RESUMEN
BACKGROUND: AnWj is a high-incidence blood group antigen associated with three clinical disorders: lymphoid malignancies, immunologic disorders, and autoimmune hemolytic anemia. The aim of this study was to determine the genetic basis of an inherited AnWj-negative phenotype. METHODS: We identified a consanguineous family with two AnWj-negative siblings and 4 additional AnWj-negative individuals without known familial relationship to the index family. We performed exome sequencing in search for rare homozygous variants shared by the two AnWj-negative siblings of the index family and searched for these variants in the four non-related AnWj-negative individuals. RESULTS: Exome sequencing revealed seven candidate genes that showed complete segregation in the index family and for which the two AnWj-negative siblings were homozygous. However, the four additional non-related AnWj-negative subjects were homozygous for only one of these variants, rs114851602 (R320Q) in the SMYD1 gene. Considering the frequency of the minor allele, the chance of randomly finding 4 consecutive such individuals is 2.56 × 10-18 . CONCLUSION: We present genetic and statistical evidence that the R320Q substitution in SMYD1 underlies an inherited form of the AnWj-negative blood group phenotype. The mechanism by which the mutation leads to this phenotype remains to be determined.
Asunto(s)
Antígenos de Grupos Sanguíneos/genética , Antígenos de Grupos Sanguíneos/metabolismo , Proteínas de Unión al ADN/genética , Proteínas Musculares/genética , Fenotipo , Factores de Transcripción/genética , Adulto , Antígenos de Grupos Sanguíneos/química , Proteínas de Unión al ADN/química , Eritrocitos/inmunología , Eritrocitos/metabolismo , Evolución Molecular , Femenino , Frecuencia de los Genes , Variación Genética , Genotipo , Humanos , Masculino , Modelos Moleculares , Proteínas Musculares/química , Linaje , Polimorfismo de Nucleótido Simple , Conformación Proteica , Factores de Transcripción/química , Secuenciación del ExomaRESUMEN
OBJECTIVES: Cryopyrin associated periodic syndromes (CAPS) comprise a spectrum of autoinflammatory disorders of varying severity caused by mutations in the NLRP3 gene. The NLRP3-Q703K allele has been reported both as a functional polymorphism and as a low penetrance mutation. METHODS: To describe the clinical phenotype of subjects with the Q703K allele and to report the frequency of this allele among patients with autoinflammatory symptoms and healthy controls. To this end, a cohort of 10 ethnically-matched controls per each Q703K-carrying patient, was composed. RESULTS: Ninety patients suspected of harboring a systemic autoinflammatory disease (SAID), exclusive of FMF, were referred to our center for genotyping between 2012 and 2015. Fourteen of them (15.5%) were found to carry the Q703K allele, compared to 22 of 130 (16.9%) healthy, ethnically matched controls. CONCLUSIONS: The similar carrier rate of the NLRP3-Q703K allele among patients with manifestations of a SAID and an ethnically matched control group suggest that this variant, does not determine the clinical phenotype. This reiterates the importance of testing a control group to avoid erroneously attributing a causative role to a gene polymorphism.
Asunto(s)
Síndromes Periódicos Asociados a Criopirina/genética , Proteína con Dominio Pirina 3 de la Familia NLR/genética , Polimorfismo Genético , Estudios de Casos y Controles , Síndromes Periódicos Asociados a Criopirina/diagnóstico , Síndromes Periódicos Asociados a Criopirina/etnología , Síndromes Periódicos Asociados a Criopirina/inmunología , Frecuencia de los Genes , Estudios de Asociación Genética , Predisposición Genética a la Enfermedad , Heterocigoto , Humanos , Israel/epidemiología , Epidemiología Molecular , Fenotipo , Factores de RiesgoRESUMEN
OBJECTIVE: To investigate the effectiveness of low-dose aspirin (LDA) in the prevention of pre-eclampsia (PE) among otherwise low-risk twin gestations. METHODS: A historical cohort study consisting of all pregnant individuals with dichorionic diamniotic (DCDA) twin pregnancy who delivered between 2014 and 2020. Patients treated with LDA were matched by a 1:4 ratio to individuals who were not treated with LDA by age, body mass index and parity. RESULTS: During the study period, 2271 individuals carrying DCDA pregnancies delivered at our center. Of these, 404 were excluded for one or more additional major risk factors. The remaining cohort consisted of 1867 individuals of whom 142 (7.6%) were treated with LDA and were compared with a 1:4 matched group of 568 individuals who were not treated. The rate of preterm PE did not differ significantly between the two groups (18 [12.7%] in the LDA group vs. 55 [9.7%] in the no-LDA group; P = 0.294, adjusted odds ratio 1.36, 95% confidence interval 0.77-2.40). There were no other significant between-group differences. CONCLUSIONS: Low-dose aspirin treatment in pregnant individuals with DCDA twin gestations without additional major risk factors was not associated with a reduction in the rate of preterm PE.