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

Abstract

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.

Diagnostic yield of patients with undiagnosed intellectual disability, global developmental delay and multiples congenital anomalies using karyotype, microarray analysis, whole exome sequencing from Central Brazil

“…Since 2010, the CMA has been considered the first-tier clinical diagnostic approach for individuals with idiopathic ID/GDD, ASD, and / or MCA due to its capacity to detect CNVs across the genome with ten times greater resolution and higher diagnostic yield than GTG banding [ 11 , 22 , 24 ]. In the current study, CMA alone yielded a proper diagnosis for approximately 1:5 children with ID/GDD/MCA, which has been in accordance to previous studies [ 11 , 22 , 25 , 26 ].…”

Copy number variation analysis in 189 Romanian patients with global developmental delay/intellectual disability

“…A similar percentage of pathogenic CNVs was also seen in other studies (7,8,9). This high number of diagnosed cases using microarray analysis, sustain the great diagnosis performance given by this investigation, indicated as rst tier test in GDD/ID (4).…”

Clinical evaluation of rare copy number variations identified by chromosomal microarray in a Hungarian neurodevelopmental disorder patient cohort

“…Said rigorous patient selection impacted our statistical observations as well (keeping in mind the limitations of the small sample size). In contrast to our results, congenital heart defects and other major congenital anomalies are often observed in signi cantly higher frequencies in patients with de nitive CMA results (3,6,7). The association of postnatal growth delay, global DD, speech and language delay and brain imaging abnormalities is in line with literature data (3,7,8).…”