Dataset Information

Genome-wide identification of disease-causing copy number variations in 450 individuals with anorectal malformations.

ABSTRACT: Anorectal 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.

SUBMITTER: Fabian J

PROVIDER: S-EPMC9822900 | biostudies-literature | 2023 Jan

REPOSITORIES: biostudies-literature

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Genome-wide identification of disease-causing copy number variations in 450 individuals with anorectal malformations.

Fabian Julia J Dworschak Gabriel C GC Waffenschmidt Lea L Schierbaum Luca L Bendixen Charlotte C Heilmann-Heimbach Stefanie S Sivalingam Sugirthan S Buness Andreas A Schwarzer Nicole N Boemers Thomas M TM Schmiedeke Eberhard E Neser Jörg J Leonhardt Johannes J Kosch Ferdinand F Weih Sandra S Gielen Helen Maya HM Hosie Stuart S Kabs Carmen C Palta Markus M Märzheuser Stefanie S Bode Lena Marie LM Lacher Martin M Schäfer Frank-Mattias FM Stehr Maximilian M Knorr Christian C Ure Benno B Kleine Katharina K Rolle Udo U Zaniew Marcin M Phillip Grote G Zwink Nadine N Jenetzky Ekkehart E Reutter Heiko H Hilger Alina C AC

European journal of human genetics : EJHG 20221101 1

Anorectal 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 ...[more]

PMID: 36319675

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Project description:MotivationCopy number variations (CNV) include net gains or losses of part or whole chromosomal regions. They differ from copy neutral loss of heterozygosity (cn-LOH) events which do not induce any net change in the copy number and are often associated with uniparental disomy. These phenomena have long been reported to be associated with diseases and particularly in cancer. Losses/gains of genomic regions are often correlated with lower/higher gene expression. On the other hand, loss of heterozygosity (LOH) and cn-LOH are common events in cancer and may be associated with the loss of a functional tumor suppressor gene. Therefore, identifying recurrent CNV and cn-LOH events can be important as they may highlight common biological components and give insights into the development or mechanisms of a disease. However, no currently available tools allow a comprehensive whole-genome visualization of recurrent CNVs and cn-LOH in groups of samples providing absolute quantification of the aberrations leading to the loss of potentially important information.ResultsTo overcome these limitations, we developed aCNViewer (Absolute CNV Viewer), a visualization tool for absolute CNVs and cn-LOH across a group of samples. aCNViewer proposes three graphical representations: dendrograms, bi-dimensional heatmaps showing chromosomal regions sharing similar abnormality patterns, and quantitative stacked histograms facilitating the identification of recurrent absolute CNVs and cn-LOH. We illustrated aCNViewer using publically available hepatocellular carcinomas (HCCs) Affymetrix SNP Array data (Fig 1A). Regions 1q and 8q present a similar percentage of total gains but significantly different copy number gain categories (p-value of 0.0103 with a Fisher exact test), validated by another cohort of HCCs (p-value of 5.6e-7) (Fig 2B).Availability and implementationaCNViewer is implemented in python and R and is available with a GNU GPLv3 license on GitHub https://github.com/FJD-CEPH/aCNViewer and Docker https://hub.docker.com/r/fjdceph/acnviewer/.ContactaCNViewer@cephb.fr.

Dataset Information

Genome-wide identification of disease-causing copy number variations in 450 individuals with anorectal malformations.

Publications

Genome-wide identification of disease-causing copy number variations in 450 individuals with anorectal malformations.

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