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1.
Am J Hum Genet ; 108(8): 1436-1449, 2021 08 05.
Artigo em Inglês | MEDLINE | ID: mdl-34216551

RESUMO

Despite widespread clinical genetic testing, many individuals with suspected genetic conditions lack a precise diagnosis, limiting their opportunity to take advantage of state-of-the-art treatments. In some cases, testing reveals difficult-to-evaluate structural differences, candidate variants that do not fully explain the phenotype, single pathogenic variants in recessive disorders, or no variants in genes of interest. Thus, there is a need for better tools to identify a precise genetic diagnosis in individuals when conventional testing approaches have been exhausted. We performed targeted long-read sequencing (T-LRS) using adaptive sampling on the Oxford Nanopore platform on 40 individuals, 10 of whom lacked a complete molecular diagnosis. We computationally targeted up to 151 Mbp of sequence per individual and searched for pathogenic substitutions, structural variants, and methylation differences using a single data source. We detected all genomic aberrations-including single-nucleotide variants, copy number changes, repeat expansions, and methylation differences-identified by prior clinical testing. In 8/8 individuals with complex structural rearrangements, T-LRS enabled more precise resolution of the mutation, leading to changes in clinical management in one case. In ten individuals with suspected Mendelian conditions lacking a precise genetic diagnosis, T-LRS identified pathogenic or likely pathogenic variants in six and variants of uncertain significance in two others. T-LRS accurately identifies pathogenic structural variants, resolves complex rearrangements, and identifies Mendelian variants not detected by other technologies. T-LRS represents an efficient and cost-effective strategy to evaluate high-priority genes and regions or complex clinical testing results.


Assuntos
Aberrações Cromossômicas , Análise Citogenética/métodos , Doenças Genéticas Inatas/diagnóstico , Doenças Genéticas Inatas/genética , Predisposição Genética para Doença , Genoma Humano , Mutação , Variações do Número de Cópias de DNA , Feminino , Testes Genéticos , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Cariotipagem , Masculino , Análise de Sequência de DNA
2.
J Pediatr Urol ; 16(2): 241-243, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32265103

RESUMO

The Mirena intrauterine device (IUD) is a hormone-secreting contraceptive device. Pregnancy with the Mirena is rare and effects to the fetus are unknown. Here we present four females with genital virilization after pregnancy with persistent Mirena IUD. All patients had a 46, XX karyotype and normal hormone evaluation. All underwent exam under anesthesia, demonstrating posterior labial fusion and short urogenital sinus with normal bladder, urethra, vagina, and cervix. Three of four patients underwent flap vaginoplasty without complications and good cosmetic outcomes. This series suggests that persistent levonorgestrel-secreting IUD during pregnancy is associated with genital virilization in female fetuses.


Assuntos
Dispositivos Intrauterinos Medicados , Levanogestrel , Feminino , Humanos , Lactente , Dispositivos Intrauterinos Medicados/efeitos adversos , Gravidez , Virilismo
3.
Am J Med Genet A ; 182(3): 543-547, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31814264

RESUMO

We describe a 5-year-old male with developmental delay, behavioral problems, and dysmorphic features who was found by microarray to have a 93-kb duplication of uncertain significance that fully encompasses the third exon of CTNND2 (delta catenin). Mate-pair sequencing was used to determine that the duplication is tandem and is predicted to lead to CTNND2 haploinsufficiency. Haploinsufficiency for CTNND2 has been shown to result in developmental delay and intellectual disability, providing a unifying diagnosis for this patient. His features overlap those associated with the larger cri-du-chat deletion of this region, expanding the clinical phenotype of isolated CTNND2 variants. The use of mate-pair sequencing to determine the orientation of the small duplication was essential to the diagnosis and avoided the use of exome sequencing, which would not have defined the arrangement of the duplication. This is only the second reported patient, to our knowledge, with a single exon duplication of CTNND2.


Assuntos
Anormalidades Múltiplas/genética , Transtorno Autístico/genética , Cateninas/genética , Predisposição Genética para Doença , Atrofia Muscular/genética , Anormalidades Múltiplas/diagnóstico , Anormalidades Múltiplas/patologia , Transtorno Autístico/diagnóstico , Transtorno Autístico/patologia , Criança , Pré-Escolar , Éxons/genética , Facies , Feminino , Genes Duplicados/genética , Haploinsuficiência/genética , Humanos , Masculino , Atrofia Muscular/diagnóstico , Atrofia Muscular/patologia , Linhagem , Comportamento Problema
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