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


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.

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
Am J Med Genet A ; 182(11): 2666-2670, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32798301


With the increasing capabilities of non-invasive prenatal testing (NIPT), detection of sub-chromosomal deletions and duplications are possible. This case series of deletion rescues resulting in segmental homozygosity helps provide a biological explanation for NIPT discrepancies and adds to the dearth of existing literature surrounding segmental UPD cases and their underlying mechanisms. In the three cases presented here, NIPT reported a sub-chromosomal deletion (in isolation or as part of a complex finding). Diagnostic testing, however, revealed segmental homozygosity or UPD for the region reported deleted on NIPT. Postnatal placental testing was pursued in two cases and confirmed the NIPT findings. This discordance between the screening and diagnostic testing is suggestive of a corrective post-zygotic event, such as telomere capture and/or deletion rescue, ultimately resulting in segmental homozygosity and fetoplacental mosaicism. Imprinted chromosomes and autosomal recessive disease genes make homozygosity an important clinical consideration. Amniocentesis with SNP microarray is particularly useful in determining both copy number and UPD issues alike.

Amniocentese/métodos , Deleção Cromossômica , Homozigoto , Mosaicismo , Placenta/metabolismo , Diagnóstico Pré-Natal/métodos , Dissomia Uniparental/diagnóstico , Adulto , Cromossomos Humanos Par 13/genética , Cromossomos Humanos Par 20/genética , Cromossomos Humanos Par 8/genética , Feminino , Humanos , Recém-Nascido , Masculino , Gravidez , Dissomia Uniparental/genética , Adulto Jovem
Case Rep Obstet Gynecol ; 2019: 3259760, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31360565


This is a case report of a 31-year-old primigravida who was diagnosed with an asymptomatic acute parvovirus B19 infection in the second trimester of pregnancy and its suspected association with an increased nuchal translucency (NT) measurement. Parvovirus B19 is a single-stranded DNA virus that is cytotoxic to erythroid progenitor cells, causing inhibition of erythropoiesis. While maternal disease is usually mild, fetal infection can result in spontaneous abortion, aplastic anemia, nonimmune fetal hydrops, and fetal demise. This fetus had an increased NT of 3.2 mm at 11 weeks' gestation with a normal male karyotype and microarray analysis on chorionic villi sampling, in addition to a normal fetal echocardiogram at 15 weeks' gestation. The anatomy scan at 20 weeks' and 1-day gestation revealed fetal ascites, pleural effusion, and increased middle cerebral artery peak systolic velocity suspicious for fetal anemia. At this time, maternal serology for parvovirus was positive for IgM and IgG. Amniocentesis, cordocentesis, and intrauterine transfusion were performed. The amniocentesis revealed elevated parvovirus B19 DNA, quantitative PCR (2,589,801 copies/mL, reference range <100 copies/mL). The patient delivered a viable male fetus at 37 weeks' and 6-day gestation, without sequelae of the previously noted hydrops. Parvovirus B19 infection should be a consideration when evaluating increased NT and hydrops fetalis. It warrants close antepartum surveillance and possible intrauterine fetal transfusions. With prompt recognition, proper treatment, and surveillance, these patients can go on to achieve healthy term deliveries. Long-term outcomes of delivered infants require further study.