Genome-wide identification of disease-causing copy number variations in 450 individuals with anorectal malformations
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Published:2022-11-01
Issue:1
Volume:31
Page:105-111
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ISSN:1018-4813
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Container-title:European Journal of Human Genetics
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language:en
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Short-container-title:Eur J Hum Genet
Author:
Fabian Julia, Dworschak Gabriel C.ORCID, Waffenschmidt Lea, Schierbaum Luca, Bendixen Charlotte, Heilmann-Heimbach StefanieORCID, Sivalingam Sugirthan, Buness Andreas, Schwarzer Nicole, Boemers Thomas M., Schmiedeke Eberhard, Neser Jörg, Leonhardt Johannes, Kosch Ferdinand, Weih Sandra, Gielen Helen Maya, Hosie Stuart, Kabs Carmen, Palta Markus, Märzheuser Stefanie, Bode Lena Marie, Lacher Martin, Schäfer Frank-Mattias, Stehr Maximilian, Knorr Christian, Ure Benno, Kleine Katharina, Rolle Udo, Zaniew Marcin, Phillip GroteORCID, Zwink Nadine, Jenetzky EkkehartORCID, Reutter HeikoORCID, Hilger Alina C.ORCID
Abstract
AbstractAnorectal malformations (ARM) represent a spectrum of rare malformations originating from a perturbated development of the embryonic hindgut. Approximately 60% occur as a part of a defined genetic syndrome or within the spectrum of additional congenital anomalies. Rare copy number variations (CNVs) have been associated with both syndromic and non-syndromic forms. The present study represents the largest study to date to explore the contribution of CNVs to the expression of ARMs. SNP-array-based molecular karyotyping was applied in 450 individuals with ARM and 4392 healthy controls. CNVs were identified from raw intensity data using PennCNV. Overlapping CNVs between cases and controls were discarded. Remaining CNVs were filtered using a stringent filter algorithm of nine filter steps. Prioritized CNVs were confirmed using qPCR. Filtering prioritized and qPCR confirmed four microscopic chromosomal anomalies and nine submicroscopic CNVs comprising seven microdeletions (del2p13.2, del4p16.2, del7q31.33, del9p24.1, del16q12.1, del18q32, del22q11.21) and two microduplications (dup2p13.2, dup17q12) in 14 individuals (12 singletons and one affected sib-pair). Within these CNVs, based on their embryonic expression data and function, we suggest FOXK2, LPP, and SALL3 as putative candidate genes. Overall, our CNV analysis identified putative microscopic and submicroscopic chromosomal rearrangements in 3% of cases. Functional characterization and re-sequencing of suggested candidate genes is warranted.
Publisher
Springer Science and Business Media LLC
Subject
Genetics (clinical),Genetics
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