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

Abstract

BackgroundArray-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).ResultsAll 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.ConclusionsAs 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.

The clinical benefit of array-based comparative genomic hybridization for detection of copy number variants in Czech children with intellectual disability and developmental delay

“…To this end, we considered their size, gene content, inheritance pattern and information from databases and relevant literature [12,14]. Overall, we identified the pathogenic/ likely pathogenic CNVs in 17.7% patients (96/542) which corresponds to the generally held diagnostic yield of 15-20% based on many multicenter studies [20][21][22][23]. Further, 5.9% of all patients had associated karyotypic findings (32/542).…”

Application of high‐resolution array platform for genome‐wide copy number variation analysis in patients with nonsyndromic cleft lip and palate

“…The presence of benign CNVs within the genome, the continual discovery of novel CNVs, and the insufficient knowledge of the phenotypic effects of most CNVs have led to the classification of many CNVs as being of unknown clinical significance.Considering that the complex etiology of CLP is not fully understood, the aim of this study was the robust detection of CNVs using a genomic microarray in an attempt to identify chromosomal regions containing causative genes of NSCLP. Although previous studies have reported that common benign CNVs are often smaller in size, with the majority of benign CNVs smaller than 20 kb,14,25,26 here we report small exonic CNVs based on the importance of the affected genes in NSCLP, possibly related to sequence variants in the genes involved in genetic susceptibility to oral clefts.…”

“…Despite advances in identifying genes associated with the NSCLP development using traditional genetic mapping strategies of candidate genes, genomewide studies, animal models, and epidemiologic and linkage analysis, microarray techniques have become important complementary tools in the search for potential causative CLP genes in genetic studies. These techniques allow investigators to scan the whole genome at once and detect submicroscopic chromosomal imbalances called copy number variants (CNVs) . These genomic imbalances include insertions, duplications, deletions, inversions, recurring mobile elements, and other rearrangements, now usually defined as abnormalities covering 50 or more base pairs .…”

“…These techniques allow investigators to scan the whole genome at once and detect submicroscopic chromosomal imbalances called copy number variants (CNVs). 5,14,15 These genomic imbalances include insertions, duplications, deletions, inversions, recurring mobile elements, and other rearrangements, now usually defined as abnormalities covering 50 or more base pairs. 16 CNV detection is a strategy to identify and confirm candidate disease gene regions, which represents a first-tier diagnostic approach for some diseases.…”

Abordagens Citogenéticas e Genómicas: Perspetiva no Diagnóstico em Oncologia e nas Patologias do Neurodesenvolvimento

“…Mais recentemente, a tecnologia de aCGH permitiu a descoberta de um grande número de novas síndromes de microdeleção e microduplicação associados a estes distúrbios do desenvolvimento (Shaffer et al, 2007;Slavotinek, 2008). Atualmente, em termos de estratégia de diagnóstico clínico, a técnica de aCGH tem sido considerada como o teste genético de primeira linha para detetar alterações genómicas em doentes com défice intelectual não sindrómico, com ou sem dismorfismos, anomalias congénitas múltiplas, dificuldades de aprendizagem e/ou distúrbios no espectro autista (Carreira et al, 2015;Miller et al, 2010).…”