Screening for Intellectual Disability Using High-Resolution CMA Technology in a Retrospective Cohort from Central Brazil

Pereira, Rodrigo Roncato; Pinto, Irene Plaza; Minasi, Lysa Bernardes; Melo, Aldaires Vieira de; Cunha, Damiana Mirian da Cruz e; Cruz, Alex Silva da; Ribeiro, Cristiano Luiz; Silva, Cláudio Carlos da; Silva, Daniela de Melo e; Cruz, Aparecido Divino da

doi:10.1371/journal.pone.0103117

Cited by 15 publications

(13 citation statements)

References 38 publications

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“…Among 95 Brazilian syndromic patients, Krepischi-Santos et al (2006) accounted for 17% of CNVs to be causally related to abnormal phenotypes. Pereira et al (2014) detected 22% of pathogenic CNVs in 15 patients from Central Brazil who had IDs.…”

Section: Discussionmentioning

confidence: 99%

Array-CGH analysis in patients with intellectual disability and/or congenital malformations in Brazil

et al. 2016

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ABSTRACT. In several patients, intellectual disability and/or congenital malformation may be attributed to chromosomal changes. In this study, we conducted an array-CGH test of 200 patients from the Northeast of Brazil with intellectual disability and/or congenital malformation. Blood samples were collected from the proband and from their parents when possible. DNA was extracted and investigated using the array-CGH test. Findings were evaluated for the pathogenicity in databases of benign and pathogenic changes (ISCA, UCSC, DGV, and DECIPHER). Forty-seven copy number variations (CNVs) were identified in 43/200 (21.5%) patients, including 25/98 (25.5%) in males and 22/102 (21.57%) in females. We considered 33 of these to be clinically significant, reaching a diagnosis rate of 16.5%. The sizes of the CNVs varied from 102 kb to 24 Mb in deletions and from 115 kb to 140 Mb in duplications. In 10/47 (21.3%) patients, the rearrangement involved a sex chromosome. Thirty-nine patients had one chromosomal aberration, while 2 concomitant abnormalities were detected in 4 patients. Ten of 47 CNVs (21.3%) were > 5Mb in size. Fifteen patients had CNVs related to known syndromes. This research highlights the contribution of submicroscopic chromosomal changes to the etiology of intellectual disability and/or congenital malformation, particularly the implication of chromosomal abnormalities detected using an array-CGH test, with a high rate of 16.5%. Thus, our results support the use of array-CGH replacing standard karyotype as the first-tier cytogenetic diagnostic test for patients with multiple congenital anomalies and/or intellectual disability.

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Section: Discussionmentioning

confidence: 99%

Array-CGH analysis in patients with intellectual disability and/or congenital malformations in Brazil

et al. 2016

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“…Additionally both, genetic and environmental factors, isolated or together, play an important role in their pathogenesis 5,6 . Currently, molecular karyotyping by chromosomal microarrays (CMA) has been clinically recommended as the first-tier cytogenetic diagnostic test of choice in the investigation of patients with idiopathic ND, such as developmental delay, intellectual disability, autism spectrum disorder and multiple congenital anomalies 7 .…”

Section: Introductionmentioning

confidence: 99%

Copy Number Variations in a Cohort of 420 Individuals with Neurodevelopmental Disorders From the South of Brazil

Chaves

Baretto

Oliveira

et al. 2019

Sci Rep

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Chromosomal microarray (CMA) is now recommended as first tier for the evaluation in individuals with unexplained neurodevelopmental disorders (ND). However, in developing countries such as Brazil, classical cytogenetic tests are still the most used in clinical practice, as reflected by the scarcity of publications of microarray investigation in larger cohorts. This is a retrospective study which analyses the reading files of CMA and available clinical data from 420 patients from the south of Brazil, mostly children, with neurodevelopmental disorders requested by medical geneticists and neurologists for diagnostic purpose. Previous karyotyping was reported for 138 and includes 17 with abnormal results. The platforms used for CMA were CYTOSCAN 750K (75%) and CYTOSCAN HD (25%). The sex ratio of the patients was 1.625 males :1 female and the mean age was 9.5 years. A total of 96 pathogenic copy number variations (CNVs), 58 deletions and 38 duplications, were found in 18% of the patients and in all chromosomes, except chromosome 11. For 12% of the patients only variants of uncertain clinical significance were found. No clinically relevant CNV was found in 70%. The main referrals for chromosomal microarrays (CMA) were developmental delay (DD), intellectual disability (ID), facial dysmorphism and autism spectrum disorder (ASD). DD/ID were present in 80%, facial dysmorphism in 52% and ASD in 32%. Some phenotypes in this population could be predictive of a higher probability to carry a pathogenic CNV, as follows: dysmorphic facial features (p-value = < 0.0001, OR = 0.32), obesity (p-value = 0.006, OR = 0.20), short stature (p-value = 0.032, OR = 0.44), genitourinary anomalies (p-value = 0.032, OR = 0.63) and ASD (p-value = 0.039, OR = 1.94). The diagnostic rate for CMA in this study was 18%. We present the largest report of CMA data in a cohort with ND in Brazil. We characterize the rare CNVs found together with the main phenotypes presented by each patient, list phenotypes which could predict a higher diagnostic probability by CMA in patients with a neurodevelopmental disorder and show how CMA and classical karyotyping results are complementary.

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“…Although Cytoscan HD array has been extensively used in prenatal diagnosis of chromosomal abnormalities and neoplastic samples [ 25 , 26 ], we focused on neurodevelopmental disorders, looking in particular to large-scale studies that have employed this platform both as unique tool and in combination with other platforms ( Table 2 ). Pereira et al [ 27 ] used Cytoscan HD to perform a study on 15 ID patients with normal karyotype analysis and negative X-fragile test. The rate of pathogenic CNV was 26.7%.…”

Section: Clinical Applications Of Cytoscan Hd Array In Neurodevelomentioning

confidence: 99%

The Cytoscan HD Array in the Diagnosis of Neurodevelopmental Disorders

et al. 2018

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Submicroscopic chromosomal copy number variations (CNVs), such as deletions and duplications, account for about 15–20% of patients affected with developmental delay, intellectual disability, multiple congenital anomalies, and autism spectrum disorder. Most of CNVs are de novo or inherited rearrangements with clinical relevance, but there are also rare inherited imbalances with unknown significance that make difficult the clinical management and genetic counselling. Chromosomal microarrays analysis (CMA) are recognized as the first-line test for CNV detection and are now routinely used in the clinical diagnostic laboratory. The recent use of CMA platforms that combine classic copy number analysis with single-nucleotide polymorphism (SNP) genotyping has increased the diagnostic yields. Here we discuss the application of the Cytoscan high-density (HD) SNP-array for the detection of CNVs. We provide an overview of molecular analyses involved in identifying pathogenic CNVs and highlight important guidelines to establish pathogenicity of CNV.

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Screening for Intellectual Disability Using High-Resolution CMA Technology in a Retrospective Cohort from Central Brazil

Cited by 15 publications

References 38 publications

Array-CGH analysis in patients with intellectual disability and/or congenital malformations in Brazil

Array-CGH analysis in patients with intellectual disability and/or congenital malformations in Brazil

Copy Number Variations in a Cohort of 420 Individuals with Neurodevelopmental Disorders From the South of Brazil

The Cytoscan HD Array in the Diagnosis of Neurodevelopmental Disorders

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