efficiency, specificity and immunogenicity must be addressed. Emerging protein engineering and synthetic chemistry approaches can offer solutions and enable the development of safe and efficacious clinical genome editing.


Assuntos
Sistemas CRISPR-Cas/genética , Edição de Genes/tendências , Doenças Genéticas Inatas/terapia , Terapia Genética , Doenças Genéticas Inatas/genética , Vetores Genéticos/genética , Vetores Genéticos/uso terapêutico , Humanos , Nanopartículas/uso terapêutico , Engenharia de Proteínas
8.
Am J Hum Genet ; 107(1): 3-14, 2020 07 02.
Artigo em Inglês | MEDLINE | ID: mdl-32619490

RESUMO

Secondary genomic findings are increasingly being returned to individuals as opportunistic screening results. A secondary finding offers the chance to identify and mitigate disease that may otherwise be unrecognized in an individual. As a form of screening, secondary findings must be considered differently from sequencing results in a diagnostic setting. For these reasons, clinicians should employ an evaluation and long-term management strategy that accounts for both the increased disease risk associated with a secondary finding and the lower positive predictive value of a screening result compared to an indication-based testing result. Here we describe an approach to the clinical evaluation and management of an individual who presents with a secondary finding. This approach enumerates five domains of evaluation-(1) medical history, (2) physical exam, (3) family history, (4) diagnostic phenotypic testing, and (5) variant correlation-through which a clinician can distinguish a molecular finding from a clinicomolecular diagnosis of genomic disease. With this framework, both geneticists and non-geneticist clinicians can optimize their ability to detect and mitigate genomic disease while avoiding the pitfalls of overdiagnosis. Our goal with this approach is to help clinicians translate secondary findings into meaningful recognition, treatment, and prevention of disease.


Assuntos
Doenças Genéticas Inatas/genética , Doenças Genéticas Inatas/diagnóstico , Doenças Genéticas Inatas/prevenção & controle , Genômica/métodos , Humanos , Anamnese
9.
Nucleic Acids Res ; 48(16): e91, 2020 09 18.
Artigo em Inglês | MEDLINE | ID: mdl-32614390

RESUMO

Gene losses provide an insightful route for studying the morphological and physiological adaptations of species, but their discovery is challenging. Existing genome annotation tools focus on annotating intact genes and do not attempt to distinguish nonfunctional genes from genes missing annotation due to sequencing and assembly artifacts. Previous attempts to annotate gene losses have required significant manual curation, which hampers their scalability for the ever-increasing deluge of newly sequenced genomes. Using extreme sequence erosion (amino acid deletions and substitutions) and sister species support as an unambiguous signature of loss, we developed an automated approach for detecting high-confidence gene loss events across a species tree. Our approach relies solely on gene annotation in a single reference genome, raw assemblies for the remaining species to analyze, and the associated phylogenetic tree for all organisms involved. Using human as reference, we discovered over 400 unique human ortholog erosion events across 58 mammals. This includes dozens of clade-specific losses of genes that result in early mouse lethality or are associated with severe human congenital diseases. Our discoveries yield intriguing potential for translational medical genetics and evolutionary biology, and our approach is readily applicable to large-scale genome sequencing efforts across the tree of life.


Assuntos
Doenças Genéticas Inatas/genética , Genômica/métodos , Filogenia , Algoritmos , Animais , Automação , Mapeamento Cromossômico/métodos , Genes Letais , Humanos , Mamíferos/genética , Camundongos , Anotação de Sequência Molecular
10.
JAMA ; 323(24): 2503-2511, 2020 06 23.
Artigo em Inglês | MEDLINE | ID: mdl-32573669

RESUMO

Importance: Widespread adoption of rapid genomic testing in pediatric critical care requires robust clinical and laboratory pathways that provide equitable and consistent service across health care systems. Objective: To prospectively evaluate the performance of a multicenter network for ultra-rapid genomic diagnosis in a public health care system. Design, Setting, and Participants: Descriptive feasibility study of critically ill pediatric patients with suspected monogenic conditions treated at 12 Australian hospitals between March 2018 and February 2019, with data collected to May 2019. A formal implementation strategy emphasizing communication and feedback, standardized processes, coordination, distributed leadership, and collective learning was used to facilitate adoption. Exposures: Ultra-rapid exome sequencing. Main Outcomes and Measures: The primary outcome was time from sample receipt to ultra-rapid exome sequencing report. The secondary outcomes were the molecular diagnostic yield, the change in clinical management after the ultra-rapid exome sequencing report, the time from hospital admission to the laboratory report, and the proportion of laboratory reports returned prior to death or hospital discharge. Results: The study population included 108 patients with a median age of 28 days (range, 0 days to 17 years); 34% were female; and 57% were from neonatal intensive care units, 33% were from pediatric intensive care units, and 9% were from other hospital wards. The mean time from sample receipt to ultra-rapid exome sequencing report was 3.3 days (95% CI, 3.2-3.5 days) and the median time was 3 days (range, 2-7 days). The mean time from hospital admission to ultra-rapid exome sequencing report was 17.5 days (95% CI, 14.6-21.1 days) and 93 reports (86%) were issued prior to death or hospital discharge. A molecular diagnosis was established in 55 patients (51%). Eleven diagnoses (20%) resulted from using the following approaches to augment standard exome sequencing analysis: mitochondrial genome sequencing analysis, exome sequencing-based copy number analysis, use of international databases to identify novel gene-disease associations, and additional phenotyping and RNA analysis. In 42 of 55 patients (76%) with a molecular diagnosis and 6 of 53 patients (11%) without a molecular diagnosis, the ultra-rapid exome sequencing result was considered as having influenced clinical management. Targeted treatments were initiated in 12 patients (11%), treatment was redirected toward palliative care in 14 patients (13%), and surveillance for specific complications was initiated in 19 patients (18%). Conclusions and Relevance: This study suggests feasibility of ultra-rapid genomic testing in critically ill pediatric patients with suspected monogenic conditions in the Australian public health care system. However, further research is needed to understand the clinical value of such testing, and the generalizability of the findings to other health care settings.


Assuntos
Estado Terminal , Doenças Genéticas Inatas/genética , Testes Genéticos/métodos , Sequenciamento Completo do Exoma/métodos , Austrália , Criança , Pré-Escolar , Estudos de Viabilidade , Feminino , Doenças Genéticas Inatas/diagnóstico , Humanos , Lactente , Recém-Nascido , Masculino , Programas Nacionais de Saúde , Estudos Prospectivos , Fatores de Tempo
11.
Nucleic Acids Res ; 48(13): 7265-7278, 2020 07 27.
Artigo em Inglês | MEDLINE | ID: mdl-32544229

RESUMO

DNA2 is an essential nuclease-helicase implicated in DNA repair, lagging-strand DNA synthesis, and the recovery of stalled DNA replication forks (RFs). In Saccharomyces cerevisiae, dna2Δ inviability is reversed by deletion of the conserved helicase PIF1 and/or DNA damage checkpoint-mediator RAD9. It has been suggested that Pif1 drives the formation of long 5'-flaps during Okazaki fragment maturation, and that the essential function of Dna2 is to remove these intermediates. In the absence of Dna2, 5'-flaps are thought to accumulate on the lagging strand, resulting in DNA damage-checkpoint arrest and cell death. In line with Dna2's role in RF recovery, we find that the loss of Dna2 results in severe chromosome under-replication downstream of endogenous and exogenous RF-stalling. Importantly, unfaithful chromosome replication in Dna2-mutant cells is exacerbated by Pif1, which triggers the DNA damage checkpoint along a pathway involving Pif1's ability to promote homologous recombination-coupled replication. We propose that Dna2 fulfils its essential function by promoting RF recovery, facilitating replication completion while suppressing excessive RF restart by recombination-dependent replication (RDR) and checkpoint activation. The critical nature of Dna2's role in controlling the fate of stalled RFs provides a framework to rationalize the involvement of DNA2 in Seckel syndrome and cancer.


Assuntos
DNA Helicases/metabolismo , Replicação do DNA , Doenças Genéticas Inatas/genética , Proteínas de Saccharomyces cerevisiae/metabolismo , Pontos de Checagem do Ciclo Celular , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , DNA , Dano ao DNA , DNA Helicases/genética , Humanos , Mutação , Saccharomyces cerevisiae , Proteínas de Saccharomyces cerevisiae/genética
15.
Nat Rev Cancer ; 20(7): 383-397, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32341551

RESUMO

Human oncoproteins promote transformation of cells into tumours by dysregulating the signalling pathways that are involved in cell growth, proliferation and death. Although oncoproteins were discovered many years ago and have been widely studied in the context of cancer, the recent use of high-throughput sequencing techniques has led to the identification of cancer-associated mutations in other conditions, including many congenital disorders. These syndromes offer an opportunity to study oncoprotein signalling and its biology in the absence of additional driver or passenger mutations, as a result of their monogenic nature. Moreover, their expression in multiple tissue lineages provides insight into the biology of the proto-oncoprotein at the physiological level, in both transformed and unaffected tissues. Given the recent paradigm shift in regard to how oncoproteins promote transformation, we review the fundamentals of genetics, signalling and pathogenesis underlying oncoprotein duality.


Assuntos
Transformação Celular Neoplásica/metabolismo , Anormalidades Congênitas/genética , Doenças Genéticas Inatas/genética , Neoplasias/genética , Neoplasias/metabolismo , Proteínas Proto-Oncogênicas/metabolismo , Animais , Transformação Celular Neoplásica/genética , Anormalidades Congênitas/metabolismo , Modelos Animais de Doenças , Interação Gene-Ambiente , Doenças Genéticas Inatas/metabolismo , Humanos , Camundongos , Mutação/genética , Proteínas Proto-Oncogênicas/genética , Proteínas Proto-Oncogênicas/fisiologia , Transdução de Sinais
17.
PLoS One ; 15(4): e0230587, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32271766

RESUMO

As high-throughput sequencing is increasingly applied to the molecular diagnosis of rare Mendelian disorders, a large number of patients with diverse phenotypes have their genetic and phenotypic data pooled together to uncover new gene-phenotype relations. We introduce Phenogenon, a statistical tool that combines, Human Phenotype Ontology (HPO) annotated patient phenotypes, gnomAD allele population frequency, and Combined Annotation Dependent Depletion (CADD) score for variant pathogenicity, in order to jointly predict the mode of inheritance and gene-phenotype associations. We ran Phenogenon on our cohort of 3,290 patients who had undergone whole exome sequencing. Among the top associations, we recapitulated previously known, such as "SRD5A3-Abnormal full-field electroretinogram-recessive" and "GRHL2 -Nail dystrophy-recessive", and discovered one potentially novel, "RRAGA-Abnormality of the skin-dominant". We also developed an interactive web interface available at https://phenogenon.phenopolis.org to visualise and explore the results.


Assuntos
Biologia Computacional/métodos , Estudos de Associação Genética , Doenças Genéticas Inatas , Sequenciamento de Nucleotídeos em Larga Escala , Doenças Raras , 3-Oxo-5-alfa-Esteroide 4-Desidrogenase/genética , Estudos de Coortes , Proteínas de Ligação a DNA/genética , Bases de Dados Genéticas , Frequência do Gene , Estudos de Associação Genética/métodos , Estudos de Associação Genética/estatística & dados numéricos , Doenças Genéticas Inatas/epidemiologia , Doenças Genéticas Inatas/genética , Predisposição Genética para Doença , Genótipo , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Sequenciamento de Nucleotídeos em Larga Escala/estatística & dados numéricos , Humanos , Proteínas de Membrana/genética , Proteínas Monoméricas de Ligação ao GTP/genética , Doenças da Unha/epidemiologia , Doenças da Unha/genética , Fenótipo , Doenças Raras/epidemiologia , Doenças Raras/genética , Distrofias Retinianas/epidemiologia , Distrofias Retinianas/genética , Dermatopatias/epidemiologia , Dermatopatias/genética , Fatores de Transcrição/genética , Sequenciamento Completo do Exoma
18.
Rinsho Shinkeigaku ; 60(5): 334-339, 2020 May 26.
Artigo em Japonês | MEDLINE | ID: mdl-32307395

RESUMO

Hereditary myopathy with early respiratory failure (HMERF) with heterozygous mutations in the titin gene (TTN) is characterized by respiratory failure developing from the early phase of limb weakness or gait disturbance. Here, we describe a characteristic distribution of muscle involvement in three members of a HMERF family with a TTN mutation. Despite the differences in severity exhibited among the father, daughter and son, the systemic imaging studies showed a similar pattern among these individuals. The semitendinosus and fibularis longus muscles were selectively affected, as described previously. In addition, we found marked atrophy in the sternocleidomastoid and psoas major muscles, regardless of the disease severity. The atrophy in selective trunk muscles observed in routine CT scans can be useful for the differential diagnosis of hereditary myopathies with heart and respiratory failure.


Assuntos
Conectina/genética , Doenças Genéticas Inatas/genética , Doenças Genéticas Inatas/patologia , Músculo Esquelético/patologia , Doenças Musculares/genética , Doenças Musculares/patologia , Mutação , Insuficiência Respiratória/genética , Insuficiência Respiratória/patologia , Adulto , Idoso , Atrofia , Diagnóstico Diferencial , Feminino , Doenças Genéticas Inatas/diagnóstico por imagem , Humanos , Masculino , Músculo Esquelético/diagnóstico por imagem , Doenças Musculares/diagnóstico por imagem , Insuficiência Respiratória/diagnóstico por imagem , Índice de Gravidade de Doença , Tomografia Computadorizada por Raios X
19.
Acta Obstet Gynecol Scand ; 99(6): 802-808, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32242916

RESUMO

INTRODUCTION: The Israeli population, encompassing 9 million citizens, is comprised of diverse communities. The Ministry of Health genetic screening program for reproductive purposes was introduced in 2013. This program is mainly aimed at severe incurable diseases with high rates of infant and childhood morbidity and/or mortality, with a carrier frequency of at least 1:60 and/or a disease frequency of 1 in 15 000 live births. In this paper, we present the results of the national genetic carrier-screening program implementation. MATERIAL AND METHODS: Data acquisition for this study was performed by retrospectively searching Ministry of Health database, which includes the reports of 18 genetic laboratories performing genetic screening tests. RESULTS: During 2015-2017, a total of 919 820 carrier-screening genetic tests were executed. The overall number rose by 14.9% over these years. For about two-thirds of the presented disorders, carrier frequency was within the expected range. A decrease of 57% was noted in the observed number of patients with spinal muscular atrophy born during 2014-2017, compared with the expected rate. Familial dysautonomia, Canavan and Tay-Sachs diseases yielded a very low prevalence. CONCLUSIONS: Our results highlight the impact of a national genetic carrier-screening program. Couples at risk of an affected fetus mostly choose to perform preconception or prenatal diagnosis and to act accordingly. Our country has several characteristics enabling us to achieve this success, including considerable rates of endogamy and consanguineous marriages, increased frequency of founder mutations, and high fertility rates. In addition, wide accessibility of the tests and good compliance of the population must be noted. Still, raising the awareness and continuing education of population and caregivers about the importance and efficiency of carrier screening remains an important issue. Finally, expanding the existing tests into a uniform, wide genetic panel seems to be the next goal.


Assuntos
Triagem de Portadores Genéticos/estatística & dados numéricos , Aborto Induzido/estatística & dados numéricos , Grupos Étnicos/genética , Feminino , Doenças Genéticas Inatas/diagnóstico , Doenças Genéticas Inatas/genética , Predisposição Genética para Doença/epidemiologia , Humanos , Israel , Gravidez , Estudos Retrospectivos
20.
Med. clín (Ed. impr.) ; 154(7): 275-278, abr. 2020. graf
Artigo em Espanhol | IBECS | ID: ibc-190912

RESUMO

INTRODUCCIÓN Y OBJETIVOS: La analbuminemia congénita (AAC) (MIM #616000) es una enfermedad autosómica recesiva (prevalencia <1/106) causada por defectos en el gen ALB que implican la ausencia o marcada disminución de la albuminemia. En este artículo, describimos un caso de AAC detectado en nuestro hospital. MATERIAL Y MÉTODOS: Mujer de 42 años con hipoproteinemia e hipoalbuminemia de causa no filiada. El estudio bioquímico se realizó siguiendo las técnicas y los controles de calidad habituales de nuestro laboratorio: albuminemia (colorimetría y nefelometría); electroforesis de proteínas (capilar y gel de agarosa) y análisis molecular del gen ALB (extracción de ADN y amplificación PCR de los 14 exones codificantes más regiones intrónicas adyacentes y secuenciación Sanger). RESULTADOS: Descartadas las causas más frecuentes de hipoalbuminemia, se confirmó la analbuminemia por electroforesis y nefelometría. El estudio molecular del gen ALB evidenció la presencia de la variante c.1289+1G>A (variante Guimarães) en homozigosis. CONCLUSIONES: Este es el primer caso confirmado mediante estudio molecular de AAC en España. La paciente presenta la variante Guimarães descrita previamente en otros 4 pacientes en el mundo


INTRODUCTION AND OBJECTIVES: Congenital analbuminaemia (CCA) (MIM #616000) is an autosomal recessive disorder (prevalence < 1/106) caused by defects in the ALB gene leading to absence or severe reduction of albuminaemia. This paper describes a case of CCA detected and diagnosed in our hospital. MATERIALS AND METHODS: A 42-year old woman showing hypoproteinaemia and hypoalbuminaemia of unknown aetiology. Biochemical study was performed according to routine quality controlled analytical procedures: Albuminaemia (colorimetric and nephelometric methods). Protein electrophoresis (capillary and agarose gel). Molecular study of the ALB gene: DNA extraction, PCR amplification of the 14 coding exons plus adjacent intron regions and Sanger sequencing. RESULTS: After discarding the most common causes of hypoalbuminaemia, the analbuminaemia was confirmed by nephelometry and protein electrophoresis. The proband was found to be homozygous for molecular defect in the ALB gene: variant c.1289+1G>A previously reported as Guimarães variant. CONCLUSIONS: This is the first case of CCA confirmed by molecular study in Spain. The proband shows the Guimarães variant previously described in 4 patients worldwide


Assuntos
Humanos , Feminino , Adulto , Doenças Genéticas Inatas/diagnóstico , Técnicas de Diagnóstico Molecular/métodos , Albumina Sérica/genética , Doenças Genéticas Inatas/genética , Eletroforese , Hipoalbuminemia/etiologia , Colorimetria/métodos , Nefelometria e Turbidimetria/métodos , Diagnóstico Diferencial
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