title: Post-mortem cytogenomic investigations in patients with congenital malformations.
abstract: Congenital anomalies are the second highest cause of infant deaths, and, in most cases, diagnosis is a challenge. In this study, we characterize patterns of DNA copy number aberrations in different samples of post-mortem tissues from patients with congenital malformations. Twenty-eight patients undergoing autopsy were cytogenomically evaluated using several methods, specifically, Multiplex Ligation-dependent Probe Amplification (MLPA), microsatellite marker analysis with a MiniFiler kit, FISH, a cytogenomic array technique and bidirectional Sanger sequencing, which were performed on samples of different tissues (brain, heart, liver, skin and diaphragm) preserved in RNAlater, in formaldehyde or by paraffin-embedding. The results identified 13 patients with pathogenic copy number variations (CNVs). Of these, eight presented aneuploidies involving chromosomes 13, 18, 21, X and Y (two presented inter- and intra-tissue mosaicism). In addition, other abnormalities were found, including duplication of the TYMS gene (18p11.32); deletion of the CHL1 gene (3p26.3); deletion of the HIC1 gene (17p13.3); and deletion of the TOM1L2 gene (17p11.2). One patient had a pathogenic missense mutation of g.8535C>G (c.746C>G) in exon 7 of the FGFR3 gene consistent with Thanatophoric Dysplasia type I. Cytogenomic techniques were reliable for the analysis of autopsy material and allowed the identification of inter- and intra-tissue mosaicism and a better understanding of the pathogenesis of congenital malformations.
authors.affiliation: Department of Pathology, Cytogenomic Laboratory - LIM 03 - HC-FMUSP, Universidade de São Paulo, SP, Brazil. Electronic address: alexandre-dias@usp.br.
authors.forename: Alexandre Torchio
authors.initials: AT
authors.lastname: Dias
authors.affiliation: Department of Pathology, Cytogenomic Laboratory - LIM 03 - HC-FMUSP, Universidade de São Paulo, SP, Brazil.
authors.forename: Évelin Aline
authors.initials: ÉA
authors.lastname: Zanardo
authors.affiliation: Department of Pathology, Cytogenomic Laboratory - LIM 03 - HC-FMUSP, Universidade de São Paulo, SP, Brazil.
authors.forename: Roberta Lelis
authors.initials: RL
authors.lastname: Dutra
authors.affiliation: Department of Pathology, Cytogenomic Laboratory - LIM 03 - HC-FMUSP, Universidade de São Paulo, SP, Brazil.
authors.forename: Flavia Balbo
authors.initials: FB
authors.lastname: Piazzon
authors.affiliation: Department of Pathology, Cytogenomic Laboratory - LIM 03 - HC-FMUSP, Universidade de São Paulo, SP, Brazil.
authors.forename: Gil Monteiro
authors.initials: GM
authors.lastname: Novo-Filho
authors.affiliation: Department of Pathology, Cytogenomic Laboratory - LIM 03 - HC-FMUSP, Universidade de São Paulo, SP, Brazil.
authors.forename: Marilia Moreira
authors.initials: MM
authors.lastname: Montenegro
authors.affiliation: Department of Pathology, Cytogenomic Laboratory - LIM 03 - HC-FMUSP, Universidade de São Paulo, SP, Brazil.
authors.forename: Amom Mendes
authors.initials: AM
authors.lastname: Nascimento
authors.affiliation: Department of Pathology, Cytogenomic Laboratory - LIM 03 - HC-FMUSP, Universidade de São Paulo, SP, Brazil; Human Reproduction and Genetic Center, Department of Coletive Health - Faculdade de Medicina do ABC, Santo André, SP, Brazil.
authors.forename: Mariana
authors.initials: M
authors.lastname: Rocha
authors.affiliation: Department of Pathology, Cytogenomic Laboratory - LIM 03 - HC-FMUSP, Universidade de São Paulo, SP, Brazil.
authors.forename: Fabricia Andreia Rosa
authors.initials: FA
authors.lastname: Madia
authors.affiliation: Department of Pathology, Cytogenomic Laboratory - LIM 03 - HC-FMUSP, Universidade de São Paulo, SP, Brazil.
authors.forename: Thais Virgínia Moura Machado
authors.initials: TV
authors.lastname: Costa
authors.affiliation: Department of Pathology, Cytogenomic Laboratory - LIM 03 - HC-FMUSP, Universidade de São Paulo, SP, Brazil.
authors.forename: Cintia
authors.initials: C
authors.lastname: Milani
authors.affiliation: Division of Pathology - Clinical Hospital - HC -FMUSP, Universidade de São Paulo, SP, Brazil.
authors.forename: Regina
authors.initials: R
authors.lastname: Schultz
authors.affiliation: Department of Legal Medicine - HC-FMUSP, Universidade de São Paulo, SP, Brazil.
authors.forename: Fernanda Toledo
authors.initials: FT
authors.lastname: Gonçalves
authors.affiliation: Department of Legal Medicine - HC-FMUSP, Universidade de São Paulo, SP, Brazil.
authors.forename: Cintia
authors.initials: C
authors.lastname: Fridman
authors.affiliation: Genetics Unit, Instituto da Criança HC-FMUSP - Universidade de São Paulo, SP, Brazil.
authors.forename: Guilherme Lopes
authors.initials: GL
authors.lastname: Yamamoto
authors.affiliation: Genetics Unit, Instituto da Criança HC-FMUSP - Universidade de São Paulo, SP, Brazil.
authors.forename: Débora Romeo
authors.initials: DR
authors.lastname: Bertola
authors.affiliation: Genetics Unit, Instituto da Criança HC-FMUSP - Universidade de São Paulo, SP, Brazil.
authors.forename: Chong Ae
authors.initials: CA
authors.lastname: Kim
authors.affiliation: Department of Pathology, Cytogenomic Laboratory - LIM 03 - HC-FMUSP, Universidade de São Paulo, SP, Brazil; Human Reproduction and Genetic Center, Department of Coletive Health - Faculdade de Medicina do ABC, Santo André, SP, Brazil.
authors.forename: Leslie Domenici
authors.initials: LD
authors.lastname: Kulikowski
mesh_terms: D041322:Chromosomes, Human, Y / Q000235:genetics; D000013:Congenital Abnormalities / Q000235:genetics*; D003582:Cytogenetics / Q000379:methods*; D015894:Genome, Human; D006801:Humans; D060885:Multiplex Polymerase Chain Reaction; D011180:Postmortem Changes
keywords: Congenital malformations; DNA copy number variations; Post-mortem cytogenomic investigation