RESUMEN
Integrating human genomics and proteomics can help elucidate disease mechanisms, identify clinical biomarkers and discover drug targets1-4. Because previous proteogenomic studies have focused on common variation via genome-wide association studies, the contribution of rare variants to the plasma proteome remains largely unknown. Here we identify associations between rare protein-coding variants and 2,923 plasma protein abundances measured in 49,736 UK Biobank individuals. Our variant-level exome-wide association study identified 5,433 rare genotype-protein associations, of which 81% were undetected in a previous genome-wide association study of the same cohort5. We then looked at aggregate signals using gene-level collapsing analysis, which revealed 1,962 gene-protein associations. Of the 691 gene-level signals from protein-truncating variants, 99.4% were associated with decreased protein levels. STAB1 and STAB2, encoding scavenger receptors involved in plasma protein clearance, emerged as pleiotropic loci, with 77 and 41 protein associations, respectively. We demonstrate the utility of our publicly accessible resource through several applications. These include detailing an allelic series in NLRC4, identifying potential biomarkers for a fatty liver disease-associated variant in HSD17B13 and bolstering phenome-wide association studies by integrating protein quantitative trait loci with protein-truncating variants in collapsing analyses. Finally, we uncover distinct proteomic consequences of clonal haematopoiesis (CH), including an association between TET2-CH and increased FLT3 levels. Our results highlight a considerable role for rare variation in plasma protein abundance and the value of proteogenomics in therapeutic discovery.
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Bancos de Muestras Biológicas , Proteínas Sanguíneas , Estudios de Asociación Genética , Genómica , Proteómica , Humanos , Alelos , Biomarcadores/sangre , Proteínas Sanguíneas/análisis , Proteínas Sanguíneas/genética , Bases de Datos Factuales , Exoma/genética , Hematopoyesis , Mutación , Plasma/química , Reino UnidoRESUMEN
The Mexico City Prospective Study is a prospective cohort of more than 150,000 adults recruited two decades ago from the urban districts of Coyoacán and Iztapalapa in Mexico City1. Here we generated genotype and exome-sequencing data for all individuals and whole-genome sequencing data for 9,950 selected individuals. We describe high levels of relatedness and substantial heterogeneity in ancestry composition across individuals. Most sequenced individuals had admixed Indigenous American, European and African ancestry, with extensive admixture from Indigenous populations in central, southern and southeastern Mexico. Indigenous Mexican segments of the genome had lower levels of coding variation but an excess of homozygous loss-of-function variants compared with segments of African and European origin. We estimated ancestry-specific allele frequencies at 142 million genomic variants, with an effective sample size of 91,856 for Indigenous Mexican ancestry at exome variants, all available through a public browser. Using whole-genome sequencing, we developed an imputation reference panel that outperforms existing panels at common variants in individuals with high proportions of central, southern and southeastern Indigenous Mexican ancestry. Our work illustrates the value of genetic studies in diverse populations and provides foundational imputation and allele frequency resources for future genetic studies in Mexico and in the United States, where the Hispanic/Latino population is predominantly of Mexican descent.
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Secuenciación del Exoma , Genoma Humano , Genotipo , Hispánicos o Latinos , Adulto , Humanos , África/etnología , Américas/etnología , Europa (Continente)/etnología , Frecuencia de los Genes/genética , Genética de Población , Genoma Humano/genética , Técnicas de Genotipaje , Hispánicos o Latinos/genética , Homocigoto , Mutación con Pérdida de Función/genética , México , Estudios ProspectivosRESUMEN
Genome-wide association studies have uncovered thousands of common variants associated with human disease, but the contribution of rare variants to common disease remains relatively unexplored. The UK Biobank contains detailed phenotypic data linked to medical records for approximately 500,000 participants, offering an unprecedented opportunity to evaluate the effect of rare variation on a broad collection of traits1,2. Here we study the relationships between rare protein-coding variants and 17,361 binary and 1,419 quantitative phenotypes using exome sequencing data from 269,171 UK Biobank participants of European ancestry. Gene-based collapsing analyses revealed 1,703 statistically significant gene-phenotype associations for binary traits, with a median odds ratio of 12.4. Furthermore, 83% of these associations were undetectable via single-variant association tests, emphasizing the power of gene-based collapsing analysis in the setting of high allelic heterogeneity. Gene-phenotype associations were also significantly enriched for loss-of-function-mediated traits and approved drug targets. Finally, we performed ancestry-specific and pan-ancestry collapsing analyses using exome sequencing data from 11,933 UK Biobank participants of African, East Asian or South Asian ancestry. Our results highlight a significant contribution of rare variants to common disease. Summary statistics are publicly available through an interactive portal ( http://azphewas.com/ ).
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Bancos de Muestras Biológicas , Bases de Datos Genéticas , Enfermedad/genética , Exoma/genética , Variación Genética/genética , Adulto , Anciano , Femenino , Estudio de Asociación del Genoma Completo , Humanos , Masculino , Persona de Mediana Edad , Fenotipo , Proteínas/química , Proteínas/genética , Reino Unido , Secuenciación del ExomaRESUMEN
Genome-wide association studies (GWASs) have established the contribution of common and low-frequency variants to metabolic blood measurements in the UK Biobank (UKB). To complement existing GWAS findings, we assessed the contribution of rare protein-coding variants in relation to 355 metabolic blood measurements-including 325 predominantly lipid-related nuclear magnetic resonance (NMR)-derived blood metabolite measurements (Nightingale Health Plc) and 30 clinical blood biomarkers-using 412,393 exome sequences from four genetically diverse ancestries in the UKB. Gene-level collapsing analyses were conducted to evaluate a diverse range of rare-variant architectures for the metabolic blood measurements. Altogether, we identified significant associations (p < 1 × 10-8) for 205 distinct genes that involved 1,968 significant relationships for the Nightingale blood metabolite measurements and 331 for the clinical blood biomarkers. These include associations for rare non-synonymous variants in PLIN1 and CREB3L3 with lipid metabolite measurements and SYT7 with creatinine, among others, which may not only provide insights into novel biology but also deepen our understanding of established disease mechanisms. Of the study-wide significant clinical biomarker associations, 40% were not previously detected on analyzing coding variants in a GWAS in the same cohort, reinforcing the importance of studying rare variation to fully understand the genetic architecture of metabolic blood measurements.
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Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma Completo , Humanos , Bancos de Muestras Biológicas , Biomarcadores , Lípidos , Reino Unido , Polimorfismo de Nucleótido SimpleRESUMEN
BACKGROUND: The U.K. 100,000 Genomes Project is in the process of investigating the role of genome sequencing in patients with undiagnosed rare diseases after usual care and the alignment of this research with health care implementation in the U.K. National Health Service. Other parts of this project focus on patients with cancer and infection. METHODS: We conducted a pilot study involving 4660 participants from 2183 families, among whom 161 disorders covering a broad spectrum of rare diseases were present. We collected data on clinical features with the use of Human Phenotype Ontology terms, undertook genome sequencing, applied automated variant prioritization on the basis of applied virtual gene panels and phenotypes, and identified novel pathogenic variants through research analysis. RESULTS: Diagnostic yields varied among family structures and were highest in family trios (both parents and a proband) and families with larger pedigrees. Diagnostic yields were much higher for disorders likely to have a monogenic cause (35%) than for disorders likely to have a complex cause (11%). Diagnostic yields for intellectual disability, hearing disorders, and vision disorders ranged from 40 to 55%. We made genetic diagnoses in 25% of the probands. A total of 14% of the diagnoses were made by means of the combination of research and automated approaches, which was critical for cases in which we found etiologic noncoding, structural, and mitochondrial genome variants and coding variants poorly covered by exome sequencing. Cohortwide burden testing across 57,000 genomes enabled the discovery of three new disease genes and 19 new associations. Of the genetic diagnoses that we made, 25% had immediate ramifications for clinical decision making for the patients or their relatives. CONCLUSIONS: Our pilot study of genome sequencing in a national health care system showed an increase in diagnostic yield across a range of rare diseases. (Funded by the National Institute for Health Research and others.).
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Genoma Humano , Enfermedades Raras/genética , Adolescente , Adulto , Niño , Preescolar , Composición Familiar , Femenino , Variación Genética , Humanos , Masculino , Persona de Mediana Edad , Proyectos Piloto , Reacción en Cadena de la Polimerasa , Enfermedades Raras/diagnóstico , Sensibilidad y Especificidad , Medicina Estatal , Reino Unido , Secuenciación Completa del Genoma , Adulto JovenRESUMEN
As an essential regulator of DNA damage, ataxia-telangiectasia mutated (ATM) gene has been widely studied in oncology. However, the independent effects of ATM missense variants and protein-truncating variants (PTVs) on neoplasms have not been heavily studied. Whole-exome sequencing data and the clinical health records of 394,694 UK Biobank European participants were used in this analysis. We mined genetic associations from gene-level and variant-level phenome-wide association studies, and conducted a variant-level conditional association study to test whether the effects of ATM missense variants on neoplasms were independent of ATM PTV carrier status. The gene-level PTV collapsing analysis was consistent with established ATM PTV literature showing that the aggregated impact of 286 ATM PTVs significantly (p < 2 × 10-9 ) associated with 31 malignant neoplasm phenotypes. Of 773 distinct protein-coding variants in ATM, three individual missense variants significantly (p < 2 × 10-9 ) associated with nine phenotypes. Remarkably, although the nine phenotypes were tumor-related, none overlapped the established ATM PTV-linked malignancies. A subsequent conditional analysis identified that the missense signals were acting independently of the known clinically relevant ATM PTVs.
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Proteínas de la Ataxia Telangiectasia Mutada , Neoplasias de la Mama , Mutación Missense , Neoplasias , Proteínas de la Ataxia Telangiectasia Mutada/genética , Bancos de Muestras Biológicas , Neoplasias de la Mama/genética , Proteínas de Ciclo Celular/genética , Proteínas de Unión al ADN/genética , Exoma , Femenino , Predisposición Genética a la Enfermedad , Humanos , Neoplasias/genética , Reino UnidoRESUMEN
Genomic technologies such as next-generation sequencing (NGS) are revolutionizing molecular diagnostics and clinical medicine. However, these approaches have proven inefficient at identifying pathogenic repeat expansions. Here, we apply a collection of bioinformatics tools that can be utilized to identify either known or novel expanded repeat sequences in NGS data. We performed genetic studies of a cohort of 35 individuals from 22 families with a clinical diagnosis of cerebellar ataxia with neuropathy and bilateral vestibular areflexia syndrome (CANVAS). Analysis of whole-genome sequence (WGS) data with five independent algorithms identified a recessively inherited intronic repeat expansion [(AAGGG)exp] in the gene encoding Replication Factor C1 (RFC1). This motif, not reported in the reference sequence, localized to an Alu element and replaced the reference (AAAAG)11 short tandem repeat. Genetic analyses confirmed the pathogenic expansion in 18 of 22 CANVAS-affected families and identified a core ancestral haplotype, estimated to have arisen in Europe more than twenty-five thousand years ago. WGS of the four RFC1-negative CANVAS-affected families identified plausible variants in three, with genomic re-diagnosis of SCA3, spastic ataxia of the Charlevoix-Saguenay type, and SCA45. This study identified the genetic basis of CANVAS and demonstrated that these improved bioinformatics tools increase the diagnostic utility of WGS to determine the genetic basis of a heterogeneous group of clinically overlapping neurogenetic disorders.
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Ataxia Cerebelosa/etiología , Biología Computacional/métodos , Intrones , Repeticiones de Microsatélite , Polineuropatías/etiología , Proteína de Replicación C/genética , Trastornos de la Sensación/etiología , Enfermedades Vestibulares/etiología , Algoritmos , Ataxia Cerebelosa/patología , Estudios de Cohortes , Familia , Femenino , Genómica , Humanos , Masculino , Persona de Mediana Edad , Polineuropatías/patología , Trastornos de la Sensación/patología , Síndrome , Enfermedades Vestibulares/patología , Secuenciación Completa del GenomaRESUMEN
PURPOSE: The aim of this study was to determine the genetic cause of autosomal dominant nonsyndromic hearing loss segregating in a multigenerational family. METHODS: Clinical examination, genome-wide linkage analysis, and exome sequencing were carried out on the family. RESULTS: Affected individuals presented with early-onset progressive mild hearing impairment with a fairly flat, gently downsloping or U-shaped audiogram configuration. Detailed clinical examination excluded any additional symptoms. Linkage analysis detected an interval on chromosome 1p21 with a logarithm of the odds (LOD) score of 8.29: designated locus DFNA37. Exome sequencing identified a novel canonical acceptor splice-site variant c.652-2A>C in the COL11A1 gene within the DFNA37 locus. Genotyping of all 48 family members confirmed segregation of this variant with the deafness phenotype in the extended family. The c.652-2A>C variant is novel, highly conserved, and confirmed in vitro to alter RNA splicing. CONCLUSION: We have identified COL11A1 as the gene responsible for deafness at the DFNA37 locus. Previously, COL11A1 was solely associated with Marshall and Stickler syndromes. This study expands its phenotypic spectrum to include nonsyndromic deafness. The implications of this discovery are valuable in the clinical diagnosis, prognosis, and treatment of patients with COL11A1 pathogenic variants.
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Colágeno Tipo XI/genética , Sordera/genética , Ligamiento Genético , Isoformas de Proteínas/genética , Adolescente , Adulto , Niño , Preescolar , Sordera/fisiopatología , Exoma/genética , Femenino , Genotipo , Humanos , Lactante , Recién Nacido , Masculino , Linaje , Fenotipo , Secuenciación del Exoma , Adulto JovenRESUMEN
Understanding how malaria parasites gain entry into human red blood cells is essential for developing strategies to stop blood stage infection. Plasmodium vivax preferentially invades reticulocytes, which are immature red blood cells. The organism has two erythrocyte-binding protein families: namely, the Duffy-binding protein (PvDBP) and the reticulocyte-binding protein (PvRBP) families. Several members of the PvRBP family bind reticulocytes, specifically suggesting a role in mediating host cell selectivity of P. vivax. Here, we present, to our knowledge, the first high-resolution crystal structure of an erythrocyte-binding domain from PvRBP2a, solved at 2.12 Å resolution. The monomeric molecule consists of 10 α-helices and one short ß-hairpin, and, although the structural fold is similar to that of PfRh5--the essential invasion ligand in Plasmodium falciparum--its surface properties are distinct and provide a possible mechanism for recognition of alternate receptors. Sequence alignments of the crystallized fragment of PvRBP2a with other PvRBPs highlight the conserved placement of disulfide bonds. PvRBP2a binds mature red blood cells through recognition of an erythrocyte receptor that is neuraminidase- and chymotrypsin-resistant but trypsin-sensitive. By examining the patterns of sequence diversity within field isolates, we have identified and mapped polymorphic residues to the PvRBP2a structure. Using mutagenesis, we have also defined the critical residues required for erythrocyte binding. Characterization of the structural features that govern functional erythrocyte binding for the PvRBP family provides a framework for generating new tools that block P. vivax blood stage infection.
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Secuencia Conservada , Eritrocitos/metabolismo , Plasmodium vivax/metabolismo , Proteínas Protozoarias/química , Proteínas Protozoarias/metabolismo , Secuencia de Aminoácidos , Área Bajo la Curva , Secuencia de Bases , Cristalografía por Rayos X , Evolución Molecular , Frecuencia de los Genes , Genes Protozoarios , Haplotipos , Humanos , Modelos Moleculares , Datos de Secuencia Molecular , Plasmodium falciparum/genética , Plasmodium falciparum/metabolismo , Plasmodium vivax/genética , Polimorfismo de Nucleótido Simple/genética , Estructura Terciaria de Proteína , Proteínas Protozoarias/genética , Dispersión del Ángulo Pequeño , Alineación de SecuenciaRESUMEN
We report siblings of consanguineous parents with an infantile-onset neurodegenerative disorder manifesting a predominant sensorimotor axonal neuropathy, optic atrophy and cognitive deficit. We used homozygosity mapping to identify an â¼12-Mbp interval identical by descent (IBD) between the affected individuals on chromosome 3q13.13-21.1 with an LOD score of 2.31. We combined family-based whole-exome and whole-genome sequencing of parents and affected siblings and, after filtering of likely non-pathogenic variants, identified a unique missense variant in syntaxin-binding protein 5-like (STXBP5L c.3127G>A, p.Val1043Ile [CCDS43137.1]) in the IBD interval. Considering other modes of inheritance, we also found compound heterozygous variants in FMNL3 (c.114G>C, p.Phe38Leu and c.1372T>G, p.Ile458Leu [CCDS44874.1]) located on chromosome 12. STXBP5L (or Tomosyn-2) is expressed in the central and peripheral nervous system and is known to inhibit neurotransmitter release through inhibition of the formation of the SNARE complexes between synaptic vesicles and the plasma membrane. FMNL3 is expressed more widely and is a formin family protein that is involved in the regulation of cell morphology and cytoskeletal organization. The STXBP5L p.Val1043Ile variant enhanced inhibition of exocytosis in comparison with wild-type (WT) STXBP5L. Furthermore, WT STXBP5L, but not variant STXBP5L, promoted axonal outgrowth in manipulated mouse primary hippocampal neurons. However, the FMNL3 p.Phe38Leu and p.Ile458Leu variants showed minimal effects in these cells. Collectively, our clinical, genetic and molecular data suggest that the IBD variant in STXBP5L is the likely cause of the disorder.
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Proteínas Portadoras/genética , Homocigoto , Enfermedades del Recién Nacido/genética , Mutación , Enfermedades Neurodegenerativas/genética , Proteínas Adaptadoras del Transporte Vesicular , Femenino , Humanos , Lactante , Recién Nacido , MasculinoRESUMEN
Leigh syndrome (LS) is a severe neurodegenerative disorder with characteristic bilateral lesions, typically in the brainstem and basal ganglia. It usually presents in infancy and is genetically heterogeneous, but most individuals with mitochondrial complex IV (or cytochrome c oxidase) deficiency have mutations in the biogenesis factor SURF1. We studied eight complex IV-deficient LS individuals from six families of Lebanese origin. They differed from individuals with SURF1 mutations in having seizures as a prominent feature. Complementation analysis suggested they had mutation(s) in the same gene but targeted massively parallel sequencing (MPS) of 1,034 genes encoding known mitochondrial proteins failed to identify a likely candidate. Linkage and haplotype analyses mapped the location of the gene to chromosome 19 and targeted MPS of the linkage region identified a homozygous c.3G>C (p.Met1?) mutation in C19orf79. Abolishing the initiation codon could potentially still allow initiation at a downstream methionine residue but we showed that this would not result in a functional protein. We confirmed that mutation of this gene was causative by lentiviral-mediated phenotypic correction. C19orf79 was recently renamed PET100 and predicted to encode a complex IV biogenesis factor. We showed that it is located in the mitochondrial inner membrane and forms a â¼300 kDa subcomplex with complex IV subunits. Previous proteomic analyses of mitochondria had overlooked PET100 because its small size was below the cutoff for annotating bona fide proteins. The mutation was estimated to have arisen at least 520 years ago, explaining how the families could have different religions and different geographic origins within Lebanon.
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Deficiencia de Citocromo-c Oxidasa/etnología , Deficiencia de Citocromo-c Oxidasa/genética , Efecto Fundador , Enfermedad de Leigh/etnología , Enfermedad de Leigh/genética , Proteínas Mitocondriales/genética , Cromosomas Humanos Par 19/genética , Ciclooxigenasa 2/genética , Ciclooxigenasa 2/metabolismo , Deficiencia de Citocromo-c Oxidasa/complicaciones , ADN Mitocondrial/genética , ADN Mitocondrial/aislamiento & purificación , Femenino , Prueba de Complementación Genética , Ligamiento Genético , Estudio de Asociación del Genoma Completo , Haplotipos , Homocigoto , Humanos , Lactante , Líbano , Enfermedad de Leigh/complicaciones , Masculino , Mitocondrias/genética , Mitocondrias/metabolismo , Mutación , Linaje , Polimorfismo de Nucleótido Simple , Proteómica , Análisis de Secuencia de ADNRESUMEN
Kufs disease, an adult-onset neuronal ceroid lipofuscinosis, is challenging to diagnose and genetically heterogeneous. Mutations in CLN6 were recently identified in recessive Kufs disease presenting as progressive myoclonus epilepsy (Type A), whereas the molecular basis of cases presenting with dementia and motor features (Type B) is unknown. We performed genome-wide linkage mapping of two families with recessive Type B Kufs disease and identified a single region on chromosome 11 to which both families showed linkage. Exome sequencing of five samples from the two families identified homozygous and compound heterozygous missense mutations in CTSF within this linkage region. We subsequently sequenced CTSF in 22 unrelated individuals with suspected recessive Kufs disease, and identified an additional patient with compound heterozygous mutations. CTSF encodes cathepsin F, a lysosomal cysteine protease, dysfunction of which is a highly plausible candidate mechanism for a storage disorder like ceroid lipofuscinosis. In silico modeling suggested the missense mutations would alter protein structure and function. Moreover, re-examination of a previously published mouse knockout of Ctsf shows that it recapitulates the light and electron-microscopic pathological features of Kufs disease. Although CTSF mutations account for a minority of cases of type B Kufs, CTSF screening should be considered in cases with early-onset dementia and may avoid the need for invasive biopsies.
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Catepsina F/genética , Mutación Missense , Lipofuscinosis Ceroideas Neuronales/genética , Adulto , Animales , Células del Asta Anterior/patología , Estudios de Casos y Controles , Catepsina F/metabolismo , Mapeo Cromosómico , Consanguinidad , Análisis Mutacional de ADN , Exoma , Femenino , Estudios de Asociación Genética , Humanos , Escala de Lod , Ratones , Ratones Noqueados , Persona de Mediana Edad , Modelos Moleculares , Lipofuscinosis Ceroideas Neuronales/enzimología , Lipofuscinosis Ceroideas Neuronales/patología , Linaje , Estructura Secundaria de Proteína , Estructura Terciaria de Proteína , Análisis de Secuencia de ARNRESUMEN
Autosomal-recessive congenital cerebellar ataxia was identified in Roma patients originating from a small subisolate with a known strong founder effect. Patients presented with global developmental delay, moderate to severe stance and gait ataxia, dysarthria, mild dysdiadochokinesia, dysmetria and tremors, intellectual deficit, and mild pyramidal signs. Brain imaging revealed progressive generalized cerebellar atrophy, and inferior vermian hypoplasia and/or a constitutionally small brain were observed in some patients. Exome sequencing, used for linkage analysis on extracted SNP genotypes and for mutation detection, identified two novel (i.e., not found in any database) variants located 7 bp apart within a unique 6q24 linkage region. Both mutations cosegregated with the disease in five affected families, in which all ten patients were homozygous. The mutated gene, GRM1, encodes metabotropic glutamate receptor mGluR1, which is highly expressed in cerebellar Purkinje cells and plays an important role in cerebellar development and synaptic plasticity. The two mutations affect a gene region critical for alternative splicing and the generation of receptor isoforms; they are a 3 bp exon 8 deletion and an intron 8 splicing mutation (c.2652_2654del and c.2660+2T>G, respectively [RefSeq accession number NM_000838.3]). The functional impact of the deletion is unclear and is overshadowed by the splicing defect. Although ataxia lymphoblastoid cell lines expressed GRM1 at levels comparable to those of control cells, the aberrant transcripts skipped exon 8 or ended in intron 8 and encoded various species of nonfunctional receptors either lacking the transmembrane domain and containing abnormal intracellular tails or completely missing the tail. The study implicates mGluR1 in human hereditary ataxia. It also illustrates the potential of the Roma founder populations for mutation identification by exome sequencing.
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Ataxia Cerebelosa/genética , Genes Recesivos , Mutación , Receptores de Glutamato Metabotrópico/genética , Adulto , Secuencia de Bases , Ataxia Cerebelosa/diagnóstico , Niño , Femenino , Humanos , Imagen por Resonancia Magnética , Masculino , LinajeRESUMEN
We performed hypothesis-free linkage analysis and exome sequencing in a family with two siblings who had neuronal ceroid lipofuscinosis (NCL). Two linkage peaks with maximum LOD scores of 3.07 and 2.97 were found on chromosomes 7 and 17, respectively. Unexpectedly, we found these siblings to be homozygous for a c.813_816del (p.Thr272Serfs∗10) mutation in the progranulin gene (GRN, granulin precursor) in the latter peak. Heterozygous mutations in GRN are a major cause of frontotemporal lobar degeneration with TDP-43 inclusions (FTLD-TDP), the second most common early-onset dementia. Reexamination of progranulin-deficient mice revealed rectilinear profiles typical of NCL. The age-at-onset and neuropathology of FTLD-TDP and NCL are markedly different. Our findings reveal an unanticipated link between a rare and a common neurological disorder and illustrate pleiotropic effects of a mutation in the heterozygous or homozygous states.
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Péptidos y Proteínas de Señalización Intercelular/genética , Mutación , Animales , Mapeo Cromosómico , Análisis Mutacional de ADN , Demencia/genética , Salud de la Familia , Femenino , Ligamiento Genético , Heterocigoto , Homocigoto , Humanos , Escala de Lod , Masculino , Ratones , Linaje , Fenotipo , ProgranulinasRESUMEN
High-throughput sequencing studies (HTS) have been highly successful in identifying the genetic causes of human disease, particularly those following Mendelian inheritance. Many HTS studies to date have been performed without utilizing available family relationships between samples. Here, we discuss the many merits and occasional pitfalls of using identity by descent information in conjunction with HTS studies. These methods are not only applicable to family studies but are also useful in cohorts of apparently unrelated, 'sporadic' cases and small families underpowered for linkage and allow inference of relationships between individuals. Incorporating familial/pedigree information not only provides powerful filtering options for the extensive variant lists that are usually produced by HTS but also allows valuable quality control checks, insights into the genetic model and the genotypic status of individuals of interest. In particular, these methods are valuable for challenging discovery scenarios in HTS analysis, such as in the study of populations poorly represented in variant databases typically used for filtering, and in the case of poor-quality HTS data.
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Secuenciación de Nucleótidos de Alto Rendimiento/métodos , Linaje , Polimorfismo de Nucleótido Simple/genética , Análisis de Secuencia de ADN/métodos , Familia , Ligamiento Genético , Variación Genética , Genotipo , Proyecto Mapa de Haplotipos , Humanos , Modelos Genéticos , Programas InformáticosRESUMEN
The molecular basis of Kufs disease is unknown, whereas a series of genes accounting for most of the childhood-onset forms of neuronal ceroid lipofuscinosis (NCL) have been identified. Diagnosis of Kufs disease is difficult because the characteristic lipopigment is largely confined to neurons and can require a brain biopsy or autopsy for final diagnosis. We mapped four families with Kufs disease for whom there was good evidence of autosomal-recessive inheritance and found two peaks on chromosome 15. Three of the families were affected by Kufs type A disease and presented with progressive myoclonus epilepsy, and one was affected by type B (presenting with dementia and motor system dysfunction). Sequencing of a candidate gene in one peak shared by all four families identified no mutations, but sequencing of CLN6, found in the second peak and shared by only the three families affected by Kufs type A disease, revealed pathogenic mutations in all three families. We subsequently sequenced CLN6 in eight other families, three of which were affected by recessive Kufs type A disease. Mutations in both CLN6 alleles were found in the three type A cases and in one family affected by unclassified Kufs disease. Mutations in CLN6 are the major cause of recessive Kufs type A disease. The phenotypic differences between variant late-infantile NCL, previously found to be caused by CLN6, and Kufs type A disease are striking; there is a much later age at onset and lack of visual involvement in the latter. Sequencing of CLN6 will provide a simple diagnostic strategy in this disorder, in which definitive identification usually requires invasive biopsy.
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Proteínas de la Membrana/genética , Mutación , Lipofuscinosis Ceroideas Neuronales/etiología , Lipofuscinosis Ceroideas Neuronales/genética , Adolescente , Adulto , Edad de Inicio , Biopsia , Demencia/patología , Exones , Femenino , Ligamiento Genético , Pruebas Genéticas/métodos , Genotipo , Heterocigoto , Humanos , Masculino , Persona de Mediana Edad , Linaje , Polimorfismo de Nucleótido SimpleRESUMEN
AIMS: To determine whether there is evidence of implicit memory formation during pediatric anesthesia using the word stem completion task. BACKGROUND: In adults, there is mixed evidence for implicit memory formation during anesthesia; however, there is no evidence in children. Implicit memory in adults has been detected using the word stem completion task. This test has not been used in a pediatric anesthetic setting. METHODS: A total of 200 patients aged 7-12 were randomized to hear one of the two lists of 10 words played continuously while anesthetized. Group 1 heard List A and Group 2 heard List B. Postoperatively, 194 completed a word stem completion task where they were required to complete the stems (the first part of words) corresponding to the words on the two word lists combined, with the first word that came to mind. RESULTS: Group 1 completed a mean of 2.78 words correctly from List A and a mean of 2.70 words correctly from List B. Group 2 completed a mean of 3.29 words correctly from List A and a mean of 3.66 words correctly from List B. For List A, there was no evidence (P = 0.70) for an association between intraoperative exposure to this list and the odds of successfully completing a stem from this list with the corresponding target word. There was little evidence (P = 0.09) for an association with List B. CONCLUSION: This study found no strong evidence that children form implicit memories for auditory words during anesthesia. Given the difference between lists, future research is warranted using carefully chosen word stems.
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Anestesia/psicología , Memoria/fisiología , Pruebas Neuropsicológicas , Niño , Monitores de Conciencia , Método Doble Ciego , Humanos , Modelos Logísticos , Recuerdo Mental/fisiologíaRESUMEN
Telomeres protect chromosome ends from damage and their length is linked with human disease and aging. We developed a joint telomere length metric, combining quantitative PCR and whole-genome sequencing measurements from 462,666 UK Biobank participants. This metric increased SNP heritability, suggesting that it better captures genetic regulation of telomere length. Exome-wide rare-variant and gene-level collapsing association studies identified 64 variants and 30 genes significantly associated with telomere length, including allelic series in ACD and RTEL1. Notably, 16% of these genes are known drivers of clonal hematopoiesis-an age-related somatic mosaicism associated with myeloid cancers and several nonmalignant diseases. Somatic variant analyses revealed gene-specific associations with telomere length, including lengthened telomeres in individuals with large SRSF2-mutant clones, compared with shortened telomeres in individuals with clonal expansions driven by other genes. Collectively, our findings demonstrate the impact of rare variants on telomere length, with larger effects observed among genes also associated with clonal hematopoiesis.
RESUMEN
Obesity is a major risk factor for many common diseases and has a substantial heritable component. To identify new genetic determinants, we performed exome-sequence analyses for adult body mass index (BMI) in up to 587,027 individuals. We identified rare loss-of-function variants in two genes (BSN and APBA1) with effects substantially larger than those of well-established obesity genes such as MC4R. In contrast to most other obesity-related genes, rare variants in BSN and APBA1 were not associated with normal variation in childhood adiposity. Furthermore, BSN protein-truncating variants (PTVs) magnified the influence of common genetic variants associated with BMI, with a common variant polygenic score exhibiting an effect twice as large in BSN PTV carriers than in noncarriers. Finally, we explored the plasma proteomic signatures of BSN PTV carriers as well as the functional consequences of BSN deletion in human induced pluripotent stem cell-derived hypothalamic neurons. Collectively, our findings implicate degenerative processes in synaptic function in the etiology of adult-onset obesity.