title: Copy number variants prioritization after array-CGH analysis - a cohort of 1000 patients.
abstract: BACKGROUND
  Array-based comparative genomic hybridization has been assumed to be the first genetic test offered to detect genomic imbalances in patients with unexplained intellectual disability with or without dysmorphisms, multiple congenital anomalies, learning difficulties and autism spectrum disorders. Our study contributes to the genotype/phenotype correlation with the delineation of laboratory criteria which help to classify the different copy number variants (CNVs) detected. We clustered our findings into five classes ranging from an imbalance detected in a microdeletion/duplication syndrome region (class I) to imbalances that had previously been reported in normal subjects in the Database of Genomic Variants (DGV) and thus considered common variants (class IV).
  
  
  RESULTS
  All the analyzed 1000 patients had at least one CNV independently of its clinical significance. Most of them, as expected, were alterations already reported in the DGV for normal individuals (class IV) or without known coding genes (class III-B). In approximately 14 % of the patients an imbalance involving known coding genes, but with partially overlapping or low frequency of CNVs described in the DGV was identified (class IIIA). In 10.4 % of the patients a pathogenic CNV that explained the phenotype was identified consisting of: 40 class I imbalances, 44 class II de novo imbalances and 21 class II X-chromosome imbalances in male patients. In 20 % of the patients a familial pathogenic or potentially pathogenic CNV, consisting of inherited class II imbalances, was identified that implied a family evaluation by the clinical geneticists.
  
  
  CONCLUSIONS
  As this interpretation can be sometimes difficult, particularly if it is not possible to study the parents, using the proposed classification we were able to prioritize the multiple imbalances that are identified in each patient without immediately having to classify them as pathogenic or benign.
authors.affiliation: Laboratório de Citogenética e Genómica - Faculdade de Medicina, Universidade de Coimbra, Pólo Ciências da Saúde, Sub-Unidade 1 - Piso 2, Azinhaga de Santa Comba, 3000-354 Coimbra, Portugal ; CIMAGO - Centro de Investigação em Meio Ambiente, Genética e Oncobiologia, Faculdade de Medicina, Universidade de Coimbra, Coimbra, Portugal ; Faculdade de Medicina, Universidade de Coimbra, Coimbra, Portugal ; CNC, IBILI - Faculdade de Medicina, Universidade de Coimbra, Coimbra, Portugal.
authors.forename: Isabel Marques
authors.initials: IM
authors.lastname: Carreira
authors.affiliation: Laboratório de Citogenética e Genómica - Faculdade de Medicina, Universidade de Coimbra, Pólo Ciências da Saúde, Sub-Unidade 1 - Piso 2, Azinhaga de Santa Comba, 3000-354 Coimbra, Portugal.
authors.forename: Susana Isabel
authors.initials: SI
authors.lastname: Ferreira
authors.affiliation: CIMAGO - Centro de Investigação em Meio Ambiente, Genética e Oncobiologia, Faculdade de Medicina, Universidade de Coimbra, Coimbra, Portugal ; Laboratório de Citogenética, Hospital Pediátrico de Coimbra, Coimbra, Portugal.
authors.forename: Eunice
authors.initials: E
authors.lastname: Matoso
authors.affiliation: Laboratório de Citogenética e Genómica - Faculdade de Medicina, Universidade de Coimbra, Pólo Ciências da Saúde, Sub-Unidade 1 - Piso 2, Azinhaga de Santa Comba, 3000-354 Coimbra, Portugal.
authors.forename: Luís Miguel
authors.initials: LM
authors.lastname: Pires
authors.affiliation: Laboratório de Citogenética e Genómica - Faculdade de Medicina, Universidade de Coimbra, Pólo Ciências da Saúde, Sub-Unidade 1 - Piso 2, Azinhaga de Santa Comba, 3000-354 Coimbra, Portugal.
authors.forename: José
authors.initials: J
authors.lastname: Ferrão
authors.affiliation: Laboratório de Citogenética e Genómica - Faculdade de Medicina, Universidade de Coimbra, Pólo Ciências da Saúde, Sub-Unidade 1 - Piso 2, Azinhaga de Santa Comba, 3000-354 Coimbra, Portugal.
authors.forename: Ana
authors.initials: A
authors.lastname: Jardim
authors.affiliation: Laboratório de Citogenética e Genómica - Faculdade de Medicina, Universidade de Coimbra, Pólo Ciências da Saúde, Sub-Unidade 1 - Piso 2, Azinhaga de Santa Comba, 3000-354 Coimbra, Portugal.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Mascarenhas
authors.affiliation: Laboratório de Citogenética e Genómica - Faculdade de Medicina, Universidade de Coimbra, Pólo Ciências da Saúde, Sub-Unidade 1 - Piso 2, Azinhaga de Santa Comba, 3000-354 Coimbra, Portugal.
authors.forename: Marta
authors.initials: M
authors.lastname: Pinto
authors.affiliation: Laboratório de Citogenética e Genómica - Faculdade de Medicina, Universidade de Coimbra, Pólo Ciências da Saúde, Sub-Unidade 1 - Piso 2, Azinhaga de Santa Comba, 3000-354 Coimbra, Portugal.
authors.forename: Nuno
authors.initials: N
authors.lastname: Lavoura
authors.affiliation: Laboratório de Citogenética e Genómica - Faculdade de Medicina, Universidade de Coimbra, Pólo Ciências da Saúde, Sub-Unidade 1 - Piso 2, Azinhaga de Santa Comba, 3000-354 Coimbra, Portugal.
authors.forename: Cláudia
authors.initials: C
authors.lastname: Pais
authors.affiliation: Laboratório de Citogenética e Genómica - Faculdade de Medicina, Universidade de Coimbra, Pólo Ciências da Saúde, Sub-Unidade 1 - Piso 2, Azinhaga de Santa Comba, 3000-354 Coimbra, Portugal.
authors.forename: Patrícia
authors.initials: P
authors.lastname: Paiva
authors.affiliation: Laboratório de Citogenética e Genómica - Faculdade de Medicina, Universidade de Coimbra, Pólo Ciências da Saúde, Sub-Unidade 1 - Piso 2, Azinhaga de Santa Comba, 3000-354 Coimbra, Portugal.
authors.forename: Lúcia
authors.initials: L
authors.lastname: Simões
authors.affiliation: Laboratório de Bioestatística e Informática Médica, IBILI - Faculdade de Medicina, Universidade de Coimbra, Coimbra, Portugal.
authors.forename: Francisco
authors.initials: F
authors.lastname: Caramelo
authors.affiliation: Laboratório de Bioestatística e Informática Médica, IBILI - Faculdade de Medicina, Universidade de Coimbra, Coimbra, Portugal.
authors.forename: Lina
authors.initials: L
authors.lastname: Ramos
authors.affiliation: Faculdade de Medicina, Universidade de Coimbra, Coimbra, Portugal ; Serviço de Genética Médica, Hospital Pediátrico - Centro Hospitalar e Universitário de Coimbra, Coimbra, Portugal.
authors.forename: Margarida
authors.initials: M
authors.lastname: Venâncio
authors.affiliation: Faculdade de Medicina, Universidade de Coimbra, Coimbra, Portugal ; Serviço de Genética Médica, Hospital Pediátrico - Centro Hospitalar e Universitário de Coimbra, Coimbra, Portugal.
authors.forename: Fabiana
authors.initials: F
authors.lastname: Ramos
authors.affiliation: Serviço de Genética Médica, Hospital Pediátrico - Centro Hospitalar e Universitário de Coimbra, Coimbra, Portugal.
authors.forename: Ana
authors.initials: A
authors.lastname: Beleza
authors.affiliation: Serviço de Genética Médica, Hospital Pediátrico - Centro Hospitalar e Universitário de Coimbra, Coimbra, Portugal.
authors.forename: Joaquim
authors.initials: J
authors.lastname: Sá
authors.affiliation: Faculdade de Medicina, Universidade de Coimbra, Coimbra, Portugal ; Serviço de Genética Médica, Hospital Pediátrico - Centro Hospitalar e Universitário de Coimbra, Coimbra, Portugal.
authors.forename: Jorge
authors.initials: J
authors.lastname: Saraiva
authors.affiliation: Laboratório de Citogenética e Genómica - Faculdade de Medicina, Universidade de Coimbra, Pólo Ciências da Saúde, Sub-Unidade 1 - Piso 2, Azinhaga de Santa Comba, 3000-354 Coimbra, Portugal ; CIMAGO - Centro de Investigação em Meio Ambiente, Genética e Oncobiologia, Faculdade de Medicina, Universidade de Coimbra, Coimbra, Portugal ; Faculdade de Medicina, Universidade de Coimbra, Coimbra, Portugal ; CNC, IBILI - Faculdade de Medicina, Universidade de Coimbra, Coimbra, Portugal.
authors.forename: Joana Barbosa
authors.initials: JB
authors.lastname: de Melo
keywords: Array comparative genomic hybridization (array-CGH); Autism spectrum disorders; Copy number variation (CNV) classification; Intellectual disability; Learning difficulties; Multiple congenital anomalies