Diagnostic application of a capture based NGS test for the concurrent detection of variants in sequence and copy number as well as LOH

A. Vetro, D. Goidin, I. Lesende, I. Limongelli, G. N. Ranzani, F. Novara, M. C. Bonaglia, B. Rinaldi, F. Franchi, E. Manolakos, F. Lonardo, F. Scarano, G. Scarano, L. Costantino, S. Tedeschi, S. Giglio, O. Zuffardi

Research output: Contribution to journalArticle

4 Citations (Scopus)

Abstract

Whole exome sequencing (WES) has made the identification of causative SNVs/InDels associated with rare Mendelian conditions increasingly accessible. Incorporation of softwares allowing CNVs detection into the WES bioinformatics pipelines may increase the diagnostic yield. However, no standard protocols for this analysis are so far available and CNVs in non-coding regions are totally missed by WES, in spite of their possible role in the regulation of the flanking genes expression. So, in a number of cases the diagnostic workflow contemplates an initial investigation by genomic arrays followed, in the negative cases, by WES. The opposite workflow may also be applied, according to the familial segregation of the disease. We show preliminary results for a diagnostic application of a single next generation sequencing panel permitting the concurrent detection of LOH and variations in sequences and copy number. This approach allowed us to highlight compound heterozygosity for a CNV and a sequence variant in a number of cases, the duplication of a non-coding region responsible for sex reversal, and a whole-chromosome isodisomy causing reduction to homozygosity for a WFS1 variant. Moreover, the panel enabled us to detect deletions, duplications, and amplifications with sensitivity comparable to that of the most widely used array-CGH platforms.

Original languageEnglish
JournalClinical Genetics
DOIs
Publication statusAccepted/In press - 2017

Fingerprint

Exome
Workflow
Safe Sex
Gene Expression Regulation
Computational Biology
Software
Chromosomes

Keywords

  • Copy number variations
  • Exome sequencing
  • Genetic diagnosis
  • Isodisomy
  • Loss of heterozygosity

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

Cite this

Diagnostic application of a capture based NGS test for the concurrent detection of variants in sequence and copy number as well as LOH. / Vetro, A.; Goidin, D.; Lesende, I.; Limongelli, I.; Ranzani, G. N.; Novara, F.; Bonaglia, M. C.; Rinaldi, B.; Franchi, F.; Manolakos, E.; Lonardo, F.; Scarano, F.; Scarano, G.; Costantino, L.; Tedeschi, S.; Giglio, S.; Zuffardi, O.

In: Clinical Genetics, 2017.

Research output: Contribution to journalArticle

Vetro, A, Goidin, D, Lesende, I, Limongelli, I, Ranzani, GN, Novara, F, Bonaglia, MC, Rinaldi, B, Franchi, F, Manolakos, E, Lonardo, F, Scarano, F, Scarano, G, Costantino, L, Tedeschi, S, Giglio, S & Zuffardi, O 2017, 'Diagnostic application of a capture based NGS test for the concurrent detection of variants in sequence and copy number as well as LOH', Clinical Genetics. https://doi.org/10.1111/cge.13060
Vetro, A. ; Goidin, D. ; Lesende, I. ; Limongelli, I. ; Ranzani, G. N. ; Novara, F. ; Bonaglia, M. C. ; Rinaldi, B. ; Franchi, F. ; Manolakos, E. ; Lonardo, F. ; Scarano, F. ; Scarano, G. ; Costantino, L. ; Tedeschi, S. ; Giglio, S. ; Zuffardi, O. / Diagnostic application of a capture based NGS test for the concurrent detection of variants in sequence and copy number as well as LOH. In: Clinical Genetics. 2017.
@article{380c33f2059344a1a167a1f9e3d564f3,
title = "Diagnostic application of a capture based NGS test for the concurrent detection of variants in sequence and copy number as well as LOH",
abstract = "Whole exome sequencing (WES) has made the identification of causative SNVs/InDels associated with rare Mendelian conditions increasingly accessible. Incorporation of softwares allowing CNVs detection into the WES bioinformatics pipelines may increase the diagnostic yield. However, no standard protocols for this analysis are so far available and CNVs in non-coding regions are totally missed by WES, in spite of their possible role in the regulation of the flanking genes expression. So, in a number of cases the diagnostic workflow contemplates an initial investigation by genomic arrays followed, in the negative cases, by WES. The opposite workflow may also be applied, according to the familial segregation of the disease. We show preliminary results for a diagnostic application of a single next generation sequencing panel permitting the concurrent detection of LOH and variations in sequences and copy number. This approach allowed us to highlight compound heterozygosity for a CNV and a sequence variant in a number of cases, the duplication of a non-coding region responsible for sex reversal, and a whole-chromosome isodisomy causing reduction to homozygosity for a WFS1 variant. Moreover, the panel enabled us to detect deletions, duplications, and amplifications with sensitivity comparable to that of the most widely used array-CGH platforms.",
keywords = "Copy number variations, Exome sequencing, Genetic diagnosis, Isodisomy, Loss of heterozygosity",
author = "A. Vetro and D. Goidin and I. Lesende and I. Limongelli and Ranzani, {G. N.} and F. Novara and Bonaglia, {M. C.} and B. Rinaldi and F. Franchi and E. Manolakos and F. Lonardo and F. Scarano and G. Scarano and L. Costantino and S. Tedeschi and S. Giglio and O. Zuffardi",
year = "2017",
doi = "10.1111/cge.13060",
language = "English",
journal = "Clinical Genetics",
issn = "0009-9163",
publisher = "Wiley-Blackwell Publishing Ltd",

}

TY - JOUR

T1 - Diagnostic application of a capture based NGS test for the concurrent detection of variants in sequence and copy number as well as LOH

AU - Vetro, A.

AU - Goidin, D.

AU - Lesende, I.

AU - Limongelli, I.

AU - Ranzani, G. N.

AU - Novara, F.

AU - Bonaglia, M. C.

AU - Rinaldi, B.

AU - Franchi, F.

AU - Manolakos, E.

AU - Lonardo, F.

AU - Scarano, F.

AU - Scarano, G.

AU - Costantino, L.

AU - Tedeschi, S.

AU - Giglio, S.

AU - Zuffardi, O.

PY - 2017

Y1 - 2017

N2 - Whole exome sequencing (WES) has made the identification of causative SNVs/InDels associated with rare Mendelian conditions increasingly accessible. Incorporation of softwares allowing CNVs detection into the WES bioinformatics pipelines may increase the diagnostic yield. However, no standard protocols for this analysis are so far available and CNVs in non-coding regions are totally missed by WES, in spite of their possible role in the regulation of the flanking genes expression. So, in a number of cases the diagnostic workflow contemplates an initial investigation by genomic arrays followed, in the negative cases, by WES. The opposite workflow may also be applied, according to the familial segregation of the disease. We show preliminary results for a diagnostic application of a single next generation sequencing panel permitting the concurrent detection of LOH and variations in sequences and copy number. This approach allowed us to highlight compound heterozygosity for a CNV and a sequence variant in a number of cases, the duplication of a non-coding region responsible for sex reversal, and a whole-chromosome isodisomy causing reduction to homozygosity for a WFS1 variant. Moreover, the panel enabled us to detect deletions, duplications, and amplifications with sensitivity comparable to that of the most widely used array-CGH platforms.

AB - Whole exome sequencing (WES) has made the identification of causative SNVs/InDels associated with rare Mendelian conditions increasingly accessible. Incorporation of softwares allowing CNVs detection into the WES bioinformatics pipelines may increase the diagnostic yield. However, no standard protocols for this analysis are so far available and CNVs in non-coding regions are totally missed by WES, in spite of their possible role in the regulation of the flanking genes expression. So, in a number of cases the diagnostic workflow contemplates an initial investigation by genomic arrays followed, in the negative cases, by WES. The opposite workflow may also be applied, according to the familial segregation of the disease. We show preliminary results for a diagnostic application of a single next generation sequencing panel permitting the concurrent detection of LOH and variations in sequences and copy number. This approach allowed us to highlight compound heterozygosity for a CNV and a sequence variant in a number of cases, the duplication of a non-coding region responsible for sex reversal, and a whole-chromosome isodisomy causing reduction to homozygosity for a WFS1 variant. Moreover, the panel enabled us to detect deletions, duplications, and amplifications with sensitivity comparable to that of the most widely used array-CGH platforms.

KW - Copy number variations

KW - Exome sequencing

KW - Genetic diagnosis

KW - Isodisomy

KW - Loss of heterozygosity

UR - http://www.scopus.com/inward/record.url?scp=85029455419&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85029455419&partnerID=8YFLogxK

U2 - 10.1111/cge.13060

DO - 10.1111/cge.13060

M3 - Article

AN - SCOPUS:85029455419

JO - Clinical Genetics

JF - Clinical Genetics

SN - 0009-9163

ER -