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Integrated sequencing and array comparative genomic hybridization in familial Parkinson disease.
Robak, Laurie A; Du, Renqian; Yuan, Bo; Gu, Shen; Alfradique-Dunham, Isabel; Kondapalli, Vismaya; Hinojosa, Evelyn; Stillwell, Amanda; Young, Emily; Zhang, Chaofan; Song, Xiaofei; Du, Haowei; Gambin, Tomasz; Jhangiani, Shalini N; Coban Akdemir, Zeynep; Muzny, Donna M; Tejomurtula, Anusha; Ross, Owen A; Shaw, Chad; Jankovic, Joseph; Bi, Weimin; Posey, Jennifer E; Lupski, James R; Shulman, Joshua M.
Afiliação
  • Robak LA; Department of Molecular and Human Genetics (L.A.R., R.D., B.Y., S.G., V.K., E.H., A.S., E.Y., C.Z., X.S., H.D., T.G., Z.C.A., A.T., C.S., W.B., J.E.P., J.R.L., J.M.S.), Department of Neurology (I.A.-D., J.J., J.M.S.), and Human Genome Sequencing Center (S.N.J., D.M.M., J.R.L.), Baylor College of Med
  • Du R; Department of Molecular and Human Genetics (L.A.R., R.D., B.Y., S.G., V.K., E.H., A.S., E.Y., C.Z., X.S., H.D., T.G., Z.C.A., A.T., C.S., W.B., J.E.P., J.R.L., J.M.S.), Department of Neurology (I.A.-D., J.J., J.M.S.), and Human Genome Sequencing Center (S.N.J., D.M.M., J.R.L.), Baylor College of Med
  • Yuan B; Department of Molecular and Human Genetics (L.A.R., R.D., B.Y., S.G., V.K., E.H., A.S., E.Y., C.Z., X.S., H.D., T.G., Z.C.A., A.T., C.S., W.B., J.E.P., J.R.L., J.M.S.), Department of Neurology (I.A.-D., J.J., J.M.S.), and Human Genome Sequencing Center (S.N.J., D.M.M., J.R.L.), Baylor College of Med
  • Gu S; Department of Molecular and Human Genetics (L.A.R., R.D., B.Y., S.G., V.K., E.H., A.S., E.Y., C.Z., X.S., H.D., T.G., Z.C.A., A.T., C.S., W.B., J.E.P., J.R.L., J.M.S.), Department of Neurology (I.A.-D., J.J., J.M.S.), and Human Genome Sequencing Center (S.N.J., D.M.M., J.R.L.), Baylor College of Med
  • Alfradique-Dunham I; Department of Molecular and Human Genetics (L.A.R., R.D., B.Y., S.G., V.K., E.H., A.S., E.Y., C.Z., X.S., H.D., T.G., Z.C.A., A.T., C.S., W.B., J.E.P., J.R.L., J.M.S.), Department of Neurology (I.A.-D., J.J., J.M.S.), and Human Genome Sequencing Center (S.N.J., D.M.M., J.R.L.), Baylor College of Med
  • Kondapalli V; Department of Molecular and Human Genetics (L.A.R., R.D., B.Y., S.G., V.K., E.H., A.S., E.Y., C.Z., X.S., H.D., T.G., Z.C.A., A.T., C.S., W.B., J.E.P., J.R.L., J.M.S.), Department of Neurology (I.A.-D., J.J., J.M.S.), and Human Genome Sequencing Center (S.N.J., D.M.M., J.R.L.), Baylor College of Med
  • Hinojosa E; Department of Molecular and Human Genetics (L.A.R., R.D., B.Y., S.G., V.K., E.H., A.S., E.Y., C.Z., X.S., H.D., T.G., Z.C.A., A.T., C.S., W.B., J.E.P., J.R.L., J.M.S.), Department of Neurology (I.A.-D., J.J., J.M.S.), and Human Genome Sequencing Center (S.N.J., D.M.M., J.R.L.), Baylor College of Med
  • Stillwell A; Department of Molecular and Human Genetics (L.A.R., R.D., B.Y., S.G., V.K., E.H., A.S., E.Y., C.Z., X.S., H.D., T.G., Z.C.A., A.T., C.S., W.B., J.E.P., J.R.L., J.M.S.), Department of Neurology (I.A.-D., J.J., J.M.S.), and Human Genome Sequencing Center (S.N.J., D.M.M., J.R.L.), Baylor College of Med
  • Young E; Department of Molecular and Human Genetics (L.A.R., R.D., B.Y., S.G., V.K., E.H., A.S., E.Y., C.Z., X.S., H.D., T.G., Z.C.A., A.T., C.S., W.B., J.E.P., J.R.L., J.M.S.), Department of Neurology (I.A.-D., J.J., J.M.S.), and Human Genome Sequencing Center (S.N.J., D.M.M., J.R.L.), Baylor College of Med
  • Zhang C; Department of Molecular and Human Genetics (L.A.R., R.D., B.Y., S.G., V.K., E.H., A.S., E.Y., C.Z., X.S., H.D., T.G., Z.C.A., A.T., C.S., W.B., J.E.P., J.R.L., J.M.S.), Department of Neurology (I.A.-D., J.J., J.M.S.), and Human Genome Sequencing Center (S.N.J., D.M.M., J.R.L.), Baylor College of Med
  • Song X; Department of Molecular and Human Genetics (L.A.R., R.D., B.Y., S.G., V.K., E.H., A.S., E.Y., C.Z., X.S., H.D., T.G., Z.C.A., A.T., C.S., W.B., J.E.P., J.R.L., J.M.S.), Department of Neurology (I.A.-D., J.J., J.M.S.), and Human Genome Sequencing Center (S.N.J., D.M.M., J.R.L.), Baylor College of Med
  • Du H; Department of Molecular and Human Genetics (L.A.R., R.D., B.Y., S.G., V.K., E.H., A.S., E.Y., C.Z., X.S., H.D., T.G., Z.C.A., A.T., C.S., W.B., J.E.P., J.R.L., J.M.S.), Department of Neurology (I.A.-D., J.J., J.M.S.), and Human Genome Sequencing Center (S.N.J., D.M.M., J.R.L.), Baylor College of Med
  • Gambin T; Department of Molecular and Human Genetics (L.A.R., R.D., B.Y., S.G., V.K., E.H., A.S., E.Y., C.Z., X.S., H.D., T.G., Z.C.A., A.T., C.S., W.B., J.E.P., J.R.L., J.M.S.), Department of Neurology (I.A.-D., J.J., J.M.S.), and Human Genome Sequencing Center (S.N.J., D.M.M., J.R.L.), Baylor College of Med
  • Jhangiani SN; Department of Molecular and Human Genetics (L.A.R., R.D., B.Y., S.G., V.K., E.H., A.S., E.Y., C.Z., X.S., H.D., T.G., Z.C.A., A.T., C.S., W.B., J.E.P., J.R.L., J.M.S.), Department of Neurology (I.A.-D., J.J., J.M.S.), and Human Genome Sequencing Center (S.N.J., D.M.M., J.R.L.), Baylor College of Med
  • Coban Akdemir Z; Department of Molecular and Human Genetics (L.A.R., R.D., B.Y., S.G., V.K., E.H., A.S., E.Y., C.Z., X.S., H.D., T.G., Z.C.A., A.T., C.S., W.B., J.E.P., J.R.L., J.M.S.), Department of Neurology (I.A.-D., J.J., J.M.S.), and Human Genome Sequencing Center (S.N.J., D.M.M., J.R.L.), Baylor College of Med
  • Muzny DM; Department of Molecular and Human Genetics (L.A.R., R.D., B.Y., S.G., V.K., E.H., A.S., E.Y., C.Z., X.S., H.D., T.G., Z.C.A., A.T., C.S., W.B., J.E.P., J.R.L., J.M.S.), Department of Neurology (I.A.-D., J.J., J.M.S.), and Human Genome Sequencing Center (S.N.J., D.M.M., J.R.L.), Baylor College of Med
  • Tejomurtula A; Department of Molecular and Human Genetics (L.A.R., R.D., B.Y., S.G., V.K., E.H., A.S., E.Y., C.Z., X.S., H.D., T.G., Z.C.A., A.T., C.S., W.B., J.E.P., J.R.L., J.M.S.), Department of Neurology (I.A.-D., J.J., J.M.S.), and Human Genome Sequencing Center (S.N.J., D.M.M., J.R.L.), Baylor College of Med
  • Ross OA; Department of Molecular and Human Genetics (L.A.R., R.D., B.Y., S.G., V.K., E.H., A.S., E.Y., C.Z., X.S., H.D., T.G., Z.C.A., A.T., C.S., W.B., J.E.P., J.R.L., J.M.S.), Department of Neurology (I.A.-D., J.J., J.M.S.), and Human Genome Sequencing Center (S.N.J., D.M.M., J.R.L.), Baylor College of Med
  • Shaw C; Department of Molecular and Human Genetics (L.A.R., R.D., B.Y., S.G., V.K., E.H., A.S., E.Y., C.Z., X.S., H.D., T.G., Z.C.A., A.T., C.S., W.B., J.E.P., J.R.L., J.M.S.), Department of Neurology (I.A.-D., J.J., J.M.S.), and Human Genome Sequencing Center (S.N.J., D.M.M., J.R.L.), Baylor College of Med
  • Jankovic J; Department of Molecular and Human Genetics (L.A.R., R.D., B.Y., S.G., V.K., E.H., A.S., E.Y., C.Z., X.S., H.D., T.G., Z.C.A., A.T., C.S., W.B., J.E.P., J.R.L., J.M.S.), Department of Neurology (I.A.-D., J.J., J.M.S.), and Human Genome Sequencing Center (S.N.J., D.M.M., J.R.L.), Baylor College of Med
  • Bi W; Department of Molecular and Human Genetics (L.A.R., R.D., B.Y., S.G., V.K., E.H., A.S., E.Y., C.Z., X.S., H.D., T.G., Z.C.A., A.T., C.S., W.B., J.E.P., J.R.L., J.M.S.), Department of Neurology (I.A.-D., J.J., J.M.S.), and Human Genome Sequencing Center (S.N.J., D.M.M., J.R.L.), Baylor College of Med
  • Posey JE; Department of Molecular and Human Genetics (L.A.R., R.D., B.Y., S.G., V.K., E.H., A.S., E.Y., C.Z., X.S., H.D., T.G., Z.C.A., A.T., C.S., W.B., J.E.P., J.R.L., J.M.S.), Department of Neurology (I.A.-D., J.J., J.M.S.), and Human Genome Sequencing Center (S.N.J., D.M.M., J.R.L.), Baylor College of Med
  • Lupski JR; Department of Molecular and Human Genetics (L.A.R., R.D., B.Y., S.G., V.K., E.H., A.S., E.Y., C.Z., X.S., H.D., T.G., Z.C.A., A.T., C.S., W.B., J.E.P., J.R.L., J.M.S.), Department of Neurology (I.A.-D., J.J., J.M.S.), and Human Genome Sequencing Center (S.N.J., D.M.M., J.R.L.), Baylor College of Med
  • Shulman JM; Department of Molecular and Human Genetics (L.A.R., R.D., B.Y., S.G., V.K., E.H., A.S., E.Y., C.Z., X.S., H.D., T.G., Z.C.A., A.T., C.S., W.B., J.E.P., J.R.L., J.M.S.), Department of Neurology (I.A.-D., J.J., J.M.S.), and Human Genome Sequencing Center (S.N.J., D.M.M., J.R.L.), Baylor College of Med
Neurol Genet ; 6(5): e498, 2020 Oct.
Article em En | MEDLINE | ID: mdl-32802956
OBJECTIVE: To determine how single nucleotide variants (SNVs) and copy number variants (CNVs) contribute to molecular diagnosis in familial Parkinson disease (PD), we integrated exome sequencing (ES) and genome-wide array-based comparative genomic hybridization (aCGH) and further probed CNV structure to reveal mutational mechanisms. METHODS: We performed ES on 110 subjects with PD and a positive family history; 99 subjects were also evaluated using genome-wide aCGH. We interrogated ES and aCGH data for pathogenic SNVs and CNVs at Mendelian PD gene loci. We confirmed SNVs via Sanger sequencing and further characterized CNVs with custom-designed high-density aCGH, droplet digital PCR, and breakpoint sequencing. RESULTS: Using ES, we discovered individuals with known pathogenic SNVs in GBA (p.Glu365Lys, p.Thr408Met, p.Asn409Ser, and p.Leu483Pro) and LRRK2 (p.Arg1441Gly and p.Gly2019Ser). Two subjects were each double heterozygotes for variants in GBA and LRRK2. Based on aCGH, we additionally discovered cases with an SNCA duplication and heterozygous intragenic GBA deletion. Five additional subjects harbored both SNVs (p.Asn52Metfs*29, p.Thr240Met, p.Pro437Leu, and p.Trp453*) and likely disrupting CNVs at the PRKN locus, consistent with compound heterozygosity. In nearly all cases, breakpoint sequencing revealed microhomology, a mutational signature consistent with CNV formation due to DNA replication errors. CONCLUSIONS: Integrated ES and aCGH yielded a genetic diagnosis in 19.3% of our familial PD cohort. Our analyses highlight potential mechanisms for SNCA and PRKN CNV formation, uncover multilocus pathogenic variation, and identify novel SNVs and CNVs for further investigation as potential PD risk alleles.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Tipo de estudo: Prognostic_studies Idioma: En Revista: Neurol Genet Ano de publicação: 2020 Tipo de documento: Article
Texto completo
Imprimir
XML
PubMed Links
Buscar no Google

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Tipo de estudo: Prognostic_studies Idioma: En Revista: Neurol Genet Ano de publicação: 2020 Tipo de documento: Article