Copy number variants prioritization after array-CGH analysis – a cohort of 1000 patients

Molecular Cytogenetics

Joana Barbosa de Melo²  Jorge Saraiva¹  Joaquim Sá¹  Ana Beleza¹  Fabiana Ramos¹  Margarida Venâncio¹  Lina Ramos⁵  Francisco Caramelo⁵  Lúcia Simões⁴  Patrícia Paiva⁴  Cláudia Pais⁴  Nuno Lavoura⁴  Marta Pinto⁴  Alexandra Mascarenhas⁴  Ana Jardim⁴  José Ferrão⁴  Luís Miguel Pires⁴  Eunice Matoso³  Susana Isabel Ferreira⁴  Isabel Marques Carreira² 

[1] Serviço de Genética Médica, Hospital Pediátrico – Centro Hospitalar e Universitário de Coimbra, Coimbra, Portugal;CNC, IBILI – Faculdade de Medicina, Universidade de Coimbra, Coimbra, Portugal;Laboratório de Citogenética, Hospital Pediátrico de Coimbra, Coimbra, Portugal;Laboratório de Citogenética e Genómica – Faculdade de Medicina, Universidade de Coimbra, Pólo Ciências da Saúde, Sub-Unidade 1 - Piso 2, Azinhaga de Santa Comba, Coimbra, 3000-354, Portugal;Laboratório de Bioestatística e Informática Médica, IBILI – Faculdade de Medicina, Universidade de Coimbra, Coimbra, Portugal

关键词: Autism spectrum disorders;    Learning difficulties;    Multiple congenital anomalies;    Intellectual disability;    Copy number variation (CNV) classification;    Array comparative genomic hybridization (array-CGH);   

Others  :  1235198
DOI  :  10.1186/s13039-015-0202-z

 received in 2015-08-10, accepted in 2015-12-17,  发布年份 2015

【 摘 要 】

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.

【 授权许可】

   
2015 Carreira et al.

【 图 表 】

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