RESUMEN
Here we describe two cases of HaNDL (Headache with Neurological Deficits and cerebrospinal fluid Lymphocytosis). A thirty year old man with episodes of headache with lateralizing symptoms and confusion and a 41 year old man with headache, aphasia and right hemiparesis. Symptoms resolved completely in both patients. Considerable cerebrospinal fluid lymphocytosis was present but no signs of CNS infection and MRIs of the brain were normal. Although the cause of HaNDL is unknown, it is thought to be triggered by a viral infection by some. The prognosis is excellent and symptoms normally resolve within 1-3 weeks. It is important to rule out more serious etiologies like stroke, subarachnoid hemorrhage or central nervous system infections.
Asunto(s)
Linfocitosis , Enfermedades del Sistema Nervioso , Accidente Cerebrovascular , Adulto , Cefalea/diagnóstico , Cefalea/etiología , Humanos , Linfocitosis/diagnóstico , Masculino , SíndromeRESUMEN
Mutation of the DNA molecule is one of the most fundamental processes in biology. In this study, we use 283 parent-offspring trios to estimate the rate of mutation for both single nucleotide variants (SNVs) and short length variants (indels) in humans and examine the mutation process. We found 17812 SNVs, corresponding to a mutation rate of 1.29 × 10-8 per position per generation (PPPG) and 1282 indels corresponding to a rate of 9.29 × 10-10 PPPG. We estimate that around 3% of human de novo SNVs are part of a multi-nucleotide mutation (MNM), with 558 (3.1%) of mutations positioned less than 20kb from another mutation in the same individual (median distance of 525bp). The rate of de novo mutations is greater in late replicating regions (p = 8.29 × 10-19) and nearer recombination events (p = 0.0038) than elsewhere in the genome.
Asunto(s)
Genoma Humano , Mutación INDEL/genética , Tasa de Mutación , Análisis Mutacional de ADN , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Polimorfismo de Nucleótido Simple/genética , Recombinación Genética/genéticaRESUMEN
Mycobacterium tuberculosis infections cause 9 million new tuberculosis cases and 1.5 million deaths annually. To identify variants conferring risk of tuberculosis, we tested 28.3 million variants identified through whole-genome sequencing of 2,636 Icelanders for association with tuberculosis (8,162 cases and 277,643 controls), pulmonary tuberculosis (PTB) and M. tuberculosis infection. We found association of three variants in the region harboring genes encoding the class II human leukocyte antigens (HLAs): rs557011[T] (minor allele frequency (MAF) = 40.2%), associated with M. tuberculosis infection (odds ratio (OR) = 1.14, P = 3.1 × 10(-13)) and PTB (OR = 1.25, P = 5.8 × 10(-12)), and rs9271378[G] (MAF = 32.5%), associated with PTB (OR = 0.78, P = 2.5 × 10(-12))--both located between HLA-DQA1 and HLA-DRB1--and a missense variant encoding p.Ala210Thr in HLA-DQA1 (MAF = 19.1%, rs9272785), associated with M. tuberculosis infection (P = 9.3 × 10(-9), OR = 1.14). We replicated association of these variants with PTB in samples of European ancestry from Russia and Croatia (P < 5.9 × 10(-4)). These findings show that the HLA class II region contributes to genetic risk of tuberculosis, possibly through reduced presentation of protective M. tuberculosis antigens to T cells.
Asunto(s)
Cadenas alfa de HLA-DQ/genética , Cadenas HLA-DRB1/genética , Mycobacterium tuberculosis/patogenicidad , Tuberculosis Pulmonar/genética , Alelos , Frecuencia de los Genes , Predisposición Genética a la Enfermedad , Variación Genética , Genoma Humano , Estudio de Asociación del Genoma Completo , Cadenas alfa de HLA-DQ/inmunología , Cadenas HLA-DRB1/inmunología , Humanos , Islandia , Mycobacterium tuberculosis/genética , Mycobacterium tuberculosis/inmunología , Factores de Riesgo , Linfocitos T/inmunología , Tuberculosis Pulmonar/inmunología , Tuberculosis Pulmonar/microbiología , Población BlancaRESUMEN
Sequence variants affecting blood lipids and coronary artery disease (CAD) may enhance understanding of the atherogenicity of lipid fractions. Using a large resource of whole-genome sequence data, we examined rare and low-frequency variants for association with non-HDL cholesterol, HDL cholesterol, LDL cholesterol, and triglycerides in up to 119,146 Icelanders. We discovered 13 variants with large effects (within ANGPTL3, APOB, ABCA1, NR1H3, APOA1, LIPC, CETP, LDLR, and APOC1) and replicated 14 variants. Five variants within PCSK9, APOA1, ANGPTL4, and LDLR associate with CAD (33,090 cases and 236,254 controls). We used genetic risk scores for the lipid fractions to examine their causal relationship with CAD. The non-HDL cholesterol genetic risk score associates most strongly with CAD (P = 2.7 × 10(-28)), and no other genetic risk score associates with CAD after accounting for non-HDL cholesterol. The genetic risk score for non-HDL cholesterol confers CAD risk beyond that of LDL cholesterol (P = 5.5 × 10(-8)), suggesting that targeting atherogenic remnant cholesterol may reduce cardiovascular risk.