Mate Pair Sequencing for the Detection of Chromosomal Aberrations in Patients with Intellectual Disability and Congenital Malformations

Overview

Journal Eur J Hum Genet

Specialty Genetics

Date 2013 Oct 10

PMID 24105367

Citations 19

Authors

Sarah Vergult

Ellen van Binsbergen

Tom Sante

Silke Nowak

Olivier Vanakker

Kathleen Claes

Bruce Poppe

Nathalie Van der Aa

Markus J van Roosmalen

Karen Duran

Masoumeh Tavakoli-Yaraki

Marielle Swinkels

Marie-Jose van den Boogaard

Mieke van Haelst

Filip Roelens

Frank Speleman

Edwin Cuppen

Geert Mortier

Wigard P Kloosterman

Bjorn Menten

Affiliations

Soon will be listed here.

Abstract

Recently, microarrays have replaced karyotyping as a first tier test in patients with idiopathic intellectual disability and/or multiple congenital abnormalities (ID/MCA) in many laboratories. Although in about 14-18% of such patients, DNA copy-number variants (CNVs) with clinical significance can be detected, microarrays have the disadvantage of missing balanced rearrangements, as well as providing no information about the genomic architecture of structural variants (SVs) like duplications and complex rearrangements. Such information could possibly lead to a better interpretation of the clinical significance of the SV. In this study, the clinical use of mate pair next-generation sequencing was evaluated for the detection and further characterization of structural variants within the genomes of 50 ID/MCA patients. Thirty of these patients carried a chromosomal aberration that was previously detected by array CGH or karyotyping and suspected to be pathogenic. In the remaining 20 patients no causal SVs were found and only benign aberrations were detected by conventional techniques. Combined cluster and coverage analysis of the mate pair data allowed precise breakpoint detection and further refinement of previously identified balanced and (complex) unbalanced aberrations, pinpointing the causal gene for some patients. We conclude that mate pair sequencing is a powerful technology that can provide rapid and unequivocal characterization of unbalanced and balanced SVs in patient genomes and can be essential for the clinical interpretation of some SVs.

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