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.

Genome-Wide Detection and Analysis of Copy Number Variation in Anhui Indigenous and Western Commercial Pig Breeds Using Porcine 80K SNP BeadChip

“…In human studies, the disruption of FOXK2 was found to be associated with central nervous system abnormalities and intellectual disability [ 39 ]. Using an SNP BeadChip, Fabian et al [ 40 ] identified some CNVs in a population with anorectal malformations (ARM) disease, confirmed the presence of nine submicroscopic CNVs using qPCR and suggested several genes, such as FOXK2 , as factors causing ARM disease. The mannose-binding lectin 2 ( MBL2 ) gene is one of the members of the C-type (Ca 2+ dependent) lectin gene superfamily and plays an important role in the first line of defense against pathogen infection [ 41 ].…”

Anorectal Malformations are Part of the Phenotypic Spectrum of Coffin-Siris Syndrome: Case Report and Review of the Literature

“…Chromosomal causes of ARMs represent 5 to 15% of the cases. They include aneuploidies (in particular trisomy 21 found approximately in 2% of ARM) and Copy Number Variations (CNV, approximately found in 3% of ARM) [5,7]. Monogenic variants explain up to 1/3 of syndromic ARMs, and are very heterogeneous [8].…”