Chromosomal microarray analyses from 5778 patients with neurodevelopmental disorders and congenital anomalies in Brazil

Abstract

Chromosomal microarray analysis (CMA) has been recommended and practiced routinely since 2010 both in the USA and Europe as the first-tier cytogenetic test for patients with unexplained neurodevelopmental delay/intellectual disability, autism spectrum disorders, and/or multiple congenital anomalies. However, in Brazil, the use of CMA is still limited, due to its high cost and complexity in integrating the results from both the private and public health systems. Although Brazil has one of the world’s largest single-payer public healthcare systems, nearly all patients referred for CMA come from the private sector, resulting in only a small number of CMA studies in Brazilian cohorts. To date, this study is by far the largest Brazilian cohort (n = 5788) studied by CMA and is derived from a joint collaboration formed by the University of São Paulo and three private genetic diagnostic centers to investigate the genetic bases of neurodevelopmental disorders and congenital abnormalities. We identified 2,279 clinically relevant CNVs in 1886 patients, not including the 26 cases of UPD found. Among detected CNVs, the corresponding frequency of each category was 55.6% Pathogenic, 4.4% Likely Pathogenic and 40% VUS. The diagnostic yield, by taking into account Pathogenic, Likely Pathogenic and UPDs, was 19.7%. Since the rational for the classification is mostly based on Mendelian or highly penetrant variants, it was not surprising that a second event was detected in 26% of those cases of predisposition syndromes. Although it is common practice to investigate the inheritance of VUS in most laboratories around the world to determine the inheritance of the variant, our results indicate an extremely low cost–benefit of this approach, and strongly suggest that in cases of a limited budget, investigation of the parents of VUS carriers using CMA should not be prioritized.

Low‐pass whole genome sequencing is a reliable and cost‐effective approach for copy number variant analysis in the clinical setting

“…This has an implication of failing to detect uniparental disomy (UPD) and parental consanguinity or ploidy changes. Although detecting consanguinity has a debatable diagnostic value, UPD and ploidy changes are relevant but not frequent (i.e., UPD and consanguinity frequency in postnatal 26/5778 (Krepischi et al., 2022)). It is estimated that triploidy affects 1% of all conceptions but most of the affected fetus cannot survive the first trimester period and the majority of these pregnancies result in miscarriage (Eftekhariyazdi et al., 2019; Massalska et al., 2021).…”

“…Log 2 ratio and B Allele Frequency (in the case of SNP-arrays) values were plotted along genomic coordinates, and the chromosome regions with either copy number or allele frequency alterations were identified. SNP-array and array-CGH analysis were conducted according to parameters previously reported (Krepischi et al, 2022;Villela et al, 2017Villela et al, , 2021.…”

SIN3A Defects Associated with Syndromic Congenital Hypogonadotropic Hypogonadism: An Overlap with Witteveen-Kolk Syndrome

“…The scientific literature was retrieved from PubMed. After this analysis, the CNVs were classified as benign, likely benign, variants of uncertain clinical significance, likely pathogenic, or pathogenic, following the joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen) [29, 30].…”

Microduplication and Microdeletion Syndromes Diagnosed Prenatally Using Single Nucleotide Polymorphism Array

“…A Brazilian study revealed that in 5778 individuals with general neurodevelopmental disorder and/or congenital abnormalities without evident cause, CNVs were found in 1886 individuals classified as pathogenic, likely pathogenic, and VUS (41%) [ 19 ].…”